Lipid-Based Nanoparticles for Drug/Gene Delivery: An Overview of the Production Techniques and Difficulties Encountered in Their Industrial DevelopmentClick to copy article linkArticle link copied!
- Meenu MehtaMeenu MehtaSchool of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Ultimo, NSW 2007, AustraliaMore by Meenu Mehta
- Thuy Anh BuiThuy Anh BuiSchool of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Ultimo, NSW 2007, AustraliaMore by Thuy Anh Bui
- Xinpu YangXinpu YangSchool of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Ultimo, NSW 2007, AustraliaMore by Xinpu Yang
- Yagiz AksoyYagiz AksoyCancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards NSW 2065 Australia - Sydney Medical School, University of Sydney, Sydney NSW 2006 AustraliaMore by Yagiz Aksoy
- Ewa M. GoldysEwa M. GoldysGraduate School of Biomedical Engineering, ARC Centre of Excellence in Nanoscale Biophotonics, Faculty of Engineering, UNSW Sydney, NSW 2052, AustraliaMore by Ewa M. Goldys
- Wei Deng*Wei Deng*Email: [email protected]School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Ultimo, NSW 2007, AustraliaMore by Wei Deng
Abstract
Over the past decade, the therapeutic potential of nanomaterials as novel drug delivery systems complementing conventional pharmacology has been widely acknowledged. Among these nanomaterials, lipid-based nanoparticles (LNPs) have shown remarkable pharmacological performance and promising therapeutic outcomes, thus gaining substantial interest in preclinical and clinical research. In this review, we introduce the main types of LNPs used in drug formulations such as liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and lipid polymer hybrid nanoparticles, focusing on their main physicochemical properties and therapeutic potential. We discuss computational studies and modeling techniques to enhance the understanding of how LNPs interact with therapeutic cargo and to predict the potential effectiveness of such interactions in therapeutic applications. We also analyze the benefits and drawbacks of various LNP production techniques such as nanoprecipitation, emulsification, evaporation, thin film hydration, microfluidic-based methods, and an impingement jet mixer. Additionally, we discuss the major challenges associated with industrial development, including stability and sterilization, storage, regulatory compliance, reproducibility, and quality control. Overcoming these challenges and facilitating regulatory compliance represent the key steps toward LNP’s successful commercialization and translation into clinical settings.
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1. Introduction
2. General Characteristics of LNPs
2.1. Main Components of LNPs
2.2. Characteristics of LNPs
2.3. Computational Modeling of LNPs: Insights into Structure, Behavior, and Interactions
3. Main Types of LNPs
3.1. Liposomes
LNP subgroup | active substance | disease/applications | products | ref |
---|---|---|---|---|
liposomes | doxorubicin/daunorubicin | cancer | Doxil, Myocet, Vixeos, DaunoXome, Transdrug | (85−89) |
other anticancer agents | cancer | Mepact, Depocyt, Marqibo, Onivyde | (90−93) | |
paclitaxel | cancer | Abraxane | (94−96) | |
amphotericin B | visceral leishmaniasis | Albecet, Ambisome, Amphotec | (97−99) | |
vaccine | HAV viral vaccine | Epaxal, Inflexal | (100,101) | |
verteporfin | age-related macular degeneration | Visudyne | (102) | |
nanoemulsions | etomidate, profol | anesthetics | Etomidat-Lipuro, Diprivan | (103,104) |
heparinoid | superficial thrombophlebitis | Nanoemulsions carrying heparinoid for topical delivery | (105) | |
ibuprofen | pain relief | Topical delivery of ibuprofen-nanoemulsions | (106) | |
cyclosporin A | immunosuppressants | Sandimmune and Sandimmun Neoral | (107) | |
ritonavir | antiviral HIV-1 medicine in children | Norvir | (108) | |
saquinavir | antiviral HIV-1 medicine in adult | Fortovase | (108) | |
solid lipid nanoparticles | mitoxantrone | hepatocarcinoma | Mitoxantrone-loaded polybutylcyanacrylate nanoparticles (DHAD-PBCA-NPs) (phase II clinical trial) | (109) |
doxorubicin | hepatocarcinoma | Doxorubicin Transdrug (DT) (Phase III clinical trial) | (110) | |
oxiconazole | tinea fungal infection | Oxiconazole nitrate solid lipid nanoparticles loaded gel (Phase I clinical trial) | (111) | |
halobetasol propionate | inflammation | Pluronic gel Halobetasol propionate-loaded lipid nanoparticles | (112) | |
Duobril (Phase IV clinical trial) | (113) | |||
siRNA targeting transthyretin gene | amyloidosis | Onpattro (Patisiran) | (10) | |
nanostructured lipid carriers | acitretin | psoriasis | Acitretin Precirol ATO 5/oleic acid/Tween 80 (Randomized Controlled Trial) | (114) |
all-trans retinoic acids | keratinization disorders | Oleic acid/Cetyl palmitate/Cineole/Limonene/Transcutol/Butylated hydroxytoluene/Tween 20/Tween 80 | (115) | |
self-amplifying RNA | COVID-19 | THEMBA II T-CELL Vaccine (phase I/II clinical trial) | (116,117) | |
mRNA-1273 | COVID-19 | Spikevax | (118) | |
BNT162b2 mRNA | COVID-19 | Comirnaty | (119) | |
lipid polymer hybrid nanoparticle | docetaxel | pancreatic cancer | Docetaxel polymeric nanoparticle (phase I clinical trial) | (120,121) |
docetaxel | lung cancer with KRAS mutation | BIND-014 (Docetaxel Nanoparticles for Injectable Suspension) (phase II clinical trial) | (122) | |
docetaxel | prostate cancer | BIND-014 (Docetaxel Nanoparticles for Injectable Suspension) (phase II clinical trial) | (123) |
3.2. Nanoemulsions
3.3. Solid Lipid Nanoparticles
3.4. Nanostructured Lipid Carriers
3.5. Lipid Polymer Hybrid Nanoparticles
4. LNP Synthesis Methods
4.1. Nanoprecipitation
4.2. Single/Double Emulsification
4.3. Nonsolvent Emulsification
4.4. Thin Film Hydration
4.5. Microfluidic Process
4.5.1. T- or Y-Mixer
4.5.2. Hydrodynamic Flow Focusing
4.5.3. Staggered Herringbone Micromixer
4.5.4. Bifurcating Mixer
4.6. Impingement Jet Mixer
4.7. Scaling-Up LNP Production by Microfluidic Devices
5. Main Challenges Associated with the Industrial Development of LNPs
5.1. Stability and Sterilization
5.2. Storage
5.3. Regulatory Compliance
Marketed formulation | active drug | toxicity symptoms | ref |
---|---|---|---|
Doxil | doxorubicin | hand-foot syndrome, stomatitis, skin toxicity (facial swelling, itching), hypersensitivity reactions, mild myelosuppression and alopecia, dyspnea | (200−202) |
Myocet | doxorubicin | neutropenia, mild cardiotoxic | (203) |
Abelcet, Amphotec, AmBisome | amphotericin B | nephrotoxicity, hypersensitivity reactions such as rash, flushing, facial edema, bronchospasm, persistent fever and rigors, hypokalemia | (204−206) |
Linhaliq/Pulmaquin | ciprofloxacin | dyspnea, bronchospasm, hemoptysis, cough, taste disorders. | (207) |
Daunoxome | daunorubicin | hematological toxicity such as neutropenia, back pain | (208,209) |
Visudyne | verteporfin | back pain, chest pain, dyspnea, dizziness, rash | (210) |
Arikace | amikacin | ototoxicity including deafness, dizziness, vertigo, dysphonia, pneumonitis, laryngitis | (211,212) |
Ambraxane | paclitaxel | neutropenia, hypersensitivity reactions, neuropathy, severe myelosuppression | (213) |
5.4. Quality Control
6. Future Prospects and Conclusion
Acknowledgments
This work was financially supported by funding (GNT1181889) from the Australian National Health and Medical Research Council, fellowship award (2019/CDF1013) from Cancer Institute NSW, Australia.
References
This article references 226 other publications.
- 1Gurevich, E. V.; Gurevich, V. V. Beyond traditional pharmacology: new tools and approaches. Br. J. Pharmacol. 2015, 172 (13), 3229– 3241, DOI: 10.1111/bph.13066Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVaqt7rI&md5=4eee579f108ec9569b7b9849368cd670Beyond traditional pharmacology: new tools and approachesGurevich, E. V.; Gurevich, V. V.British Journal of Pharmacology (2015), 172 (13), 3229-3241CODEN: BJPCBM; ISSN:1476-5381. (Wiley-Blackwell)A review. Traditional pharmacol. is defined as the science that deals with drugs and their actions. While small mol. drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to a particular disease etiol. they cannot possibly be effective. A dominant feature of the small mol. drugs is their single mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance or, in some cases, sensitization and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small mols. are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and the introduction of specially designed self-replicating cells. It is clear that no single method is going to be a 'silver bullet', but collectively, these novel approaches hold promise for curing practically every disorder. Linked Articles : This article is part of a themed section on 5th BPS Focused Meeting on Cell Signalling. To view the other articles in this section visit.
- 2Tenchov, R.; Bird, R.; Curtze, A. E.; Zhou, Q. Lipid Nanoparticles─From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement. ACS Nano 2021, 15 (11), 16982– 17015, DOI: 10.1021/acsnano.1c04996Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVSqsr%252FM&md5=c824f1ae324b984f94d2e33741ceef8bLipid Nanoparticles-From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and AdvancementTenchov, Rumiana; Bird, Robert; Curtze, Allison E.; Zhou, QiongqiongACS Nano (2021), 15 (11), 16982-17015CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)A review. Lipid nanoparticles (LNPs) have emerged across the pharmaceutical industry as promising vehicles to deliver a variety of therapeutics. Currently in the spotlight as vital components of the COVID-19 mRNA vaccines, LNPs play a key role in effectively protecting and transporting mRNA to cells. Liposomes, an early version of LNPs, are a versatile nanomedicine delivery platform. A no. of liposomal drugs have been approved and applied to medical practice. Subsequent generations of lipid nanocarriers, such as solid lipid nanoparticles, nanostructured lipid carriers, and cationic lipid-nucleic acid complexes, exhibit more complex architectures and enhanced phys. stabilities. With their ability to encapsulate and deliver therapeutics to specific locations within the body and to release their contents at a desired time, LNPs provide a valuable platform for treatment of a variety of diseases. We present a landscape of LNP-related scientific publications, including patents and journal articles, based on anal. of the CAS Content Collection, the largest human-curated collection of published scientific knowledge. Rising trends are identified, such as nanostructured lipid carriers and solid lipid nanoparticles becoming the preferred platforms for numerous formulations. Recent advancements in LNP formulations as drug delivery platforms, such as antitumor and nucleic acid therapeutics and vaccine delivery systems, are discussed. Challenges and growth opportunities are also evaluated in other areas, such as medical imaging, cosmetics, nutrition, and agrochems. This report is intended to serve as a useful resource for those interested in LNP nanotechnologies, their applications, and the global research effort for their development.
- 3Mittal, D.; Kaur, G.; Singh, P.; Yadav, K.; Ali, S. A. Nanoparticle-Based Sustainable Agriculture and Food Science: Recent Advances and Future Outlook. Frontiers in Nanotechnology 2020, 2, Review, DOI: 10.3389/fnano.2020.579954Google ScholarThere is no corresponding record for this reference.
- 4Shah, S.; Dhawan, V.; Holm, R.; Nagarsenker, M. S.; Perrie, Y. Liposomes: Advancements and innovation in the manufacturing process. Adv. Drug Deliv Rev. 2020, 154–155, 102– 122, DOI: 10.1016/j.addr.2020.07.002Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFajsbrN&md5=c9130c9d0145f30febd9ed8814fc2c47Liposomes: Advancements and innovation in the manufacturing processShah, Sanket; Dhawan, Vivek; Holm, Rene; Nagarsenker, Mangal S.; Perrie, YvonneAdvanced Drug Delivery Reviews (2020), 154-155 (), 102-122CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Liposomes are well recognized as effective drug delivery systems, with a range of products approved, including follow on generic products. Current manufg. processes used to produce liposomes are generally complex multi-batch processes. Furthermore, liposome prepn. processes adopted in the lab. setting do not offer easy translation to large scale prodn., which may delay the development and adoption of new liposomal systems. To promote advancement and innovation in liposome manufg. processes, this considers the range of manufg. processes available for liposomes, from lab. scale and scale up, through to large-scale manuf. and evaluates their advantages and limitations. The regulatory considerations assocd. with the manuf. of liposomes is also discussed. New innovations that support leaner scalable technologies for liposome fabrication are outlined including self-assembling liposome systems and microfluidic prodn. The crit. process attributes that impact on the liposome product attributes are outlined to support potential wider adoption of these innovations.
- 5Beck, H.; Harter, M.; Hass, B.; Schmeck, C.; Baerfacker, L. Small molecules and their impact in drug discovery: A perspective on the occasion of the 125th anniversary of the Bayer Chemical Research Laboratory. Drug Discov Today 2022, 27 (6), 1560– 1574, DOI: 10.1016/j.drudis.2022.02.015Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xmt1Wgt78%253D&md5=cbe69624052680dc1ee1f31bda8efd62Small molecules and their impact in drug discovery: A perspective on the occasion of the 125th anniversary of the Bayer Chemical Research LaboratoryBeck, Hartmut; Haerter, Michael; Hass, Bastian; Schmeck, Carsten; Baerfacker, LarsDrug Discovery Today (2022), 27 (6), 1560-1574CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. The year 2021 marks the 125th anniversary of the Bayer Chem. Research Lab. in Wuppertal, Germany. A significant no. of prominent small-mol. drugs, from Aspirin to Xarelto, have emerged from this research site. In this review, we shed light on historic cornerstones of small-mol. drug research, discussing current and future trends in drug discovery as well as providing a personal outlook on the future of drug research with a focus on small mols.
- 6Forbes, N.; Hussain, M. T.; Briuglia, M. L.; Edwards, D. P.; Horst, J. H. T.; Szita, N.; Perrie, Y. Rapid and scale-independent microfluidic manufacture of liposomes entrapping protein incorporating in-line purification and at-line size monitoring. Int. J. Pharm. 2019, 556, 68– 81, DOI: 10.1016/j.ijpharm.2018.11.060Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFejtr3P&md5=6900bd56f564a4aeb16a13b55ed6b410Rapid and scale-independent microfluidic manufacture of liposomes entrapping protein incorporating in-line purification and at-line size monitoringForbes, Neil; Hussain, Maryam T.; Briuglia, Maria L.; Edwards, Darren P.; Horst, Joop H. ter; Szita, Nicolas; Perrie, YvonneInternational Journal of Pharmaceutics (Amsterdam, Netherlands) (2019), 556 (), 68-81CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)Within this paper we present work that has the ability to de-risk the translation of liposomes from bench to the clinic. We have used microfluidics for the rapid and scale-independent manuf. of liposomes and have incorporated in-line purifn. and at-line monitoring of particle size. Using this process, we have manufd. a range of neutral and anionic liposomes incorporating protein. Factors investigated include the microfluidics operating parameters (flow rate ratio (FRR) and total flow rate (TFR)) and the liposome formulation. From these studies, we demonstrate that FRR is a key factor influencing liposome size, protein loading and release profiles. The liposome formulations produced by microfluidics offer high protein loading (20-35%) compared to prodn. by sonication or extrusion (<5%). This high loading achieved by microfluidics results from the manufg. process and is independent of lipid selection and concn. across the range tested. Using in-line purifn. and at-line size monitoring, we outline the normal operating range for effective prodn. of size controlled (60-100 nm), homogenous (PDI <0.2) high load liposomes. This easy microfluidic process provides a translational manufg. pathway for liposomes in a wide-range of applications.
- 7Verma, M.; Ozer, I.; Xie, W.; Gallagher, R.; Teixeira, A.; Choy, M. The landscape for lipid-nanoparticle-based genomic medicines. Nat. Rev. Drug Discov 2023, 22, 349, DOI: 10.1038/d41573-023-00002-2Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXpsVCjsbw%253D&md5=7a55a8cb1f6bd726db065fcc89d4ee1aThe landscape for lipid-nanoparticle-based genomic medicinesVerma, Malvika; Ozer, Imran; Xie, Wen; Gallagher, Ryan; Teixeira, Alexandra; Choy, MichaelNature Reviews Drug Discovery (2023), 22 (5), 349-350CODEN: NRDDAG; ISSN:1474-1776. (Nature Portfolio)There is no expanded citation for this reference.
- 8Wang, Y.; Grainger, D. W. Regulatory Considerations Specific to Liposome Drug Development as Complex Drug Products. Frontiers in Drug Delivery 2022, 2, 901281, DOI: 10.3389/fddev.2022.901281Google ScholarThere is no corresponding record for this reference.
- 9Wang, Z.; Cui, K.; Costabel, U.; Zhang, X. Nanotechnology-facilitated vaccine development during the coronavirus disease 2019 (COVID-19) pandemic. Exploration (Beijing) 2022, 2 (5), 20210082, DOI: 10.1002/EXP.20210082Google ScholarThere is no corresponding record for this reference.
- 10Akinc, A.; Maier, M. A.; Manoharan, M.; Fitzgerald, K.; Jayaraman, M.; Barros, S.; Ansell, S.; Du, X.; Hope, M. J.; Madden, T. D. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol 2019, 14 (12), 1084– 1087, DOI: 10.1038/s41565-019-0591-yGoogle Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlWit7vO&md5=3184ac1c3c74e6924fb1bb14b5229e95The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugsAkinc, Akin; Maier, Martin A.; Manoharan, Muthiah; Fitzgerald, Kevin; Jayaraman, Muthusamy; Barros, Scott; Ansell, Steven; Du, Xinyao; Hope, Michael J.; Madden, Thomas D.; Mui, Barbara L.; Semple, Sean C.; Tam, Ying K.; Ciufolini, Marco; Witzigmann, Dominik; Kulkarni, Jayesh A.; van der Meel, Roy; Cullis, Pieter R.Nature Nanotechnology (2019), 14 (12), 1084-1087CODEN: NNAABX; ISSN:1748-3387. (Nature Research)The regulatory approval of Onpattro, a lipid nanoparticle-based short interfering RNA drug for the treatment of polyneuropathies induced by hereditary transthyretin amyloidosis, paves the way for clin. development of many nucleic acid-based therapies enabled by nanoparticle delivery.
- 11Guo, S.; Li, K.; Hu, B.; Li, C.; Zhang, M.; Hussain, A.; Wang, X.; Cheng, Q.; Yang, F.; Ge, K. Membrane-destabilizing ionizable lipid empowered imaging-guided siRNA delivery and cancer treatment. Exploration (Beijing) 2021, 1 (1), 35– 49, DOI: 10.1002/EXP.20210008Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB2svhsVyhsw%253D%253D&md5=1cebeae80e9177f542d0cbd32bbd15adMembrane-destabilizing ionizable lipid empowered imaging-guided siRNA delivery and cancer treatmentGuo Shuai; Li Kun; Hu Bo; Li Chunhui; Zhang Mengjie; Hussain Abid; Weng Yuhua; Huang Yuanyu; Wang Xiaoxia; Cheng Qiang; Yang Feng; Ge Kun; Zhang Jinchao; Chang Jin; Liang Xing-JieExploration (Beijing, China) (2021), 1 (1), 35-49 ISSN:.One of the imperative medical requirements for cancer treatment is how to establish an imaging-guided nanocarrier that combines therapeutic and imaging agents into one system. siRNA therapeutics have shown promising prospects in controlling life-threatening diseases. However, it is still challenging to develop siRNA formulations with excellent cellular entry capability, efficient endosomal escape, and simultaneous visualization. Herein, we fabricated multifunctional ionizable lipid nanoparticles (iLNPs) for targeted delivery of siRNA and MRI contrast agent. The iLNPs comprises DSPC, cholesterol, PEGylated lipid, contrast agent DTPA-BSA (Gd), and ionizable lipid termed iBL0104. siRNA-loaded iLNPs (iLNPs/siRNA) could be decorated with a tumor targeting cyclic peptide (c(GRGDSPKC)) (termed GARP), or without targeting modification (termed GAP). Data revealed that GARP/siRNA iLNPs exhibited significantly higher cellular entry efficiency than GAP/siRNA iLNPs. GARP/siRNA iLNPs rapidly and effectively escaped from endosome and lysosome after internalization. Compared with GAP/siPLK1, GARP/siPLK1 exhibited better tumor inhibition efficacy in both cell-line derived xenograft and liver cancer patient derived xenograft murine models. In addition, GARP formulation displayed ideal MRI effect in tumor-bearing mice, and was well tolerated by testing animals. Therefore, this study provides an excellent example for achieving imaging-guided and tumor-targeted siRNA delivery and cancer treatment, highlighting its promising potential for translational medicine application.
- 12Kumar, G.; Kant, A.; Kumar, M.; Masram, D. T. Synthesis, characterizations and kinetic study of metal organic framework nanocomposite excipient used as extended release delivery vehicle for an antibiotic drug. Inorg. Chim. Acta 2019, 496, 119036, DOI: 10.1016/j.ica.2019.119036Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVGmt73L&md5=464524d27963d681d35e2ab3a1ad6c88Synthesis, characterizations and kinetic study of metal organic framework nanocomposite excipient used as extended release delivery vehicle for an antibiotic drugKumar, Gyanendra; Kant, Arun; Kumar, Manish; Masram, Dhanraj T.Inorganica Chimica Acta (2019), 496 (), 119036CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)The present work was to investigate the zinc-based metal-org. frameworks (MOF-5) as oral drug delivery vehicle for the extended in-vitro release of antibiotic drug metronidazole (MTD). The MOF-5 was synthesized by the solvothermal process and characterized by a series of anal. techniques such as PXRD, FTIR, FESEM, HRTEM, TGA and BET. The TEM anal. of the drug loaded nanocomposite (MTD@MOF5) shows the particles size less than in the range of 40-90 nm in dimension. Adsorption of metronidazole on MOF-5 was then estd. as a function of pH in the aq. drug soln., contact time and initial drug concn. High loading of metronidazole was found to be 539.33 mg/g of MOF-5 at pH 2. The kinetic results follow the pseudo-second-order model and the isotherm was best described by Freundlich adsorption and Temkin isotherm model resp. The comparison of in-vitro release behavior of metronidazole drug and the present nanocomposite were explored in the simulated gastric (PBS, pH 1.2) and simulated intestinal fluids (PBS, pH 7.4). The drug shows the excellent releasing power from the MTD@MOF5 nanocomposite as compare to the pure metronidazole drug in terms of availability for the extended time periods.
- 13Kumar, G.; Chaudhary, K.; Mogha, N. K.; Kant, A.; Masram, D. T. Extended Release of Metronidazole Drug Using Chitosan/Graphene Oxide Bionanocomposite Beads as the Drug Carrier. ACS Omega 2021, 6 (31), 20433– 20444, DOI: 10.1021/acsomega.1c02422Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1Kqsr%252FF&md5=c0290b465d4e4dbb3140660adfc2648fExtended Release of Metronidazole Drug Using Chitosan/Graphene Oxide Bionanocomposite Beads as the Drug CarrierKumar, Gyanendra; Chaudhary, Karan; Mogha, Navin Kumar; Kant, Arun; Masram, Dhanraj T.ACS Omega (2021), 6 (31), 20433-20444CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)This study depicts the facile approach for the synthesis of chitosan/graphene oxide bionanocomposite (Chi/GO) beads via the gelation process. This is the first-ever study in which these Chi/GO beads have been utilized as a drug carrier for the oral drug delivery of metronidazole (MTD) drug, and investigations were made regarding the release pattern of the MTD drug using these Chi/GO beads as a drug carrier for a prolonged period of 84 h. The MTD is loaded on the surface as well as the cavity of the Chi/GO beads to result in MTD-Chi/GO bionanocomposite beads. The MTD drug loading was found to be 683 mg/g. Furthermore, the in vitro release patterns of pure drug and the drug encapsulated with Chi/GO beads are explored in simulated gastric as well as simulated intestinal fluids with phosphate-buffered saline (PBS) of pH 1.2 and 7.4, resp. As-synthesized bionanocomposite beads have shown excellent stability and capacity for extended release of the MTD drug as compared to the pure drug in terms of bioavailability in both media. The cumulative release data are fitted with the Korsmeyer-Peppas kinetics and first-order reaction kinetics at pH 1.2 and 7.4. The synthesized bionanocomposite beads have good potential to minimize the multiple-dose frequency with the sustained drug release property and can reduce the side effects due to the drug.
- 14Wuttke, S.; Braig, S.; Preiß, T.; Zimpel, A.; Sicklinger, J.; Bellomo, C.; Rädler, J. O.; Vollmar, A. M.; Bein, T. MOF nanoparticles coated by lipid bilayers and their uptake by cancer cells. Chem. Commun. (Camb) 2015, 51 (87), 15752– 15755, DOI: 10.1039/C5CC06767GGoogle Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsV2nsLrM&md5=a59a6beb2c5e85b75af50cb50c51842cMOF nanoparticles coated by lipid bilayers and their uptake by cancer cellsWuttke, Stefan; Braig, Simone; Preiss, Tobias; Zimpel, Andreas; Sicklinger, Johannes; Bellomo, Claudia; Raedler, Joachim O.; Vollmar, Angelika M.; Bein, ThomasChemical Communications (Cambridge, United Kingdom) (2015), 51 (87), 15752-15755CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)We report the synthesis of MOF@lipid nanoparticles as a versatile and powerful novel class of nanocarriers based on metal-org. frameworks (MOFs). We show that the MOF@lipid system can effectively store dye mols. inside the porous scaffold of the MOF while the lipid bilayer prevents their premature release. Efficient uptake of the MOF@lipid nanoparticles by cancer cells makes these nanocarriers promising for drug delivery and diagnostic purposes.
- 15Róg, T.; Girych, M.; Bunker, A. Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design. Pharmaceuticals 2021, 14 (10), 1062, DOI: 10.3390/ph14101062Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVKqu7jO&md5=aa41f0ab1dfdf72579f8e81a69753fedMechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug DesignRog, Tomasz; Girych, Mykhailo; Bunker, AlexPharmaceuticals (2021), 14 (10), 1062CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)A review. We review the use of mol. dynamics simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug mols. and lipid membranes. In the std. "lock and key" paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophys. perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiol. processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biol. barriers in the path of the drugs, the behavior of drug mols. within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are assocd., can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.
- 16Hathout, R. M.; Metwally, A. A. Towards better modelling of drug-loading in solid lipid nanoparticles: Molecular dynamics, docking experiments and Gaussian Processes machine learning. Eur. J. Pharm. Biopharm. 2016, 108, 262– 268, DOI: 10.1016/j.ejpb.2016.07.019Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1ymtL7P&md5=e32e697c70ab5e346af70c1383ccc254Towards better modelling of drug-loading in solid lipid nanoparticles: Molecular dynamics, docking experiments and Gaussian Processes machine learningHathout, Rania M.; Metwally, Abdelkader A.European Journal of Pharmaceutics and Biopharmaceutics (2016), 108 (), 262-268CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)This study represents one of the series applying computer-oriented processes and tools in digging for information, analyzing data and finally extg. correlations and meaningful outcomes. In this context, binding energies could be used to model and predict the mass of loaded drugs in solid lipid nanoparticles after mol. docking of literature-gathered drugs using MOE software package on molecularly simulated tripalmitin matrixes using GROMACS. Consequently, Gaussian processes as a supervised machine learning artificial intelligence technique were used to correlate the drugs' descriptors (e.g. M.W., x Log P, TPSA and fragment complexity) with their mol. docking binding energies. Lower percentage bias was obtained compared to previous studies which allows the accurate estn. of the loaded mass of any drug in the investigated solid lipid nanoparticles by just projecting its chem. structure to its main features (descriptors).
- 17Cheng, X.; Lee, R. J. The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery. Adv. Drug Deliv Rev. 2016, 99 (Pt A), 129– 137, DOI: 10.1016/j.addr.2016.01.022Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVGktr0%253D&md5=1151e67ab34b5dc882b898c8fc2ece6aThe role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide deliveryCheng, Xinwei; Lee, Robert J.Advanced Drug Delivery Reviews (2016), 99 (Part_A), 129-137CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Lipid nanoparticles (LNPs) have shown promise as delivery vehicles for therapeutic oligonucleotides, including antisense oligos (ONs), siRNA, and microRNA mimics and inhibitors. In addn. to a cationic lipid, LNPs are typically composed of helper lipids that contribute to their stability and delivery efficiency. Helper lipids with cone-shape geometry favoring the formation hexagonal II phase, such as dioleoylphosphatidylethanolamine (DOPE), can promote endosomal release of ONs. Meanwhile, cylindrical-shaped lipid phosphatidylcholine can provide greater bilayer stability, which is important for in vivo application of LNPs. Cholesterol is often included as a helper that improves intracellular delivery as well as LNP stability in vivo. Inclusion of a PEGylating lipid can enhance LNP colloidal stability in vitro and circulation time in vivo but may reduce uptake and inhibit endosomal release at the cellular level. This problem can be addressed by choosing reversible PEGylation in which the PEG moiety is gradually released in blood circulation. pH-sensitive anionic helper lipids, such as fatty acids and cholesteryl hemisuccinate (CHEMS), can trigger low-pH-induced changes in LNP surface charge and destabilization that can facilitate endosomal release of ONs. Generally speaking, there is no correlation between LNP activity in vitro and in vivo because of differences in factors limiting the efficiency of delivery. Designing LNPs requires the striking of a proper balance between the need for particle stability, long systemic circulation time, and the need for LNP destabilization inside the target cell to release the oligonucleotide cargo, which requires the proper selection of both the cationic and helper lipids. Customized design and empirical optimization is needed for specific applications.
- 18Puri, A.; Loomis, K.; Smith, B.; Lee, J. H.; Yavlovich, A.; Heldman, E.; Blumenthal, R. Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit Rev. Ther Drug Carrier Syst 2009, 26 (6), 523– 580, DOI: 10.1615/CritRevTherDrugCarrierSyst.v26.i6.10Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntVaks7Y%253D&md5=8216b1fe248eaece6faba755cd9d6d87Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinicPuri, Anu; Loomis, Kristin; Smith, Brandon; Lee, Jae-Ho; Yavlovich, Amichai; Heldman, Eliahu; Blumenthal, RobertCritical Reviews in Therapeutic Drug Carrier Systems (2009), 26 (6), 523-580CODEN: CRTSEO; ISSN:0743-4863. (Begell House, Inc.)A review. In recent years, various nanotechnol. platforms in the area of medical biol., including both diagnostics and therapy, have gained remarkable attention. Moreover, research and development of engineered multifunctional nanoparticles as pharmaceutical drug carriers have spurred exponential growth in applications to medicine in the last decade. Design principles of these nanoparticles, including nanoemulsions, dendrimers, nano-gold, liposomes, drug-carrier conjugates, antibody-drug complexes, and magnetic nanoparticles, are primarily based on unique assemblies of synthetic, natural, or biol. components, including but not limited to synthetic polymers, metal ions, oils, and lipids as their building blocks. However, the potential success of these particles in the clinic relies on consideration of important parameters such as nanoparticle fabrication strategies, their phys. properties, drug loading efficiencies, drug release potential, and, most importantly, min. toxicity of the carrier itself. Among these, lipid-based nanoparticles bear the advantage of being the least toxic for in vivo applications, and significant progress has been made in the area of DNA/ENA and drug delivery using lipid-based nanoassemblies. In this review, we will primarily focus on the recent advances and updates on lipid-based nanoparticles for their projected applications in drug delivery. We begin with a review of current activities in the field of liposomes (the so-called honorary nanoparticles), and challenging issues of targeting and triggering will be discussed in detail. We will further describe nanoparticles derived from a novel class of amphipathic lipids called bolaamphiphiles with unique lipid assembly features that have been recently examd. as drug/DNA delivery vehicles. Finally, an overview of an emerging novel class of particles (based on lipid components other than phospholipids), solid lipid nanoparticles and nanostructured lipid carriers will be presented. We conclude with a few examples of clin. successful formulations of currently available lipid-based nanoparticles.
- 19Xu, L.; Wang, X.; Liu, Y.; Yang, G.; Falconer, R. J.; Zhao, C.-X. Lipid Nanoparticles for Drug Delivery. Advanced NanoBiomed Research 2022, 2 (2), 2100109, DOI: 10.1002/anbr.202100109Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXis1emsbo%253D&md5=bf29ddd0cacb4e6f69590216dbf32b7bLipid Nanoparticles for Drug DeliveryXu, Letao; Wang, Xing; Liu, Yun; Yang, Guangze; Falconer, Robert J.; Zhao, Chun-XiaAdvanced NanoBiomed Research (2022), 2 (2), 2100109CODEN: ANRDBI; ISSN:2699-9307. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Lipid nanoparticles have attracted significant interests in the last two decades, and have achieved tremendous clin. success since the first clin. approval of Doxil in 1995. At the same time, lipid nanoparticles have also demonstrated enormous potential in delivering nucleic acid drugs as evidenced by the approval of two RNA therapies and mRNA COVID-19 vaccines. In this review, an overview on different classes of lipid nanoparticles, including liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, is first provided, followed by the introduction of their prepn. methods. Then the characterizations of lipid nanoparticles are briefly reviewed and their applications in encapsulating and delivering hydrophobic drugs, hydrophilic drugs, and RNAs are highlighted. Finally, various applications of lipid nanoparticles for overcoming different delivery challenges, including crossing the blood-brain barrier, targeted delivery, and various routes of administration, are summarized. Lipid nanoparticles as drug delivery systems offer many attractive benefits such as great biocompatibility, ease of prepn., feasibility of scale-up, nontoxicity, and targeted delivery, while current challenges in drug delivery warrant future studies about structure-function correlations, large-scale prodn., and targeted delivery to realize the full potential of lipid nanoparticles for wider clin. and pharmaceutical applications in future.
- 20Mora-Huertas, C. E.; Fessi, H.; Elaissari, A. Polymer-based nanocapsules for drug delivery. Int. J. Pharm. 2010, 385 (1–2), 113– 142, DOI: 10.1016/j.ijpharm.2009.10.018Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1Sls7bJ&md5=3239884325cafc3dabb00e0625ece4a2Polymer-based nanocapsules for drug deliveryMora-Huertas, C. E.; Fessi, H.; Elaissari, A.International Journal of Pharmaceutics (2010), 385 (1-2), 113-142CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)A review of the state of knowledge on nanocapsules prepd. from preformed polymers as active substances carriers is presented. This entails a general review of the different prepn. methods: nanopptn., emulsion-diffusion, double emulsification, emulsion-coacervation, polymer-coating and layer-by-layer, from the point of view of the methodol. and mechanistic aspects involved, encapsulation of the active substance and the raw materials used. Similarly, a comparative anal. is given of the size, zeta-potential, dispersion pH, shell thickness, encapsulation efficiency, active substance release, stability and in vivo and in vitro pharmacol. performances, using as basis the data reported in the different research works published. Consequently, the information obtained allows establishing criteria for selecting a method for prepn. of nanocapsules according to its advantages, limitations and behaviors as a drug carrier.
- 21Martínez Rivas, C. J.; Tarhini, M.; Badri, W.; Miladi, K.; Greige-Gerges, H.; Nazari, Q. A.; Galindo Rodríguez, S. A.; Román, R.; Fessi, H.; Elaissari, A. Nanoprecipitation process: From encapsulation to drug delivery. Int. J. Pharm. 2017, 532 (1), 66– 81, DOI: 10.1016/j.ijpharm.2017.08.064Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVGlsrfN&md5=8a015ec3d2565cf05071d17c34b03126Nanoprecipitation process: From encapsulation to drug deliveryMartinez Rivas, Claudia Janeth; Tarhini, Mohamad; Badri, Waisudin; Miladi, Karim; Greige-Gerges, Helene; Nazari, Qand Agha; Galindo Rodriguez, Sergio Arturo; Roman, Rocio Alvarez; Fessi, Hatem; Elaissari, AbdelhamidInternational Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 532 (1), 66-81CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)Drugs encapsulation is a suitable strategy in order to cope with the limitations of conventional dosage forms such as unsuitable bioavailability, stability, taste, and odor. Nanopptn. technique has been used in the pharmaceutical and agricultural research as clean alternative for other drug carrier formulations. This technique is based on pptn. mechanism. Polymer pptn. occurs after the addn. of a non-solvent to a polymer soln. in four steps mechanism: supersatn., nucleation, growth by condensation, and growth by coagulation that leads to the formation of polymer nanoparticles or aggregates. The scale-up of lab.-based nanopptn. method shows a good reproducibility. In addn., flash nanopptn. is a good strategy for industrial scale prodn. of nanoparticles. Nanopptn. is usually used for encapsulation of hydrophobic or hydrophilic compds. Nanopptn. was also shown to be a good alternative for the encapsulation of natural compds. As a whole, process and formulation related parameters in nanopptn. technique have crit. effect on nanoparticles characteristics. Biodegradable or non-biodegradable polymers have been used for the prepn. of nanoparticles intended to in vivo studies. Literature studies have demonstrated the biodistribution of the active loaded nanoparticles in different organs after administration via various routes. In general, in vitro drug release from nanoparticles prepd. by nanopptn. includes two phases: a first phase of "burst release" which is followed by a second phase of prolonged release. Moreover, many encapsulated active mols. have been commercialized in the pharmaceutical market.
- 22Rasmussen, M. K.; Pedersen, J. N.; Marie, R. Size and surface charge characterization of nanoparticles with a salt gradient. Nat. Commun. 2020, 11 (1), 2337, DOI: 10.1038/s41467-020-15889-3Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXptleht78%253D&md5=565bf9ec96af027b599234a31ec7c4b2Size and surface charge characterization of nanoparticles with a salt gradientRasmussen, Martin K.; Pedersen, Jonas N.; Marie, RodolpheNature Communications (2020), 11 (1), 2337CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)Abstr.: Exosomes are nanometer-sized lipid vesicles present in liq. biopsies and used as biomarkers for several diseases including cancer, Alzheimer's, and central nervous system diseases. Purifn. and subsequent size and surface characterization are essential to exosome-based diagnostics. Sample purifn. is, however, time consuming and potentially damaging, and no current method gives the size and zeta potential from a single measurement. Here, we conc. exosomes from a dil. soln. and measure their size and zeta potential in a one-step measurement with a salt gradient in a capillary channel. The salt gradient causes oppositely directed particle and fluid transport that trap particles. Within minutes, the particle concn. increases more than two orders of magnitude. A fit to the spatial distribution of a single or an ensemble of exosomes returns both their size and surface charge. Our method is applicable for other types of nanoparticles. The capillary is fabricated in a low-cost polymer device.
- 23Smith, M. C.; Crist, R. M.; Clogston, J. D.; McNeil, S. E. Zeta potential: a case study of cationic, anionic, and neutral liposomes. Anal Bioanal Chem. 2017, 409 (24), 5779– 5787, DOI: 10.1007/s00216-017-0527-zGoogle Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1OisbbP&md5=4e7ef292af9e8c081b6c6fc104f83222Zeta potential: a case study of cationic, anionic, and neutral liposomesSmith, Mackensie C.; Crist, Rachael M.; Clogston, Jeffrey D.; McNeil, Scott E.Analytical and Bioanalytical Chemistry (2017), 409 (24), 5779-5787CODEN: ABCNBP; ISSN:1618-2642. (Springer)Zeta potential is often used to approx. a nanoparticle's surface charge, i.e., cationic, anionic, or neutral character, and has become a std. characterization technique to evaluate nanoparticle surfaces. While useful, zeta potential values provide only very general conclusions about surface charge character. Without a thorough understanding of the measurement parameters and limitations of the technique, these values can become meaningless. This case study attempts to explore the sensitivity of zeta potential measurement using specifically formulated cationic, anionic, and neutral liposomes. This study examines zeta potential dependence on pH and ionic strength, resolving power, and highlights the sensitivity of zeta potential to charged liposomes. Liposomes were prepd. with cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and varying amts. of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS). A strong linear relation was noted between zeta potential values and the mole percentage of charged lipids within a liposome (e.g., cationic DOTAP or anionic DOPS). This finding could be used to formulate similar liposomes to a specific zeta potential, potentially of importance for systems sensitive to highly charged species. In addn., cationic and anionic liposomes were titrated with up to two mole percent of the neutral lipid 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (lipid-PEG; LP). Very small amts. of the lipid-PEG (<0.2 mol%) were found to impart stability to the DOTAP- and DOPS-contg. liposomes without significantly affecting other physicochem. properties of the formulation, providing a simple approach to making stable liposomes with cationic and anionic surface charge.
- 24Ruozi, B.; Belletti, D.; Tombesi, A.; Tosi, G.; Bondioli, L.; Forni, F.; Vandelli, M. A. AFM, ESEM, TEM, and CLSM in liposomal characterization: a comparative study. Int. J. Nanomedicine 2011, 6, 557– 563, DOI: 10.2147/IJN.S14615Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjvVyksbk%253D&md5=7503f301cdcf86e55a0ade3204d656f7AFM, ESEM, TEM, and CLSM in liposomal characterization: a comparative studyRuozi, Barbara; Belletti, Daniela; Tombesi, Andrea; Tosi, Giovanni; Bondioli, Lucia; Forni, Flavio; Vandelli, Maria AngelaInternational Journal of Nanomedicine (2011), 6 (), 557-563CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)An outstanding aspect of pharmaceutical nanotechnol. lies in the characterization of nanocarriers for targeting of drugs and other bioactive agents. The development of microscopic techniques has made the study of the surface and systems architecture more attractive. In the field of pharmaceutical nanosystems, researchers have collected vital information on size, stability, and bilayer organization through the microscopic characterization of liposomes. This paper aims to compare the results obtained by at. force microscopy, environmental SEM, transmission electron microscopy, and confocal laser scanning microscopy to point out the limits and advantages of these applications in the evaluation of vesicular systems. Besides this comparative aim, our work proposes a simple confocal laser scanning microscopy procedure to rapidly and easily detect the liposomal membrane.
- 25Zhigaltsev, I. V.; Cullis, P. R. Morphological Behavior of Liposomes and Lipid Nanoparticles. Langmuir 2023, 39 (9), 3185– 3193, DOI: 10.1021/acs.langmuir.2c02794Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXjs1Cnt7c%253D&md5=7164d2dd6b962572d1d4716591d3e177Morphological Behavior of Liposomes and Lipid NanoparticlesZhigaltsev, Igor V.; Cullis, Pieter R.Langmuir (2023), 39 (9), 3185-3193CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)Liposomes, which consist of bilayer lipids surrounding interior aq. compartment(s), were first characterized nearly 60 years ago. Remarkably, many fundamental properties of liposomes and their micellar-like "solid core" counterparts (a lipid monolayer surrounding a hydrophobic core) and transitions between these structures remain poorly understood. In this work, we examine the effects of basic variables on the morphol. adopted by lipid-based systems produced by rapid mixing of lipids in ethanol with aq. media. We show that, for lipids such as distearolyphosphatidylcholine (DSPC)-cholesterol mixts. that form bilayer vesicles on hydration, osmotic stress can induce regions of high pos. membrane curvature, leading to fusion between unilamellar vesicles to produce bilamellar vesicles. Addn. of lyso PC, an "inverted cone"-shaped lipid that supports regions of high pos. curvature, can inhibit the formation of these bilamellar vesicles by stabilizing a hemifused intermediate structure. Conversely, the presence of "cone"-shaped lipids such as dioleoylphosphatidylethanolamine (DOPE) that results in neg. membrane curvature promotes fusion events subsequent to vesicle formation (during the ethanol dialysis stage), leading to bilamellar and multilamellar systems even in the absence of osmotic stress. Alternatively, the presence of increasing amts. of triolein, a lipid that is insol. in lipid bilayers, results in increasing internal solid core structures until micellar-like systems with a hydrophobic core of triolein are achieved. These results are interpreted in terms of the intrinsic membrane curvature that bilayer vesicles can stably maintain as well as the ability of bilayer lipids to first form a monolayer around a solid core of hydrophobic material such as triolein and then, as the proportion of bilayer lipids is increased, progressively form bilayer structures that can eventually form a complete bilayer encapsulating both a hydrophobic core and an aq. compartment. These hybrid intermediate structures may have utility as novel drug delivery systems.
- 26Knop, K.; Hoogenboom, R.; Fischer, D.; Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem., Int. Ed. Engl. 2010, 49 (36), 6288– 6308, DOI: 10.1002/anie.200902672Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3cjntFaisg%253D%253D&md5=405891d08fa43a94b34ed849ed58c0d2Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternativesKnop Katrin; Hoogenboom Richard; Fischer Dagmar; Schubert Ulrich SAngewandte Chemie (International ed. in English) (2010), 49 (36), 6288-308 ISSN:.Poly(ethylene glycol) (PEG) is the most used polymer and also the gold standard for stealth polymers in the emerging field of polymer-based drug delivery. The properties that account for the overwhelming use of PEG in biomedical applications are outlined in this Review. The first approved PEGylated products have already been on the market for 20 years. A vast amount of clinical experience has since been gained with this polymer--not only benefits, but possible side effects and complications have also been found. The areas that might need consideration and more intensive and careful examination can be divided into the following categories: hypersensitivity, unexpected changes in pharmacokinetic behavior, toxic side products, and an antagonism arising from the easy degradation of the polymer under mechanical stress as a result of its ether structure and its non-biodegradability, as well as the resulting possible accumulation in the body. These possible side effects will be discussed in this Review and alternative polymers will be evaluated.
- 27Battaglia, L.; Gallarate, M. Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery. Expert Opin Drug Deliv 2012, 9 (5), 497– 508, DOI: 10.1517/17425247.2012.673278Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlvVGrt7g%253D&md5=2291ffdfea37d3020960774d4f68bd87Lipid nanoparticles: state of the art, new preparation methods and challenges in drug deliveryBattaglia, Luigi; Gallarate, MarinaExpert Opinion on Drug Delivery (2012), 9 (5), 497-508CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)A review. Introduction: Nanoparticles are rapidly developing as drug carriers because of their size-dependent properties. Lipid nanoparticles (LNPs) are widely employed in drug delivery because of the biocompatibility of the lipid matrix. Areas covered: Many different types of LNPs have been engineered in the last 20 years, the most important being solid lipid nanoparticles (SLNs), nanostrucured lipid carriers (NLCs), lipid-drug conjugates (LDCs) and lipid nanocapsules (LNCs). This review gives an overview of LNPs, including their physico-chem. properties and pharmacol. uses. Moreover, it highlights the most important innovations in the prepn. techniques of LNPs, aimed to encapsulate different mols. within the lipid matrix. Finally, it gives a short perspective on the challenges of drug delivery, which are a potential field of application for LNPs: cancer therapy, overcoming the blood-brain barrier and gene and protein delivery. Expert opinion: LNPs are a safe and versatile vehicles for drug and active delivery, suitable for different administration routes. New technologies have been developed for LNP prepn. and studies are currently underway in order to obtain the encapsulation of different drugs and to deliver the active mol. to the site of action.
- 28Yu, F.; Miao, Y.; Wang, M.; Liu, Q.; Yuan, L.; Geng, R.; Qiu, Q.; Ni, C.; Kay, M. Predicting nanoemulsion formulation and studying the synergism mechanism between surfactant and cosurfactant: A combined computational and experimental approach. Int. J. Pharm. 2022, 615, 121473, DOI: 10.1016/j.ijpharm.2022.121473Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitlGntLY%253D&md5=e7620ad881c9c60c1c10678f9ee4197cPredicting nanoemulsion formulation and studying the synergism mechanism between surfactant and cosurfactant: A combined computational and experimental approachYu, Fan; Miao, Yiye; Wang, Mengjie; Liu, Qisong; Yuan, Lun; Geng, Rongqing; Qiu, Qianqian; Ni, Chunjie; Kay, MatthewInternational Journal of Pharmaceutics (Amsterdam, Netherlands) (2022), 615 (), 121473CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)Nanoemulsion (NE) is a dosage form widely used in pharmaceutical, food, agrochem., cosmetics, and personal care industries. NE systems are usually formulated through trial and error via numerous semi-empirical expts. Moreover, the complex interaction mechanisms between the formulation surfactant and cosurfactant are difficult to understand. Dissipative particle dynamics (DPD) may be helpful in solving these formulation problems. Silibinin is a flavonolignan isolated from milk thistle, which has demonstrated antioxidant and antimicrobial effects. For this project, silibinin-loaded nanoemulsion (SBNE) was formulated by DPD, including surfactant and cosurfactant screening, pseudo-ternary phase construction, and SBNE characterization, all of which were verified by experimentation. Most importantly, this work shows that DPD can be adopted to explore the synergetic mechanisms between the surfactant and cosurfactant, including emulsification efficiency, distance, angle, arrangement, and order parameter. Addnl. verification expts. on the antioxidant and antimicrobial applications of simulation-designed SBNE were also carried out and confirmed DPD-predicted results. As such, predicting NE formulation by DPD has been proven to be feasible. For SBNE, the addn. of PEG400 cosurfactant stretches the Cremophor RH40 surfactant mols. and assists in a more orderly arrangement. An enhanced interfacial thickness in SBNE could be attributed to the stretched hydrophilic head group and the decreased angle between the mol. axis and interface normal. These DPD and exptl.-verified results indicated that a proper cosurfactant will enhance the interfacial thickness, decrease the consumption of surfactant, and benefit NE formation. This new computationally applied knowledge should facilitate optimizing, designing, and understanding NE formulation more rationally and scientifically.
- 29Balouch, M.; Storchmannova, K.; Stepanek, F.; Berka, K. Computational Prodrug Design Methodology for Liposome Formulability Enhancement of Small-Molecule APIs. Mol. Pharmaceutics 2023, 20 (4), 2119– 2127, DOI: 10.1021/acs.molpharmaceut.2c01078Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXlsVajt7s%253D&md5=67152c6e297c5566f97d5276ce5511daComputational Prodrug Design Methodology for Liposome Formulability Enhancement of Small-Molecule APIsBalouch, Martin; Storchmannova, Katerina; Stepanek, Frantisek; Berka, KarelMolecular Pharmaceutics (2023), 20 (4), 2119-2127CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Encapsulation into liposomes is a formulation strategy that can improve efficacy and reduce side effects of active pharmaceutical ingredients (APIs) that exhibit poor biodistribution or pharmacokinetics when administered alone. However, many APIs are unsuitable for liposomal formulations intended for parenteral administration due to their inherent physicochem. properties-lipid bilayer permeability and water-lipid equil. partitioning coeff. Too high permeability results in premature leakage from liposomes, while too low permeability means the API is not able to pass across biol. barriers. There are several options for solving this issue: (i) change of the lipid bilayer compn., (ii) addn. of a permeability enhancer, or (iii) modification of the chem. structure of the API to design a prodrug. The latter approach was taken in the present work, and the effect of small changes in the mol. structure of the API on its permeation rate across a lipidic bilayer was systematically explored utilizing computer simulations. An in silico methodol. for prodrug design based on the COSMOperm approach has been proposed and applied to four APIs (abiraterone, cytarabine, 5-fluorouracil, and paliperidone). It is shown that the addn. of aliph. hydrocarbon chains via ester or amide bonds can render the mol. more lipophilic and increase its permeability by approx. 1 order of magnitude for each 2 carbon atoms added, while the formation of fructose adducts can provide a more hydrophilic character to the mol. and reduce its lipid partitioning. While partitioning was found to depend only on the size and type of the added group, permeability was found to depend also on the added group location. Overall, it has been shown that both permeability and lipid partitioning coeff. can be systematically shifted into the desired liposome formulability window by appropriate group contributions to the parental drug. This can significantly increase the portfolio of APIs for which liposome or lipid nanoparticle formulations become feasible.
- 30Chaban, V. V.; Khandelia, H. Distribution of neutral lipids in the lipid droplet core. J. Phys. Chem. B 2014, 118 (38), 11145– 11151, DOI: 10.1021/jp506693dGoogle Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVyktbfL&md5=38023d7480e883c6403f6584bf79ade3Distribution of Neutral Lipids in the Lipid Droplet CoreChaban, Vitaly V.; Khandelia, HimanshuJournal of Physical Chemistry B (2014), 118 (38), 11145-11151CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)Cholesteryl esters (CEs) are a form of cholesterol (CHOL) storage in the living cells, as opposed to free CHOL. CEs are major constituents of low d. lipoprotein particles. Therefore, CEs are implicated in provoking atherosclerosis. Arranged into cytoplasmic lipid droplets (LDs), CEs are stored intracellularly. They can also be transported extracellularly by lipoproteins. Large-scale mol. dynamics (MD) simulations were used to characterize the mol. structure of LDs contg. various fractions (10-50 mol %) of cholesteryl oleate (CO) with respect to triolein (TO) fraction. The simulated LDs were covered by a phospholipid monolayer formed by a mixt. of 1-palmitoyl-2-oleoylphosphatidylcholine, POPC (75 mol %), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, POPE (25 mol %), mols. The authors report that most CO mols. are located within the hydrophobic core of LDs, whereas a small fraction (0.3-1.9 mol %) penetrates the monolayer. The soly. of CO in the phospholipid monolayer is relatively small. Due to a good miscibility with TO mols., CO forms a liq. phase inside LD at 333 K. There is long-range order in the liq. TO-CO droplet core up to 8 nm from the phospholipid interface, resulting from the structuring of hydrophilic groups. This structuring slowly decays in the direction toward the LD center of mass. No sorting of TO and CO was detected, irresp. of the molar fractions simulated. The distribution of CO within the LDs is significant in detg. the rate of their hydrolysis by surface-bound enzyme lipases, and thus has a subsequent impact on the levels of CO in plasma and LDLs.
- 31Chaban, V. V.; Khandelia, H. Lipid structure in triolein lipid droplets. J. Phys. Chem. B 2014, 118 (35), 10335– 10340, DOI: 10.1021/jp503223zGoogle Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlOntb%252FL&md5=330cece2f841909cfc5d163e3a58ef34Lipid Structure in Triolein Lipid DropletsChaban, Vitaly V.; Khandelia, HimanshuJournal of Physical Chemistry B (2014), 118 (35), 10335-10340CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)Lipid droplets (LDs) are primary repositories of esterified fatty acids and sterols in animal cells. These organelles originate on the lumenal or cytoplasmic side of endoplasmic reticulum (ER) membrane and are released to the cytosol. In contrast to other intracellular organelles, LDs are composed of a mass of hydrophobic lipid esters coved by phospholipid monolayer. The small size and unique architecture of LDs makes it complicated to study LD structure by modern exptl. methods. We discuss coarse-grained mol. dynamics (MD) simulations of LD formation in systems contg. 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), triolein (TO), cholesterol (CHOL), and water. We find that (1) there is more cholesterol in the LD core, than at the interface. (2) No crystn. occurs inside the LD core. (3) According to coarse-grained simulations, the presence of PE lipids at the interface has a little impact on distribution of components and on the overall LD structure. (4) The thickness of the lipid monolayer at the surface of the droplet is similar to the thickness of one leaflet of a bilayer. Computer simulations are shown to be a mighty tool to provide mol.-level insights, which are not available to the exptl. techniques.
- 32Chan, C.; Du, S.; Dong, Y.; Cheng, X. Computational and Experimental Approaches to Investigate Lipid Nanoparticles as Drug and Gene Delivery Systems. Curr. Top Med. Chem. 2021, 21 (2), 92– 114, DOI: 10.2174/1568026620666201126162945Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitVSjsL0%253D&md5=de769a8a1eeb5e62e47f32be00f732f2Computational and Experimental Approaches to Investigate Lipid Nanoparticles as Drug and Gene Delivery SystemsChan, Chun; Du, Shi; Dong, Yizhou; Cheng, XiaolinCurrent Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2021), 21 (2), 92-114CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. Lipid nanoparticles (LNPs) have been widely applied in drug and gene delivery. More than twenty years ago, DoxilTM was the first LNPs-based drug approved by the US Food and Drug Administration (FDA). Since then, with decades of research and development, more and more LNP-based therapeutics have been used to treat diverse diseases, which often offer the benefits of reduced toxicity and/or enhanced efficacy compared to the active ingredients alone. Here, we provide a of recent advances in the development of efficient and robust LNPs for drug/gene delivery. We emphasize the importance of rationally combining exptl. and computational approaches, esp. those providing multiscale structural and functional information of LNPs, to the design of novel and powerful LNP-based delivery systems.
- 33Metwally, A. A.; Hathout, R. M. Computer-Assisted Drug Formulation Design: Novel Approach in Drug Delivery. Mol. Pharmaceutics 2015, 12 (8), 2800– 2810, DOI: 10.1021/mp500740dGoogle Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKitLfM&md5=57b666a6af7ed423a1b73d30c0532fc1Computer-assisted drug formulation design: Novel approach in drug deliveryMetwally, Abdelkader A.; Hathout, Rania M.Molecular Pharmaceutics (2015), 12 (8), 2800-2810CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)We hypothesize that, by using several chemo/bio informatics tools and statistical computational methods, we can study and then predict the behavior of several drugs in model nanoparticulate lipid and polymeric systems. Accordingly, two different matrixes comprising tripalmitin, a core component of solid lipid nanoparticles (SLN), and PLGA were first modeled using mol. dynamics simulation, and then the interaction of drugs with these systems was studied by means of computing the free energy of binding using the mol. docking technique. These binding energies were hence correlated with the loadings of these drugs in the nanoparticles obtained exptl. from the available literature. The obtained relations were verified exptl. in our lab. using curcumin as a model drug. Artificial neural networks were then used to establish the effect of the drugs' mol. descriptors on the binding energies and hence on the drug loading. The results showed that the used soft computing methods can provide an accurate method for in silico prediction of drug loading in tripalmitin-based and PLGA nanoparticulate systems. These results have the prospective of being applied to other nano drug-carrier systems, and this integrated statistical and chemo/bio informatics approach offers a new toolbox to the formulation science by proposing what we present as computer-assisted drug formulation design (CADFD).
- 34Yadav, D. K.; Kumar, S.; Choi, E. H.; Chaudhary, S.; Kim, M. H. Computational Modeling on Aquaporin-3 as Skin Cancer Target: A Virtual Screening Study. Front Chem. 2020, 8, 250, DOI: 10.3389/fchem.2020.00250Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFGisb%252FE&md5=b0e62339792806b448a3b544b6d2e42dComputational modeling on Aquaporin-3 as skin cancer target: a virtual screening studyYadav, Dharmendra Kumar; Kumar, Surendra; Choi, Eun-Ha; Chaudhary, Sandeep; Kim, Mi-HyunFrontiers in Chemistry (Lausanne, Switzerland) (2020), 8 (), 00250CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)Aquaporin-3 (AQP3) is one of the aquaglyceroporins, which is expressed in the basolateral layer of the skin membrane. Studies have reported that human skin squamous cell carcinoma overexpresses AQP3 and inhibition of its function may alleviate skin tumorigenesis. In the present study, we have applied a virtual screening method that encompasses filters for physicochem. properties and mol. docking to select potential hit compds. that bind to the Aquaporin-3 protein. Based on mol. docking results, the top 20 hit compds. were analyzed for stability in the binding pocket using unconstrained mol. dynamics simulations and further evaluated for binding free energy. Furthermore, examd. the ligand-unbinding pathway of the inhibitor fromits bound formto explore possible routes for inhibitor approach to the ligand-binding site.With a good docking score, stability in the binding pocket, and free energy of binding, these hit compds. can be developed as Aquaporin-3 inhibitors in the near future.
- 35Bangham, A. D.; Standish, M. M.; Watkins, J. C. Diffusion of univalent ions across the lamellae of swollen phospholipids. J. Mol. Biol. 1965, 13 (1), 238– 252, DOI: 10.1016/S0022-2836(65)80093-6Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXkvVWru7g%253D&md5=85306fa331a39c349bf93d130eba7acfDiffusion of univalent ions across the lamellae of swollen phospholipidsBangham, A. D.; Standish, M. M.; Watkins, J. C.Journal of Molecular Biology (1965), 13 (1), 238-52CODEN: JMOBAK; ISSN:0022-2836.cf. CA 61, 5954e. Ovolecithin was treated with a long-chain ion (dicetyl phosphoric acid, stearylamine, or docosanylpyridinium bromide) in CHCl3 to give a pos. or neg. charge, dried, and mixed with the swelling salt soln. The dispersion was placed in a dialysis bag in a bottle contg. isotonic salt. Efficient dialysis was obtained by thorough mixing of the dialyzate and mixing of the dispersion, using 5 successive 30-min. dialyses at room temp. In a rapid method for the exchange of untrapped salt soln., the lipid dispersion was placed on a column of Sephadex G-50, swollen in dialyzing soln., and chased through with the dialyzing soln. Untrapped salt was eluted after the dispersion. The diffusion of univalent cations and anions out of spontaneously formed liquid crystals of lecithin was remarkably similar to the diffusion of such ions across biol. membranes. If the unit structure of the liquid crystals is accepted as being that of a bimol. leaflet, then these leaflets are many orders of magnitude more permeable to anions than to cations. The diffusion rate for cations was very significantly controlled by the sign and magnitude of the surface charge at the water-lipid interface. There was a decrease of the diffusion rate for cations as the neg. charge on the lipid structure decreased, diminishing to zero for a pos. charged membrane. The diffusion rate of anions remained very high. The exchange diffusion rate of Cl- and I- was greater than that of F-, NO3-, SO4--, and HPO4--, but no significant differences were detectable for the cation series, Li+, Na+, K+, Rb+, and choline. The membranes were very permeable to water. Because the diffusion rate of cations was low, the phospholipid liquid cryst. structures appeared to bind or capture cations. As the surface charge of the lipid lamellae was increased, the amt. of cation/micromole of lipid increased. It was argued that if the cation was sequestered in aq. compartments between the bimol. leaflets, and if the thickness of the aq. compartments was detd. by the surface charge density of the lipid head groups and by the ionic strength of the aq. phase in accordance with double-layer theory, the amt. of cation trapped would also be expected to vary.
- 36Wang, H. F.; Ran, R.; Liu, Y.; Hui, Y.; Zeng, B.; Chen, D.; Weitz, D. A.; Zhao, C. X. Tumor-Vasculature-on-a-Chip for Investigating Nanoparticle Extravasation and Tumor Accumulation. ACS Nano 2018, 12 (11), 11600– 11609, DOI: 10.1021/acsnano.8b06846Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVKiurbN&md5=92af53162fb1631c4df08cadea9de9e8Tumor-Vasculature-on-a-Chip for Investigating Nanoparticle Extravasation and Tumor AccumulationWang, Hao-Fei; Ran, Rui; Liu, Yun; Hui, Yue; Zeng, Bijun; Chen, Dong; Weitz, David A.; Zhao, Chun-XiaACS Nano (2018), 12 (11), 11600-11609CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Nanoparticle tumor accumulation relies on a key mechanism, the enhanced permeability and retention (EPR) effect, but it remains challenging to decipher the exact impact of the EPR effect. Animal models in combination with imaging modalities are useful, but it is impossible to delineate the roles of multiple biol. barriers involved in nanoparticle tumor accumulation. Here we report a microfluidic tumor-vasculature-on-a-chip (TVOC) mimicking two key biol. barriers, namely, tumor leaky vasculature and 3D tumor tissue with dense extracellular matrix (ECM), to study nanoparticle extravasation through leaky vasculature and the following accumulation in tumor tissues. Intact 3D tumor vasculature was developed with selective permeability of small mols. (20 kDa) but not large ones (70 kDa). The permeability was further tuned by cytokine stimulation, demonstrating the independent control of the leaky tumor vasculature. Combined with tumor spheroids in dense ECM, our TVOC model is capable of predicting nanoparticles' in vivo tumor accumulation, thus providing a powerful platform for nanoparticle evaluation.
- 37Has, C.; Sunthar, P. A comprehensive review on recent preparation techniques of liposomes. J. Liposome Res. 2020, 30 (4), 336– 365, DOI: 10.1080/08982104.2019.1668010Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVGntL3N&md5=8a224f78b2356da1539e1a35bad7b076A comprehensive review on recent preparation techniques of liposomesHas, C.; Sunthar, P.Journal of Liposome Research (2020), 30 (4), 336-365CODEN: JLREE7; ISSN:0898-2104. (Taylor & Francis Ltd.)A review Liposomes (or lipid vesicles) are a versatile platform as carriers for the delivery of the drugs and other macromols. into human and animal bodies. Though the method of using liposomes has been known since 1960s, and major developments and commercialization of liposomal formulations took place in the late nineties (or early part of this century), newer methods of liposome synthesis and drug encapsulation continue to be an active area of research. With the developments in related fields, such as electrohydrodynamics and microfluidics, and a growing understanding of the mechanisms of lipid assembly from colloidal and intermol. forces, liposome prepn. techniques have been enriched and more predictable than before. This has led to better methods that can also scale at an industrial prodn. level. In this review, we present several novel methods that were introduced over the last decade and compare their advantages over conventional methods. Researchers beginning to explore liposomal formulations will find this resource useful to give an overall direction for an appropriate choice of method. Where possible, we have also provided the known mechanisms behind the prepn. methods.
- 38Harashima, H.; Sakata, K.; Funato, K.; Kiwada, H. Enhanced hepatic uptake of liposomes through complement activation depending on the size of liposomes. Pharm. Res. 1994, 11 (3), 402– 406, DOI: 10.1023/A:1018965121222Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXisVWmsLY%253D&md5=dfb774568bec762f1336aef04e744831Enhanced hepatic uptake of liposomes through complement activation depending on the size of liposomesHarashima, Hideyoshi; Sakata, Kazuya; Funato, Kouichi; Kiwada, HiroshiPharmaceutical Research (1994), 11 (3), 402-6CODEN: PHREEB; ISSN:0724-8741.The objective of this study was to differentiate the roles of opsonins and phagocytic cells in the size-dependent hepatic uptake of liposomes in the submicron region. The extent of opsonization decreased with the decrease in size of liposomes (from 800 to 200 nm in diam.) and no enhancement of uptake was obsd. at 200 nm. There was no effect of liposome size on the uptake of unopsonized liposomes. Serum was pretreated with empty liposomes of each size and its opsonic activity was measured in the perfused liver. The small liposomes could not consume the opsonic activity, while the larger ones did so substantially. These results suggest that opsonins bind to liposomes depending on the size of liposomes and phagocytic cells take up liposomes in proportion to the extent of opsonization. Size-dependent liposome degrdn. in serum was also found, which was consistent with the size-dependent complement activation, because liposomes with this compns. have been shown to be degraded by complement. The mechanism of opsonization was examd. by treating serum at 56° for 30 min or with anti-C3 antiserum. Since both treatments inhibited the opsonic activity, the hepatic uptake of liposomes is considered to occur via complement receptor. In conclusion, the size of liposomes affected complement recognition, and the liposomes were taken up by the liver depending on the extend of opsonization.
- 39Parchekani, J.; Allahverdi, A.; Taghdir, M.; Naderi-Manesh, H. Design and simulation of the liposomal model by using a coarse-grained molecular dynamics approach towards drug delivery goals. Sci. Rep 2022, 12 (1), 2371, DOI: 10.1038/s41598-022-06380-8Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XjsVGrs7g%253D&md5=6fb7b1e12e1acab86547d0074367d1d9Design and simulation of the liposomal model by using a coarse-grained molecular dynamics approach towards drug delivery goalsParchekani, Jalil; Allahverdi, Abdollah; Taghdir, Majid; Naderi-Manesh, HosseinScientific Reports (2022), 12 (1), 2371CODEN: SRCEC3; ISSN:2045-2322. (Nature Portfolio)The simulated liposome models provide events in mol. biol. science and cellular biol. These models may help to understand the cell membrane mechanisms, biol. cell interactions, and drug delivery systems. In addn., the liposomes model may resolve specific issues such as membrane transports, ion channels, drug penetration in the membrane, vesicle formation, membrane fusion, and membrane protein function mechanism. One of the approaches to investigate the lipid membranes and the mechanism of their formation is by mol. dynamics (MD) simulations. In this study, we used the coarse-grained MD simulation approach and designed a liposome model system. To simulate the liposome model, we used phospholipids that are present in the structure of natural cell membranes (1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)). Simulation conditions such as temp., ions, water, lipid concn. were performed based on exptl. conditions. Our results showed a liposome model (ellipse vesicle structure) during the 2100 ns was formed. Moreover, the anal. confirmed that the stretched and ellipse structure is the best structure that could be formed. The eukaryotic and even the bacterial cells have elliptical and flexible structures. Usually, an elliptical structure is more stable than other assembled structures. The results indicated the assembly of the lipids is directed through short-range interactions (electrostatic interactions and, van der Waals interactions). Total energy (Van der Waals and electrostatic interaction energy) confirmed the designed elliptical liposome structure has suitable stability at the end of the simulation process. Our findings confirmed that phospholipids DOPC and DOPE have a good tendency to form bilayer membranes (liposomal structure) based on their geometric shapes and chem.-phys. properties. Finally, we expected the simulated liposomal structure as a simple model to be useful in understanding the function and structure of biol. cell membranes. Furthermore, it is useful to design optimal, suitable, and biocompatible liposomes as potential drug carriers.
- 40Lemaalem, M.; Hadrioui, N.; Derouiche, A.; Ridouane, H. Structure and dynamics of liposomes designed for drug delivery: coarse-grained molecular dynamics simulations to reveal the role of lipopolymer incorporation. RSC Adv. 2020, 10 (7), 3745– 3755, DOI: 10.1039/C9RA08632CGoogle Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFWjsbk%253D&md5=45ff87c3f389f344b26d9509bb23e9f2Structure and dynamics of liposomes designed for drug delivery: coarse-grained molecular dynamics simulations to reveal the role of lipopolymer incorporationLemaalem, Mohammed; Hadrioui, Nourddine; Derouiche, Abdelali; Ridouane, HamidRSC Advances (2020), 10 (7), 3745-3755CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)In this work, coarse-grained mol. dynamics simulations are carried out in NPTH and NVTE statistical ensembles in order to study the structure and dynamics properties of liposomes coated with polyethylene glycol (PEG). The considered liposomes are made by membrane bilayer DPPC with DPPC-PEG incorporated lipopolymers, in an aq. environment. We have described the two essential PEG conformation regimes, mushroom and brush, and their properties which depend on the grafting d. The effects of grafting d. on the structure and dynamics of the membrane were also studied. Our simulations were then discussed by comparing with the available exptl. results and by referring to the suitable theor. models. The results from the NPTH simulations agree with the exptl. data of X-ray diffraction and with scale and mean-field theories in terms of thickness of the PEG layer and thickness of the DPPC bilayer membrane. The results from NVTE simulations are found in good agreement with the exptl. results from studying the diffusion of the DPPC bilayer membrane and the PEG. The anal. of the mean square displacement revealed that the dynamics of the membranes in the plane show a subdiffusion due to the cage effect and that the grafted PEG dynamics is better described by the Rouse diffusion-mode. Thus, from a macroscopic viewpoint, the incorporation of DPPC-PEG plays an important role in the protection and lubrication of the liposome.
- 41Jambeck, J. P.; Eriksson, E. S.; Laaksonen, A.; Lyubartsev, A. P.; Eriksson, L. A. Molecular Dynamics Studies of Liposomes as Carriers for Photosensitizing Drugs: Development, Validation, and Simulations with a Coarse-Grained Model. J. Chem. Theory Comput 2014, 10 (1), 5– 13, DOI: 10.1021/ct400466mGoogle Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vjtlGntg%253D%253D&md5=b4a7dcd055d636562ba7e2933c9c8899Molecular Dynamics Studies of Liposomes as Carriers for Photosensitizing Drugs: Development, Validation, and Simulations with a Coarse-Grained ModelJambeck Joakim P M; Laaksonen Aatto; Lyubartsev Alexander P; Eriksson Emma S E; Eriksson Leif AJournal of chemical theory and computation (2014), 10 (1), 5-13 ISSN:.Liposomes are proposed as drug delivery systems and can in principle be designed so as to cohere with specific tissue types or local environments. However, little detail is known about the exact mechanisms for drug delivery and the distributions of drug molecules inside the lipid carrier. In the current work, a coarse-grained (CG) liposome model is developed, consisting of over 2500 lipids, with varying degrees of drug loading. For the drug molecule, we chose hypericin, a natural compound proposed for use in photodynamic therapy, for which a CG model was derived and benchmarked against corresponding atomistic membrane bilayer model simulations. Liposomes with 21-84 hypericin molecules were generated and subjected to 10 microsecond simulations. Distribution of the hypericins, their orientations within the lipid bilayer, and the potential of mean force for transferring a hypericin molecule from the interior aqueous "droplet" through the liposome bilayer are reported herein.
- 42Dzieciuch, M.; Rissanen, S.; Szydlowska, N.; Bunker, A.; Kumorek, M.; Jamroz, D.; Vattulainen, I.; Nowakowska, M.; Rog, T.; Kepczynski, M. PEGylated Liposomes as Carriers of Hydrophobic Porphyrins. J. Phys. Chem. B 2015, 119 (22), 6646– 6657, DOI: 10.1021/acs.jpcb.5b01351Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXot1ehsb4%253D&md5=a9e5a30c9db7a692c9d4763501383e52PEGylated Liposomes as Carriers of Hydrophobic PorphyrinsDzieciuch, Monika; Rissanen, Sami; Szydlowska, Natalia; Bunker, Alex; Kumorek, Marta; Jamroz, Dorota; Vattulainen, Ilpo; Nowakowska, Maria; Rog, Tomasz; Kepczynski, MariuszJournal of Physical Chemistry B (2015), 119 (22), 6646-6657CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)Sterically stabilized liposomes (SSLs) (PEGylated liposomes) are applied as effective drug delivery vehicles. Understanding the interactions between hydrophobic compds. and PEGylated membranes is therefore important to det. the effectiveness of PEGylated liposomes for delivery of drugs or other bioactive substances. In this study, we have combined fluorescence quenching anal. (FQA) expts. and all-atom mol. dynamics (MD) simulations to study the effect of membrane PEGylation on the location and orientation of 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (p-THPP) that has been used in our study as a model hydrophobic compd. First, we consider the properties of p-THPP in the presence of different fluid phosphatidylcholine bilayers that we use as model systems for protein-free cell membranes. Next, we studied the interaction between PEGylated membranes and p-THPP. Our MD simulation results indicated that the arrangement of p-THPP within zwitterionic membranes is dependent on their free vol., and p-THPP solubilized in PEGylated liposomes is localized in two preferred positions: deep within the membrane (close to the center of the bilayer) and in the outer PEG corona (p-THPP mols. being wrapped with the polymer chains). Fluorescence quenching methods confirmed the results of atomistic MD simulations and showed two populations of p-THPP mols. as in MD simulations. Our results provide both an explanation for the exptl. observation that PEGylation improves the drug-loading efficiency of membranes and also a more detailed mol.-level description of the interactions between porphyrins and lipid membranes.
- 43Lehtinen, J.; Magarkar, A.; Stepniewski, M.; Hakola, S.; Bergman, M.; Rog, T.; Yliperttula, M.; Urtti, A.; Bunker, A. Analysis of cause of failure of new targeting peptide in PEGylated liposome: molecular modeling as rational design tool for nanomedicine. Eur. J. Pharm. Sci. 2012, 46 (3), 121– 130, DOI: 10.1016/j.ejps.2012.02.009Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktlGktrc%253D&md5=772f08b875910e6a550491218330ef54Analysis of cause of failure of new targeting peptide in PEGylated liposome: Molecular modeling as rational design tool for nanomedicineLehtinen, Julia; Magarkar, Aniket; Stepniewski, Michal; Hakola, Satu; Bergman, Mathias; Rog, Tomasz; Yliperttula, Marjo; Urtti, Arto; Bunker, AlexEuropean Journal of Pharmaceutical Sciences (2012), 46 (3), 121-130CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)Drug nanocarriers are often derivatized with targeting moieties to achieve site specific delivery, however, the results from this approach have, as yet, not reached expectations. We have tested a new phage display based targeting moiety, the activated endothelium targeting peptide (AETP), for its vascular endothelium directed targeting efficiency, when anchored to a PEGylated liposome via maleimide chem. Our results have, however, not shown any evidence of improved targeting. We have hypothesized that the failure of the AETP moiety is due to its availability to target receptors being restricted, as a result of steric hindrance due to the PEG polymer, and possibly affinity for bloodstream proteins, particularly human serum albumin (HSA). In this context, mol. modeling was used to contrast the properties of the AETP moiety to those of the RGD targeting peptide, already found to be effective in previous trials. Our mol. dynamics simulation results indicate the AETP moiety is located within the PEG layer, and its hydrophobic nature causes it to be obscured by PEG to a greater extent than the more hydrophilic RGD targeting peptide. Protein-ligand docking results indicated similar affinities for HSA of both the AETP moiety and a PEG fragment, and a significantly lower affinity for the RGD peptide. We know of no means to investigate this exptl. with at. level resoln., thus our use of computational methods to investigate this can be seen as a new tool for rational design in nanomedicine.
- 44Wagner, A.; Vorauer-Uhl, K. Liposome technology for industrial purposes. Journal of drug delivery 2011, 2011, 1, DOI: 10.1155/2011/591325Google ScholarThere is no corresponding record for this reference.
- 45Sercombe, L.; Veerati, T.; Moheimani, F.; Wu, S. Y.; Sood, A. K.; Hua, S. Advances and Challenges of Liposome Assisted Drug Delivery. Front Pharmacol 2015, 6, 286, DOI: 10.3389/fphar.2015.00286Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlaqsrnE&md5=4a475019a1cae3a07587d47f2fae92a0Advances and challenges of liposome assisted drug deliverySercombe, Lisa; Veerati, Tejaswi; Moheimani, Fatemeh; Wu, Sherry Y.; Sood, Anil K.; Hua, SusanFrontiers in Pharmacology (2015), 6 (), 286/1-286/13CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)The application of liposomes to assist drug delivery has already had a major impact on many biomedical areas. They have been shown to be beneficial for stabilizing therapeutic compds., overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compds. to target sites in vivo. This enables effective delivery of encapsulated compds. to target sites while minimizing systemic toxicity. Liposomes present as an attractive delivery system due to their flexible physicochem. and biophys. properties, which allow easy manipulation to address different delivery considerations. Despite considerable research in the last 50 years and the plethora of pos. results in preclin. studies, the clin. translation of liposome assisted drug delivery platforms has progressed incrementally. In this review, we will discuss the advances in liposome assisted drug delivery, biol. challenges that still remain, and current clin. and exptl. use of liposomes for biomedical applications. The translational obstacles of liposomal technol. will also be presented.
- 46Immordino, M. L.; Dosio, F.; Cattel, L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int. J. Nanomedicine 2006, 1 (3), 297– 315Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtlantb7E&md5=0ecb6e03b94783f06b71f41dc2d1fe78Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potentialImmordino, Maria Laura; Dosio, Franco; Cattel, LuigiInternational Journal of Nanomedicine (2006), 1 (3), 297-315CODEN: IJNNHQ; ISSN:1176-9114. (Dove Medical Press (NZ) Ltd.)A review. Among several promising new drug-delivery systems, liposomes represent an advanced technol. to deliver active mols. to the site of action, and at present several formulations are in clin. use. Research on liposome technol. has progressed from conventional vesicles ("first-generation liposomes") to "second-generation liposomes", in which long-circulating liposomes are obtained by modulating the lipid compn., size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several mols., such as glycolipids or sialic acid. A significant step in the development of long-circulating liposomes came with inclusion of the synthetic polymer poly-(ethylene glycol) (PEG) in liposome compn. The presence of PEG on the surface of the liposomal carrier has been shown to extend blood-circulation time while reducing mononuclear phagocyte system uptake (stealth liposomes). This technol. has resulted in a large no. of liposome formulations encapsulating active mols., with high target efficiency and activity. Further, by synthetic modification of the terminal PEG mol., stealth liposomes can be actively targeted with monoclonal antibodies or ligands. This review focuses on stealth technol. and summarizes pre-clin. and clin. data relating to the principal liposome formulations; it also discusses emerging trends of this promising technol.
- 47Lee, Y.; Thompson, D. H. Stimuli-responsive liposomes for drug delivery. Wiley Interdiscip Rev. Nanomed Nanobiotechnol 2017, 9 (5), e1450, DOI: 10.1002/wnan.1450Google ScholarThere is no corresponding record for this reference.
- 48Ismail, M.; Yang, W.; Li, Y.; Chai, T.; Zhang, D.; Du, Q.; Muhammad, P.; Hanif, S.; Zheng, M.; Shi, B. Targeted liposomes for combined delivery of artesunate and Temozolomide to resistant glioblastoma. Biomaterials 2022, 287, 121608, DOI: 10.1016/j.biomaterials.2022.121608Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsFKjtLbE&md5=a87e39a7b711f4c98d9682c486d8f36aTargeted liposomes for combined delivery of artesunate and temozolomide to resistant glioblastomaIsmail, Muhammad; Yang, Wen; Li, Yanfei; Chai, Tianran; Zhang, Dongya; Du, Qiuli; Muhammad, Pir; Hanif, Sumaira; Zheng, Meng; Shi, BingyangBiomaterials (2022), 287 (), 121608CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)The effective treatment of glioblastoma (GBM) is a great challenge because of the blood-brain barrier (BBB) and the growing resistance to single-agent therapeutics. Targeted combined co-delivery of drugs could circumvent these challenges; however, the absence of more effective combination drug delivery strategies presents a potent barrier. Here, a unique combination ApoE-functionalized liposomal nanoplatform based on artesunate-phosphatidylcholine (ARTPC) encapsulated with temozolomide (ApoE-ARTPC@TMZ) was presented that can successfully co-deliver dual therapeutic agents to TMZ-resistant U251-TR GBM in vivo. Examn. in vitro showed ART-mediated inhibition of DNA repair through the Wnt/β-catenin signaling cascade, which also improved GBM sensitivity to TMZ, resulting in enhanced synergistic DNA damage and induction of apoptosis. In assessing BBB permeation, the targeted liposomes were able to effectively traverse the BBB through low-d. lipoprotein family receptors (LDLRs)-mediated transcytosis and achieved deep intracranial tumor penetration. More importantly, the targeted combination liposomes resulted in a significant decrease of U251-TR glioma burden in vivo that, in concert, substantially improved the survival of mice. Addnl., by lowering the effective dosage of TMZ, the combination liposomes reduced systemic TMZ-induced toxicity, highlighting the preclin. potential of this novel integrative strategy to deliver combination therapies to brain tumors.
- 49Barenholz, Y.; Haran, G. Method of amphophilic drug loading into liposomes by pH gradient, US Patent 1993, 5 192 549.Google ScholarThere is no corresponding record for this reference.Gabizon, A.; Catane, R.; Uziely, B.; Kaufman, B.; Safra, T.; Cohen, R.; Martin, F.; Huang, A.; Barenholz, Y. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene glycol-coated liposomes. Cancer Res. 1994, 54, 987– 992Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXhslegs70%253D&md5=385637397a9a4c1e402f198020ccd74aProlonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene glycol-coated liposomesGabizon, Alberto; Catane, Raphael; Uziely, Beatrice; Kaufman, Bela; Safra, TAmar; Cohen, Rivka; Martin, Francis; Huang, Anthony; Barenholz, YechezkelCancer Research (1994), 54 (4), 987-92CODEN: CNREA8; ISSN:0008-5472.In preclin. studies, a doxorubicin liposome formulation contg. polyethylene glycol (Doxil) shows a long circulation time in plasma, enhanced accumulation in murine tumors, and a superior therapeutic activity over free (unencapsulated) doxorubicin (DOX). The purpose of this study was to characterize the pharmacokinetics of Doxil in cancer patients in comparison with free DOX and examine its accumulation in malignant effusions. The pharmacokinetics of doxorubicin and/or liposome-assocd. doxorubicin were analyzed in seven patients after injections of equiv. doses of free DOX and Doxil and in an addnl. group of nine patients after injection of Doxil only. Two dose levels were examd., 25 and 50 mg/m2. When possible, drug levels were also measured in malignant effusions. The plasma elimination of Doxil followed a biexponential curve with half-lives of 2 and 45 h (median values), most of the dose being cleared from plasma under the longer half-life. Nearly 100% of the drug detected in plasma after Doxil injection was in liposome-encapsulated form. A slow plasma clearance (0.1 L/h for Doxil vs. 45 L/h for free DOX) and a small vol. of distribution (4 L for Doxil vs. 254 L for free DOX) are characteristic of Doxil. Doxorubicin metabolites were detected in the urine of Doxil-treated patients with a pattern similar to that reported for free DOX, although the overall urinary excretion of drug and metabolites was significantly reduced. Doxil treatment resulted in a 4- to 16-fold enhancement of drug levels in malignant effusions, peaking between 3 to 7 days after injection. Stomatitis related to Doxil occurred in 5 of 15 evaluable patients and appears to be the most significant side effect in heavily pretreated patients. The results of this study are consistent with preclin. findings indicating that the pharmacokinetics of doxorubicin are drastically altered using Doxil and follow a pattern dictated by the liposome carrier. The enhanced drug accumulation in malignant effusions is apparently related to liposome longevity in circulation. Further clin. investigation is needed to establish the relevance of these findings with regard to the ability of liposomes to modify the delivery of doxorubicin to solid tumors and its pattern of antitumor activity.
- 50Barenholz, Y. C. Doxil®─The first FDA-approved nano-drug: Lessons learned. Journal of controlled release 2012, 160 (2), 117– 134, DOI: 10.1016/j.jconrel.2012.03.020Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlslSntrw%253D&md5=3e1f7b6cfcbb39e0baf4c99c01676139Doxil - The first FDA-approved nano-drug: Lessons learnedBarenholz, YechezkelJournal of Controlled Release (2012), 160 (2), 117-134CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Doxil, the first FDA-approved nano-drug (1995), is based on three unrelated principles: (i) prolonged drug circulation time and avoidance of the RES due to the use of PEGylated nano-liposomes; (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor; and (iii) having the liposome lipid bilayer in a liq. ordered phase composed of the high-Tm (53 °C) phosphatidylcholine, and cholesterol. Due to the EPR effect, Doxil is passively targeted to tumors and its doxorubicin is released and becomes available to tumor cells by as yet unknown means. This review summarizes historical and scientific perspectives of Doxil development and lessons learned from its development and 20 years of its use. It demonstrates the obligatory need for applying an understanding of the cross talk between physicochem., nano-technol., and biol. principles. However, in spite of the large reward, ~ 2 years after Doxil-related patents expired, there is still no FDA-approved generic Doxil available.
- 51Tadros, T.; Izquierdo, P.; Esquena, J.; Solans, C. Formation and stability of nano-emulsions. Adv. Colloid Interface Sci. 2004, 108–109, 303– 318, DOI: 10.1016/j.cis.2003.10.023Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXivFGmsbw%253D&md5=6ba669d47a247af5f9ec43b213c04c80Formation and stability of nano-emulsionsTadros, Tharwat; Izquierdo, P.; Esquena, J.; Solans, C.Advances in Colloid and Interface Science (2004), 108-109 (), 303-318CODEN: ACISB9; ISSN:0001-8686. (Elsevier Science B.V.)A review. This review describes the principles of formation and stability of nano-emulsions. It starts with an introduction highlighting the main advantages of nano-emulsions over macroemulsions for personal care and cosmetic formulations. It also describes the main problems with lack of progress on nano-emulsions. The 2nd section deals with the mechanism of emulsification and the dynamic light scattering technique for measurement of the droplet size of nano-emulsions. This is followed by a section on methods of emulsification and the role of surfactants. Three methods are described for nano-emulsion prepn., high energy emulsification (using homogenizers), low energy emulsification whereby H2O is added to an oil soln. of the surfactant and the principle of the phase inversion temp. (PIT). A section is devoted to steric stabilization and the role of the adsorbed layer thickness. The problem of Ostwald ripening (which is the main instability process of nano-emulsions) is described. The methods that can be applied to reduce Ostwald ripening are briefly described. This involves the addn. of a 2nd less sol. oil phase such as squalene and/or addn. of a strongly adsorbed and H2O insol. polymeric surfactant. The last part of the review gives some examples of nano-emulsions that are prepd. by the PIT method as well as using high pressure homogenizer. A comparison of the 2 methods is given and the rate of Ostwald ripening is measured in both cases. The effect of changing the alkyl chain length and branching of the oil was studied using decane, dodecane, tetradecane, hexadecane and isohexadecane. The branched oil isohexadcecane showed higher Ostwald ripening rate when compared with a linear chain oil with the same C no.
- 52Gupta, A. Nanoemulsions. In Nanoparticles for Biomedical Applications, Chung, E. J.; Leon, L., Rinaldi, C., Eds.; Elsevier, 2020; Ch. 21, pp 371– 384.Google ScholarThere is no corresponding record for this reference.
- 53Aswathanarayan, J. B.; Vittal, R. R. Nanoemulsions and Their Potential Applications in Food Industry. Frontiers in Sustainable Food Systems 2019, 3, 95, DOI: 10.3389/fsufs.2019.00095Google ScholarThere is no corresponding record for this reference.
- 54Kralova, I.; Sjöblom, J. Surfactants Used in Food Industry: A Review. J. Dispersion Sci. Technol. 2009, 30 (9), 1363– 1383, DOI: 10.1080/01932690902735561Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtF2iu7bE&md5=cbc9022a51b15f7582cac39a38887755Surfactants Used in Food Industry: A ReviewKralova, Iva; Sjoblom, JohanJournal of Dispersion Science and Technology (2009), 30 (9), 1363-1383CODEN: JDTEDS; ISSN:0193-2691. (Taylor & Francis, Inc.)A review. The understanding of the formation, structures, and properties of emulsions is essential to the creation and stabilization of structures in food. The increasing use of surfactants, the identification of compds. with low toxicity and good surface activity properties is of great interest. The relevance of the major end points specified in the Organization for Economic Co-operation and Development (OECD) guidelines for the hazard assessment of food chems. is critically analyzed and main parameters are acute toxicity, subacute repeated studies, allergy, reproductive toxicity, long-term studies, and mutagenicity tests. We focus this article on surfactant assocn. structures and food colloids. There is almost infinite no. of combinations are organized and arranged in very complex internal microstructures with various types of assemblies such as dispersions, emulsions, foams, gels, etc. Low-mass surfactants are very mobile at the interface and they are particularly efficient reducing the interfacial tension. As a result, they rapidly coat the freshly created oil-water interface during emulsification. In this category, we mainly mentioned monoglycerides, lecithins, glycolipids, fatty alcs. and fatty acids. High-mass surfactants cover protein and polysaccharide groups. The protein mol. may interpenetrate in the lipid phase to various degrees. The specific binding is predominantly electrostatic: The headgroups of the surfactants bind to groups of opposite charge on the protein. The satn. binding for anionic surfactants is pH-independent and seems to be controlled by the cooperative hydrophobic interactions. Polysaccharides and smallmol. surfactants are two of the predominant groups of amphiphilic materials that have been explored for the stabilization of emulsions. One of the most important aspects of polymer-surfactant systems is their ability to control stability and rheol. over a wide range of compn. Biocompatible, biodegradable, and/or nontoxic emulsion-based formulations have great potential for applications in the food. The combination of particular characteristics such as emulsifying, anti-adhesive and antimicrobial activities presented by biosurfactants suggests potential application as multipurpose ingredients or additives.
- 55Ikeuchi-Takahashi, Y.; Kobayashi, A.; Ishihara, C.; Matsubara, T.; Matsubara, H.; Onishi, H. Influence of Polysorbate 60 on Formulation Properties and Bioavailability of Morin-Loaded Nanoemulsions with and without Low-Saponification-Degree Polyvinyl Alcohol. Biol. Pharm. Bull. 2018, 41 (5), 754– 760, DOI: 10.1248/bpb.b17-00964Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit12hu7zM&md5=981ac849b4b0f7c4e8239b6140aeea21Influence of polysorbate 60 on formulation properties and bioavailability of morin-loaded nanoemulsions with and without low-saponification-degree polyvinyl alcoholIkeuchi-Takahashi, Yuri; Kobayashi, Ayaka; Ishihara, Chizuko; Matsubara, Takumi; Matsubara, Hiroaki; Onishi, HirakuBiological & Pharmaceutical Bulletin (2018), 41 (5), 754-760CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)The aim of the present study was to investigate the influence of polysorbate 60 (Tween 60) on the development of morin-loaded nanoemulsions to improve the oral bioavailability of morin. Nanoemulsions were prepd. using Tween 60 and polyvinyl alc. (PVA) as emulsifiers, and medium chain triglycerides (MCT) as the lipid base. Low-sapon.-degree PVA (LL-810) was also added to stabilize dispersed droplets. MCT-LL810 nanoemulsion contg. LL-810 was prepd. with a reduced amt. of Tween 60. However, the area under the blood concn.-time curve (AUC) of MCT-LL810 (0.18) nanoemulsion contg. a small amt. of Tween 60 did not increase because the absorption of morin was limited by P-glycoprotein (P-gp)-mediated efflux. MCT-LL810 (0.24) nanoemulsion contg. a large amt. of Tween 60 showed the highest AUC, dispersed droplets contg. Tween 60 may have been transported into epithelial cells in the small intestine, and P-gp transport activity appeared to be suppressed by permeated Tween 60. Based on the plasma concn. profile, dispersed droplets in MCT-LL810 (0.24) nanoemulsion permeated more rapidly through the mucus layer and the intestinal membrane than MCT (0.24) nanoemulsion without LL-810. In conclusion, a novel feature of Tween 60 incorporated into the dispersed droplets of a nanoemulsion interacting with P-gp was demonstrated herein. Dispersed droplets in MCT-LL810 (0.24) nanoemulsion contg. LL-810 permeated rapidly through the mucus layer and intestinal membrane.
- 56Silva, H. D.; Cerqueira, M. A.; Vicente, A. A. Influence of surfactant and processing conditions in the stability of oil-in-water nanoemulsions. Journal of Food Engineering 2015, 167, 89– 98, DOI: 10.1016/j.jfoodeng.2015.07.037Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yhurbL&md5=bf278fb8e838e2ea5101c82518a25ab5Influence of surfactant and processing conditions in the stability of oil-in-water nanoemulsionsSilva, Helder D.; Cerqueira, Miguel A.; Vicente, Antonio A.Journal of Food Engineering (2015), 167 (Part_B), 89-98CODEN: JFOEDH; ISSN:0260-8774. (Elsevier Ltd.)This work evaluates the influence of the type of surfactant (Tween 20, SDS and DTAB) and processing conditions on the stability of oil-in-water nanoemulsions, measured in terms of hydrodynamic diam. (Hd), polydispersity index (PdI) and zeta potential (Zp). Nanoemulsions were prepd. using high-pressure homogenization based on a 24 level factorial design. Results show that processing parameters such as homogenization pressure, surfactant concns. and oil:water ratio significantly affected the values of Hd and PdI of nanoemulsions. The value of Hd of anionic nanoemulsions decreased (from 177 to 128 nm) with the increase of the homogenization pressure. The increase in the surfactant concn. and the decrease of the oil:water ratio lead to a decrease of Hd for the cationic nanoemulsions (from 198 to 135 nm). The increase of the oil:water ratio lead to a decrease of Hd for the non-ionic nanoemulsions (from 341 to 171 nm); this is contrary to the usual assumption that higher content in oil results in higher values of Hd. Those nanoemulsions showed a good kinetic stability (evaluated after centrifugation, heating-cooling cycles and thermal stress) upon measuring the Hd during 28 and 35 days of storage, without visual evidence of creaming and phase sepn. After one year of storage the nanoemulsions produced with the anionic surfactant remained kinetically stable, without visual evidence of creaming and/or phase sepn.
- 57Wilson, R. J.; Li, Y.; Yang, G.; Zhao, C.-X. Nanoemulsions for drug delivery. Particuology 2022, 64, 85– 97, DOI: 10.1016/j.partic.2021.05.009Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsFGhtrvL&md5=3bccb2da3f0c4a77721e57d3a2aeaaabNanoemulsions for drug deliveryWilson, Russell J.; Li, Yang; Yang, Guangze; Zhao, Chun-XiaParticuology (2022), 64 (), 85-97CODEN: PARTC5; ISSN:1674-2001. (Elsevier B.V.)A review. Emulsions are liq.-liq. dispersions with one liq. phase dispersed in the other liq. phase as small droplets. Nanoemulsions are nano-sized emulsions with sizes ranging from tens to hundreds of nanometers, and have great potential applications in pharmaceutics, foods and cosmetics due to their attractive properties, such as small sizes, high surface area per unit vol., improved dispersion of active hydrophobic components and enhanced absorption. The article provides an overview of nanoemulsions for drug delivery, starting with an introduction of emulsion types, nanoemulsion prepn. and nanoemulsion stability. Surfactants play crit. roles in producing and stabilizing nanoemulsions. Different types of surfactants are summarized including small mol. surfactants, particle surfactants, phospholipids, peptide and protein surfactants. Then the applications of nanoemulsions as nanomedicine in drug delivery are presented. Finally, clin. applications of nanoemulsions are discussed.
- 58Ammar, H. O.; Salama, H. A.; Ghorab, M.; Mahmoud, A. A. Development of dorzolamide hydrochloride in situ gel nanoemulsion for ocular delivery. Drug Dev. Ind. Pharm. 2010, 36 (11), 1330– 1339, DOI: 10.3109/03639041003801885Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOit7fJ&md5=ec7686a0719dd178bb4fc0b802430430Development of dorzolamide hydrochloride in situ gel nanoemulsion for ocular deliveryAmmar, H. O.; Salama, H. A.; Ghorab, M.; Mahmoud, A. A.Drug Development and Industrial Pharmacy (2010), 36 (11), 1330-1339CODEN: DDIPD8; ISSN:0363-9045. (Informa Healthcare)Several in situ gel-forming systems were developed to prolong the precorneal residence time of a drug and to improve ocular bioavailability. Poloxamer 407 with its thermoreversible gelation and surface active properties was utilized to formulate a novel dorzolamide hydrochloride in situ gel nanoemulsion (NE) delivery system for ocular use. Improvement of both ocular bioavailability and duration of action for dorzolamide hydrochloride was the aim of this study. Physicochem. properties, in vitro drug release studies and biol. evaluation of the prepd. NEs were investigated. The optimum formulation of in situ gel NE consisted of Triacetin (7.80%), Poloxamer 407 (13.65%), Poloxamer 188 (3.41%), Miranol C2M (4.55%), and water (70.59%). Biol. evaluation of the designed dorzolamide formulation on normotensive albino rabbits indicated that this formulation had better biol. performance, faster onset of action, and prolonged effect relative to either drug soln. or the market product. The formula showed a superior pharmacodynamic activity compared to the in situ gel dorzolamide eye drops. This indicated the effectiveness of the in situ gel properties of poloxamer 407, besides formulating the drug in an NE form for improving the therapeutic efficacy of the drug. These results demonstrate the superiority of in situ gel NE to conventional ocular eye drops and in situ gels to enhance ocular drug bioavailability.
- 59Kumar, M.; Misra, A.; Babbar, A. K.; Mishra, A. K.; Mishra, P.; Pathak, K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int. J. Pharm. 2008, 358 (1–2), 285– 291, DOI: 10.1016/j.ijpharm.2008.03.029Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmsFagur4%253D&md5=87b60eeaa2fd519f4f71c574ca5e1231Intranasal nanoemulsion based brain targeting drug delivery system of risperidoneKumar, Mukesh; Misra, Ambikanandan; Babbar, A. K.; Mishra, A. K.; Mishra, Puspa; Pathak, KamlaInternational Journal of Pharmaceutics (2008), 358 (1-2), 285-291CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)The objective of investigation was to prep. nanoemulsion contg. risperidone (RSP) to accomplish the delivery of drug to the brain via nose. Risperidone nanoemulsion (RNE) and mucoadhesive nanoemulsion (RMNE) were characterized for drug content, pH, percentage transmittance, globule size and zeta potential. Biodistribution of RNE, RMNE, and risperidone soln. (RS) in the brain and blood of Swiss albino rats following intranasal (i.n.) and i.v. administration was examd. using optimized technetium labeled (99mTc-labeled) RSP formulations. Gamma scintigraphy imaging of rat brain following i.v. and i.n. administrations were performed to ascertain the localization of drug in brain. The brain/blood uptake ratio of 0.617, 0.754, 0.948, and 0.054 for RS (i.n.), RNE (i.n.), RMNE (i.n.), and RNE (i.v.), resp., at 0.5 h are indicative of direct nose to brain transport bypassing the blood-brain barrier. Higher drug transport efficiency (DTE%) and direct nose to brain drug transport (direct transport percentage, DTP%) for mucoadhesive nanoemulsions indicated more effective and best brain targeting of RSP amongst the prepd. nanoemulsions. Studies conclusively demonstrated rapid and larger extent of transport of RSP by RMNE (i.n.) when compared to RS (i.n.), RNE (i.n.) and RNE (i.v.) into the rat brain.
- 60Jaiswal, M.; Dudhe, R.; Sharma, P. K. Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech 2015, 5 (2), 123– 127, DOI: 10.1007/s13205-014-0214-0Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czptlGruw%253D%253D&md5=1a5a22e0147feae7a3663c9807035ab5Nanoemulsion: an advanced mode of drug delivery systemJaiswal Manjit; Dudhe Rupesh; Sharma P K3 Biotech (2015), 5 (2), 123-127 ISSN:2190-572X.An advanced mode of drug delivery system has been developed to overcome the major drawbacks associated with conventional drug delivery systems. This review gives a detailed idea about a nanoemulsion system. Nanoemulsions are nano-sized emulsions, which are manufactured for improving the delivery of active pharmaceutical ingredients. These are the thermodynamically stable isotropic system in which two immiscible liquids are mixed to form a single phase by means of an emulsifying agent, i.e., surfactant and co-surfactant. The droplet size of nanoemulsion falls typically in the range 20-200 nm. The main difference between emulsion and nanoemulsion lies in the size and shape of particles dispersed in the continuous phase. In this review, the attention is focused to give a basic idea about its formulation, method of preparation, characterization techniques, evaluation parameters, and various applications of nanoemulsion.
- 61Hormann, K.; Zimmer, A. Drug delivery and drug targeting with parenteral lipid nanoemulsions - A review. J. Controlled Release 2016, 223, 85– 98, DOI: 10.1016/j.jconrel.2015.12.016Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rktlSrsw%253D%253D&md5=a9f37c2797277a39e72c821276c50611Drug delivery and drug targeting with parenteral lipid nanoemulsions - A reviewHormann Karl; Zimmer AndreasJournal of controlled release : official journal of the Controlled Release Society (2016), 223 (), 85-98 ISSN:.Lipid nanosized emulsions or nanoemulsions (NE) are oil in water dispersions with an oil droplet size of about 200nm. This size of oil droplets dispersed in a continuous water phase is a prerequisite for the parenteral, namely intravenous administration. Many parenteral nutrition and drug emulsions on the market confirm the safe use of NE over years. Parenteral emulsions loaded with APIs (active pharmaceutical ingredients) are considered as drug delivery systems (DDS). DDS focuses on the regulation of the in vivo dynamics, such as absorption, distribution, metabolism, and extended bioavailability, thereby improving the effectiveness and the safety of the drugs. Using an emulsion as a DDS, or through the use of surface diversification of the dispersed oil droplets of emulsions, a targeted increase of the API concentration in some parts of the human body can be achieved. This review focuses on NE similar to the marketed once with no or only low amount of additional surfactants beside the emulsifier from a manufacturing point of view (technique, used raw materials).
- 62Pirhadi, S.; Amani, A. Molecular dynamics simulation of self-assembly in a nanoemulsion system. Chemical Papers 2020, 74 (8), 2443– 2448, DOI: 10.1007/s11696-020-01050-3Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXivFOjs78%253D&md5=4d37fc07ae7ad71f34e3e58a2f22040eMolecular dynamics simulation of self-assembly in a nanoemulsion systemPirhadi, Somayeh; Amani, AmirChemical Papers (2020), 74 (8), 2443-2448CODEN: CHPAEG; ISSN:1336-9075. (Springer International Publishing AG)Abstr.: Nanoemulsions can be applied as delivery systems that improve solubilization capacity for poorly sol. drugs, and enhance the drug loading. In this work, a mol. self-assembly of a nanoemulsion composed of benzalkonium chloride as surfactant, cyclohexane as oil phase, and ethanol as co-surfactant in water, was investigated by three 1 micros coarse-grained mol. dynamics simulations. Simulation results showed that the oil mols. placed in the hydrophobic core of the nanoemulsion and made its size larger, while the polar terminal groups of benzalkonium chloride chains dominated the surface. The ethanol co-surfactant mols. distributed throughout the system so that they did not conc. in the hydrophilic shell of the nanoemulsion. After formation of the droplet, it remained stable until the end of the simulation. The nanoemulsion structure was compact and exhibited a prolate ellipsoid shape. The av. value of radius of gyration of the nanoemulsion was 1.68 nm and phys. radius, detd. from the radius of gyration was 2.17 nm.
- 63Pyrhönen, J.; Bansal, K. K.; Bhadane, R.; Wilén, C.-E.; Salo-Ahen, O. M. H.; Rosenholm, J. M. Molecular Dynamics Prediction Verified by Experimental Evaluation of the Solubility of Different Drugs in Poly(decalactone) for the Fabrication of Polymeric Nanoemulsions. Advanced NanoBiomed Research 2022, 2 (1), 2100072, DOI: 10.1002/anbr.202100072Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXis1enu78%253D&md5=d983b55343eca6458def67f2cbe39e0eMolecular Dynamics Prediction Verified by Experimental Evaluation of the Solubility of Different Drugs in Poly(decalactone) for the Fabrication of Polymeric NanoemulsionsPyrhonen, Jasmin; Bansal, Kuldeep K.; Bhadane, Rajendra; Wilen, Carl-Eric; Salo-Ahen, Outi M. H.; Rosenholm, Jessica M.Advanced NanoBiomed Research (2022), 2 (1), 2100072CODEN: ANRDBI; ISSN:2699-9307. (Wiley-VCH Verlag GmbH & Co. KGaA)Nanoemulsions are a rapidly growing drug delivery technol. capable of increasing a drug's aq. soly. and stability. A novel oil-in-water nanoemulsion using a polymer, poly(decalactone) (PDL), instead of a conventional oil was recently reported. The amt. of drug loading in a polymer-based formulation is mainly governed by the drug's soly. in the polymer. Thus, herein the power of mol. dynamics simulations (MDS) for the calcn. of the Hildebrand soly. parameter to predict PDL-drug miscibility is utilized. The MDS results are subsequently verified by formulating a PDL nanoemulsion with a dispersed droplet size of less than 200 nm by using a block copolymer of PDL (mPEG-b-PDL) as a surfactant, with seven different hydrophobic drug mols. The MDS results are consistent with the exptl. findings in terms of increment in the aq. solubilities of the drugs in PDL nanoemulsion, where celecoxib demonstrated the highest while methotrexate exhibited the lowest soly. increment. Consequently, the reported MDS method can be utilized to predict a drug's soly./miscibility in PDL to est. the level of drug loading. The MDS facilitated screening of drugs could consequently emerge as an efficient approach in designing PDL nanoemulsions stabilized by mPEG-b-PDL or other similar systems.
- 64Hong, Z.; Xiao, N.; Li, L.; Xie, X. Investigation of nanoemulsion interfacial properties: A mesoscopic simulation. Journal of Food Engineering 2020, 276, 109877, DOI: 10.1016/j.jfoodeng.2019.109877Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXivV2gtw%253D%253D&md5=e04a62d1fcb4ec5c0d0ffe06273b18c4Investigation of nanoemulsion interfacial properties: A mesoscopic simulationHong, Zehan; Xiao, Nan; Li, Lu; Xie, XinanJournal of Food Engineering (2020), 276 (), 109877CODEN: JFOEDH; ISSN:0260-8774. (Elsevier Ltd.)The interfacial and structural properties of lycopene nanoemulsions stabilized by modified octenyl succinic anhydride (OSA) starch were studied by dissipative particle dynamics (DPD) simulations. These dynamics simulations accurately reproduce nanoemulsion formation from dispersion to aggregation. NMR diffusivity studies provided data that were consistent with the model output, indicating that the model successfully reveals lycopene embedment in the emulsion as well as interactions between lycopene and starch mols., which limit their resp. movements. The interface between the oil and water phases, and emulsifier amphiphilicity, were apparent in the simulation snapshots and OSA starch d. profiles. The simulations and exptl. studies reveal that the emulsifier reduces interfacial tension more effectively within a suitable concn. range. The root mean square (RMS) end-to-end distance and Raman spectroscopic anal. both show that the emulsifiers at the interface are aligned and become more ordered at higher concns. These findings expand our understanding of this nanoemulsion system.
- 65Glotzer, S. C.; Paul, W. Molecular and Mesoscale Simulation Methods for Polymer Materials. Annu. Rev. Mater. Res. 2002, 32 (1), 401– 436, DOI: 10.1146/annurev.matsci.32.010802.112213Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xos1Gju7Y%253D&md5=21bd73dc6fe7e5d0c0854bc6823355c2Molecular and mesoscale simulation methods for polymer materialsGlotzer, Sharon C.; Paul, WolfgangAnnual Review of Materials Research (2002), 32 (), 401-436CODEN: ARMRCU; ISSN:1531-7331. (Annual Reviews Inc.)A review. Polymers offer a wide spectrum of possibilities for materials applications, in part because of the chem. complexity and variability of the constituent mols., and in part because they can be blended together with other org. as well as inorg. components. The majority of applications of polymeric materials is based on their excellent mech. properties, which arise from the long-chain nature of the constituents. Microscopically, this means that polymeric materials are able to respond to external forces in a broad frequency range, i.e., with a broad range of relaxation processes. Computer simulation methods are ideally suited to help to understand these processes and the structural properties that lead to them and to further the ability to predict materials properties and behavior. However, the broad range of timescales and underlying structure prohibits any one single simulation method from capturing all of these processes. This is an overview of some of the more popular computational models and methods used today in the field of mol. and mesoscale simulation of polymeric materials, ranging from mol. models and methods that treat electronic degrees of freedom to mesoscopic field theoretic methods.
- 66Polchi, A.; Magini, A.; Mazuryk, J.; Tancini, B.; Gapinski, J.; Patkowski, A.; Giovagnoli, S.; Emiliani, C. Rapamycin Loaded Solid Lipid Nanoparticles as a New Tool to Deliver mTOR Inhibitors: Formulation and in Vitro Characterization. Nanomaterials (Basel) 2016, 6 (5), 87, DOI: 10.3390/nano6050087Google ScholarThere is no corresponding record for this reference.
- 67Shah, R. M.; Mata, J. P.; Bryant, G.; Campo, L.; Ife, A.; Karpe, A. V.; Jadhav, S. R.; Eldridge, D. S.; Palombo, E. A.; Harding, I. H. Structure Analysis of Solid Lipid Nanoparticles for Drug Delivery: A Combined USANS/SANS Study. Particle & Particle Systems Characterization 2019, 36 (1), 1800359, DOI: 10.1002/ppsc.201800359Google ScholarThere is no corresponding record for this reference.
- 68Duan, Y.; Dhar, A.; Patel, C.; Khimani, M.; Neogi, S.; Sharma, P.; Siva Kumar, N.; Vekariya, R. L. A brief review on solid lipid nanoparticles: part and parcel of contemporary drug delivery systems. RSC Adv. 2020, 10 (45), 26777– 26791, DOI: 10.1039/D0RA03491FGoogle Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVSis7bO&md5=dab88b10bb2d97f6f99bf5be70d5f586A brief review on solid lipid nanoparticles: part and parcel of contemporary drug delivery systemsDuan, Yongtao; Dhar, Abhishek; Patel, Chetan; Khimani, Mehul; Neogi, Swarnali; Sharma, Prolay; Siva Kumar, Nadavala; Vekariya, Rohit L.RSC Advances (2020), 10 (45), 26777-26791CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)A review. Drug delivery technol. has a wide spectrum, which is continuously being upgraded at a stupendous speed. Different fabricated nanoparticles and drugs possessing low soly. and poor pharmacokinetic profiles are the two major substances extensively delivered to target sites. Among the colloidal carriers, nanolipid dispersions (liposomes, deformable liposomes, virosomes, ethosomes, and solid lipid nanoparticles) are ideal delivery systems with the advantages of biodegrdn. and nontoxicity. Among them, nano-structured lipid carriers and solid lipid nanoparticles (SLNs) are dominant, which can be modified to exhibit various advantages, compared to liposomes and polymeric nanoparticles. Nano-structured lipid carriers and SLNs are non-biotoxic since they are biodegradable. Besides, they are highly stable. Their (nano-structured lipid carriers and SLNs) morphol., structural characteristics, ingredients used for prepn., techniques for their prodn., and characterization using various methods are discussed in this review. Also, although nano-structured lipid carriers and SLNs are based on lipids and surfactants, the effect of these two matrixes to build excipients is also discussed together with their pharmacol. significance with novel theranostic approaches, stability and storage.
- 69Geszke-Moritz, M.; Moritz, M. Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies. Mater. Sci. Eng. C Mater. Biol. Appl. 2016, 68, 982– 994, DOI: 10.1016/j.msec.2016.05.119Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xps1yhtb8%253D&md5=bd4d99af06c43580c31c58a977ddd14eSolid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategiesGeszke-Moritz, Malgorzata; Moritz, MichalMaterials Science & Engineering, C: Materials for Biological Applications (2016), 68 (), 982-994CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)This work briefly reviews up-to-date developments in solid lipid nanoparticles (SLNs) as effective nanocolloidal system for drug delivery. It summarizes SLNs in terms of their prepn., surface modification and properties. The application of SLNs as a carrier system enables to improve the therapeutic efficacy of drugs from various therapeutic groups. Present uses of SLNs include cancer therapy, dermatol., bacterial infections, brain targeting and eye disorders among others. The usage of SLNs provides enhanced pharmacokinetic properties and modulated release of drugs. SLN ubiquitous application results from their specific features such as possibility of surface modification, increased permeation through biol. barriers, resistance to chem. degrdn., possibility of co-delivery of various therapeutic agents or stimuli-responsiveness. This paper will be useful to the scientists working in the domain of SLN-based drug delivery systems.
- 70Qiu, S.; Liang, D.; Guo, F.; Deng, T.; Peng, T.; Gao, Y.; Zhang, X.; Zhong, H. Solid lipid nanoparticles modified with amphipathic chitosan derivatives for improved stability in the gastrointestinal tract. Journal of Drug Delivery Science and Technology 2018, 48, 288– 299, DOI: 10.1016/j.jddst.2018.10.007Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFSitbnK&md5=124cae54f083f2cdf277cb0b931d7e5fSolid lipid nanoparticles modified with amphipathic chitosan derivatives for improved stability in the gastrointestinal tractQiu, Suping; Liang, Desheng; Guo, Feng; Deng, Tiantian; Peng, Taoxing; Gao, Yuan; Zhang, Xiuying; Zhong, HaijunJournal of Drug Delivery Science and Technology (2018), 48 (), 288-299CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)In order to reduce enzymic degrdn. and thereby improve the stability of solid lipid nanoparticles (SLNs) in the gastrointestinal tract (GIT), two comb-shaped amphiphilic macromol. materials of N-stearyl-N-trimethyl chitosan (STMC) and N-linoleoyl-N-trimethyl chitosan (LTMC) were fabricated as emulsifier to modify SLNs. Some influence factors of lipolysis medium were investigated to establish in vitro lipolysis model for SLNs. The results showed that the lipolysis curves were fluctuant and variable when the amts. of SLNs were low. The lipolysis of SLNs increased with pancreatic enzyme activity ascending from 150 to 450 USPU/mL and achieved a threshold between 450 and 600 USPU/mL. The lipolysis of STMC-SLNs increased with the initial calcium concn. rising from 0 to 1.4 mM, but had no obvious change from 1.4 to 5 and 10 mM. Besides, SLNs lipolysis increased with bile acid salt and phospholipid concn. increasing. Finally, SLNs stability in GIT was tested with the optimized in vitro lipolysis model. The results revealed that as compared to P188-SLNs and Tween-SLNs, STMC-SLNs lipolysis decreased by 27.33% and 48.55%, and LTMC-SLNs decreased by 22.64% and 43.86%, resp. Besides, the drug pptns. for STMC-SLNs and LTMC-SLNs were significantly decreased. These results demonstrated that both STMC-SLNs and LTMC-SLNs had excellent gastrointestinal stability.
- 71Kuo, Y. C.; Chung, J. F. Physicochemical properties of nevirapine-loaded solid lipid nanoparticles and nanostructured lipid carriers. Colloids Surf. B Biointerfaces 2011, 83 (2), 299– 306, DOI: 10.1016/j.colsurfb.2010.11.037Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnsFSmtQ%253D%253D&md5=65bb1ebbf3b5189721432eae5ead0703Physicochemical properties of nevirapine-loaded solid lipid nanoparticles and nanostructured lipid carriersKuo, Yung-Chih; Chung, Jui-FangColloids and Surfaces, B: Biointerfaces (2011), 83 (2), 299-306CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) coated with human serum albumin (HSA) were fabricated for formulating nevirapine (NVP). Here, NLCs contained low-melting-point oleic acid (OA) in the internal lipid phase. The results revealed that the two nanoparticles were uniformly distributed with the av. diam. ranging from 145 to 180 nm. The surface HSA neutralized the pos. charge of dimethyldioctadecyl ammonium bromide (DODAB) on SLNs and NLCs and reduced their zeta potential. In a fixed ratio of solid lipids, SLNs entrapped more NVP than NLCs. The incorporation of OA also reduced the thermal resistance of NLCs and accelerated the release of NVP from the nanocarriers. When incubated with DODAB-stabilized SLNs, the viability of human brain-microvascular endothelial cells (HBMECs) reduced. However, the surface HSA increased the viability of HBMECs about 10% when the concn. of SLNs was higher than 0.8 mg/mL. HSA-grafted SLNs and NLCs can be effective formulations in the delivery of NVP for viral therapy.
- 72Venishetty, V. K.; Komuravelli, R.; Kuncha, M.; Sistla, R.; Diwan, P. V. Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles. Nanomedicine 2013, 9 (1), 111– 121, DOI: 10.1016/j.nano.2012.03.003Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsFGhsrk%253D&md5=12855a7197fd7edd48dc82ea2c5c00c3Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticlesVenishetty, Vinay Kumar; Komuravelli, Rojarani; Kuncha, Madhusudana; Sistla, Ramakrishna; Diwan, Prakash V.Nanomedicine (New York, NY, United States) (2013), 9 (1), 111-121CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Docetaxel is used in the treatment of many types of cancer, but its entry into the brain is restricted by p-glycoprotein (p-gp) efflux. A potential drug-drug interaction exists between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P 450 system, and ketoconazole can inhibit p-gp efflux of docetaxel at blood brain barrier. Hence, these 2 drugs were loaded in solid lipid nanoparticles (SLNPs) and surface of these NPs were modified with folic acid for brain targeting. These NPs were characterized for particle size, zeta potential, entrapment efficiency, in vitro drug release, cytotoxicity, and cell uptake in brain endothelial cell lines. Plasma and brain pharmacokinetics have shown increased brain uptake of docetaxel with surface-modified dual drug-loaded SLNPs. Brain permeation coeff. (Kin) of folate-grafted docetaxel and ketoconazole loaded SLNPs was 44 times higher than that of Taxotere. Hence, these NPs were suitable for the delivery of lipophilic anticancer drugs to the brain. In this paper, successful delivery of docetaxel and ketoconazole is reported using solid lipid nanoparticles surface modified with folic acid for brain targeting, which may pave the way to optimized clin. applications of lipophilic anticancer drugs to the brain.
- 73Kuo, Y. C.; Liang, C. T. Inhibition of human brain malignant glioblastoma cells using carmustine-loaded catanionic solid lipid nanoparticles with surface anti-epithelial growth factor receptor. Biomaterials 2011, 32 (12), 3340– 3350, DOI: 10.1016/j.biomaterials.2011.01.048Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisVOiurg%253D&md5=29a72a43c14c42827dd75938d6d8946aInhibition of human brain malignant glioblastoma cells using carmustine-loaded catanionic solid lipid nanoparticles with surface anti-epithelial growth factor receptorKuo, Yung-Chih; Liang, Cheng-TeBiomaterials (2011), 32 (12), 3340-3350CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Innovated catanionic solid lipid nanoparticles (CASLNs) carrying carmustine (BCNU) (BCNU-CASLNs) were grafted with anti-epithelial growth factor receptor (EGFR) (anti-EGFR/BCNU-CASLNs) and applied to inhibiting the propagation of human brain malignant glioblastomas cells. U87MG cells were treated with anti-EGFR/BCNU-CASLNs and stained for the expression of EGFR. The minimal av. diam. of BCNU-CASLNs and maximal entrapment efficiency of BCNU emerged when the concn. of catanionic surfactants was 1 mm. An increase in the wt. percentage of cacao butter (CB) reduced the zeta potential, enhanced the viability of human brain microvascular endothelial cells (HBMECs), and decreased the expression of tumor necrosis factor-α by HBMECs. The dissoln. rate of BCNU and inhibition against the multiplication of U87MG cells using anti-EGFR/BCNU-CASLNs followed the order: 100% CB > 0% CB > 50% CB. Anti-EGFR/BCNU-CASLNs demonstrated the properties including an effective delivery to U87MG cells and antiproliferative efficacy against the growth of malignant brain tumors.
- 74Abdel-Mageed, H. M.; Abd El Aziz, A. E.; Mohamed, S. A.; AbuelEzz, N. Z. The tiny big world of solid lipid nanoparticles and nanostructured lipid carriers: an updated review. J. Microencapsul 2022, 39 (1), 72– 94, DOI: 10.1080/02652048.2021.2021307Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XntlCjsA%253D%253D&md5=abc2a027769e0cb2ef2728ca9af21f43The tiny big world of solid lipid nanoparticles and nanostructured lipid carriers: an updated reviewAbdel-Mageed, Heidi M.; Abd El Aziz, Amira E.; Mohamed, Saleh A.; AbuelEzz, Nermeen Z.Journal of Microencapsulation (2022), 39 (1), 72-94CODEN: JOMIEF; ISSN:0265-2048. (Taylor & Francis Ltd.)A review. Nanotechnol. is currently a field of endeavour that has reached a maturation phase beyond the initial hypotheses with an undercurrent challenge to optimize the safety, and scalability for prodn. and clin. trials. Lipid-based nanoparticles (LNP), namely solid lipid nanoparticles (SLN) and nanostructured lipid (NLC), carriers are presently among the most attractive and fast-growing areas of research. SLN and NLC are safe, biocompatible nanotechnol.-enabled platforms with ubiquitous applications. This review presents a modern vision that starts with a brief description of characteristics, prepn. strategies, and compn. ingredients, benefits, and limitations. Next, a discussion of applications and functionalization approaches for the delivery of therapeutics via different routes of delivery. Addnl., the review presents a concise perspective into limitations and future advances. A brief recap on the prospects of mol. dynamics simulations in better understanding NP bio-interface interactions is provided. Finally, the alliance between 3D printing and nanomaterials is presented here as well.
- 75Hathout, R. M.; Metwally, A. A. Towards better modelling of drug-loading in solid lipid nanoparticles: Molecular dynamics, docking experiments and Gaussian Processes machine learning. Eur. J. Pharm. Biopharm 2016, 108, 262– 268, DOI: 10.1016/j.ejpb.2016.07.019Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1ymtL7P&md5=e32e697c70ab5e346af70c1383ccc254Towards better modelling of drug-loading in solid lipid nanoparticles: Molecular dynamics, docking experiments and Gaussian Processes machine learningHathout, Rania M.; Metwally, Abdelkader A.European Journal of Pharmaceutics and Biopharmaceutics (2016), 108 (), 262-268CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)This study represents one of the series applying computer-oriented processes and tools in digging for information, analyzing data and finally extg. correlations and meaningful outcomes. In this context, binding energies could be used to model and predict the mass of loaded drugs in solid lipid nanoparticles after mol. docking of literature-gathered drugs using MOE software package on molecularly simulated tripalmitin matrixes using GROMACS. Consequently, Gaussian processes as a supervised machine learning artificial intelligence technique were used to correlate the drugs' descriptors (e.g. M.W., x Log P, TPSA and fragment complexity) with their mol. docking binding energies. Lower percentage bias was obtained compared to previous studies which allows the accurate estn. of the loaded mass of any drug in the investigated solid lipid nanoparticles by just projecting its chem. structure to its main features (descriptors).
- 76Pink, D. L.; Loruthai, O.; Ziolek, R. M.; Wasutrasawat, P.; Terry, A. E.; Lawrence, M. J.; Lorenz, C. D. On the Structure of Solid Lipid Nanoparticles. Small 2019, 15 (45), e1903156 DOI: 10.1002/smll.201903156Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVWktrfJ&md5=d8303a7b0638f6e1037ccf41ca1d5ea3On the structure of solid lipid nanoparticlesPink, Demi L.; Loruthai, Orathai; Ziolek, Robert M.; Wasutrasawat, Prawarisa; Terry, Ann E.; Lawrence, M. Jayne; Lorenz, Christian D.Small (2019), 15 (45), 1903156CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)Solid lipid nanoparticles (SLNs) have a cryst. lipid core which is stabilized by interfacial surfactants. SLNs are considered favorable candidates for drug delivery vehicles since their ability to store and release org. mols. can be tailored through the identity of the lipids and surfactants used. When stored, polymorphic transitions in the core of drug-loaded SLNs lead to the premature release of drug mols. Significant exptl. studies have been conducted with the aim of investigating the physicochem. properties of SLNs, however, no mol. scale investigations have been reported on the behaviors that drive SLN formation and their polymorphic transitions. A combination of small angle neutron scattering and all-atom mol. dynamics simulations is therefore used to yield a detailed atomistic description of the internal structure of an SLN comprising triglyceride, tripalmitin, and the nonionic surfactant, Brij O10 (C18:1E10). The mol. scale mechanisms by which the surfactants stabilize the cryst. structure of the SLN lipid core are uncovered. By comparing these results to simulated liq. and solid aggregates of tripalmitin lipids, how the morphol. of the lipids vary between these systems is demonstrated providing further insight into the mechanisms that control drug encapsulation and release from SLNs.
- 77Gastaldi, L.; Battaglia, L.; Peira, E.; Chirio, D.; Muntoni, E.; Solazzi, I.; Gallarate, M.; Dosio, F. Solid lipid nanoparticles as vehicles of drugs to the brain: current state of the art. Eur. J. Pharm. Biopharm 2014, 87 (3), 433– 444, DOI: 10.1016/j.ejpb.2014.05.004Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXos1Gks7Y%253D&md5=5b8f0e54ccebc6b1d64f089826a16685Solid lipid nanoparticles as vehicles of drugs to the brain: Current state of the artGastaldi, Lucia; Battaglia, Luigi; Peira, Elena; Chirio, Daniela; Muntoni, Elisabetta; Solazzi, Ilaria; Gallarate, Marina; Dosio, FrancoEuropean Journal of Pharmaceutics and Biopharmaceutics (2014), 87 (3), 433-444CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)A review. Central nervous system disorders are already prevalent and steadily increasing among populations worldwide. However, most of the pharmaceuticals present on world markets are ineffective in treating cerebral diseases, because they cannot effectively cross the blood brain barrier (BBB). Solid lipid nanoparticles (SLN) are nanospheres made from biocompatible solid lipids, with unique advantages among drug carriers: they can be used as vehicles to cross the BBB. This review examines the main aspects surrounding brain delivery with SLN, and illustrates the principal mechanisms used to enhance brain uptake of the delivered drug.
- 78Soares, S.; Fonte, P.; Costa, A.; Andrade, J.; Seabra, V.; Ferreira, D.; Reis, S.; Sarmento, B. Effect of freeze-drying, cryoprotectants and storage conditions on the stability of secondary structure of insulin-loaded solid lipid nanoparticles. Int. J. Pharm. 2013, 456 (2), 370– 381, DOI: 10.1016/j.ijpharm.2013.08.076Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFWmtLbO&md5=7d276a4570972f7cfd97c69ec14b226fEffect of freeze-drying, cryoprotectants and storage conditions on the stability of secondary structure of insulin-loaded solid lipid nanoparticlesSoares, Sandra; Fonte, Pedro; Costa, Ana; Andrade, Jose; Seabra, Vitor; Ferreira, Domingos; Reis, Salette; Sarmento, BrunoInternational Journal of Pharmaceutics (Amsterdam, Netherlands) (2013), 456 (2), 370-381CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)This study aims to monitor the secondary structure behavior of insulin when it is encapsulated into solid lipid nanoparticles (SLN), under the influence of several crit. processing parameters. Insulin was used as a therapeutic protein model. Physicochem. properties of insulin-loaded SLN (Ins-SLN) were assessed, with special focus on the insulin secondary structure after its encapsulation into SLN and after freeze-drying using different cryoprotectants (glucose, fructose and sorbitol). Addnl., a 6-mo stability study was performed to evaluate the maintenance of insulin secondary structure over time at different storage conditions (4 °C/60% RH, 25 °C/60% RH, 40 °C/75% RH). Ins-SLN were successfully produced with a mean and narrow particle size around 400 nm, zeta potential around -13 mV, an insulin assocn. efficiency of 84%. Phys.-chem. properties of SLN were maintained after freeze-drying. FTIR results showed that encapsulated insulin maintained a native-like structure in a degree of similarity around 92% after prodn., and 84% after freeze-drying. After 6 mo, freeze-dried Ins-SLN without cryoprotectant stored at 40 °C/75% RH presented the same degree of structure preservation and morphol. Results revealed that insulin structure can be significantly protected by SLN matrix itself, without a cryoprotectant agent, even using a non-optimized freeze-drying process, and under the harsher storage conditions. Multivariable exptl. settled the process parameters to fit with the desired product quality attributes regarding protein and nanoparticle stability.
- 79Mehnert, W.; Mäder, K. Solid lipid nanoparticles: production, characterization and applications. Adv. Drug Deliv Rev. 2001, 47 (2–3), 165– 196, DOI: 10.1016/S0169-409X(01)00105-3Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXislGls7g%253D&md5=bfaa2c8fd57ef944188ee342a7374ac7Solid lipid nanoparticles. Production, characterization and applicationsMehnert, W.; Mader, K.Advanced Drug Delivery Reviews (2001), 47 (2-3), 165-196CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)A review with 195 refs. Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN prodn. and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liq. crystals) and the phys. state of the lipid (supercooled melts, different lipid modifications). Appropriate anal. methods are needed for the characterization of SLN. The use of several anal. techniques is a necessity. Alternative structures and dynamic phenomena on the mol. level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.
- 80Shegokar, R.; Singh, K. K.; Muller, R. H. Production & stability of stavudine solid lipid nanoparticles-from lab to industrial scale. Int. J. Pharm. 2011, 416 (2), 461– 470, DOI: 10.1016/j.ijpharm.2010.08.014Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVSqsLfM&md5=02376b016d00305eeaa55f34eda4aa12Production & stability of stavudine solid lipid nanoparticles-From lab to industrial scaleShegokar, R.; Singh, K. K.; Mueller, R. H.International Journal of Pharmaceutics (2011), 416 (2), 461-470CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)The prodn. of stavudine-loaded solid lipid nanoparticles (SLN) for i.v. injection was scaled up from lab scale (40 g) to medium scale (10 kg) and large scale (20/60 kg). The SLN were produced by high pressure homogenization of stavudine lipid melt dispersed in hot surfactant soln. (pre-emulsion) applying 800 bar pressure. Employed were piston-gap homogenizers with increasing capacity (APV Gaulin products LAB 40, LAB 60 and Gaulin 5.5, and Avestin C50), using them in the continuous (circulation) and discontinuous mode. Size anal. was performed by photon correlation spectroscopy (PCS), laser diffractometry and light microscopy. At lab scale a PCS size of 53 nm was obtained. At the same pressure, all homogenizers on larger scale yielded a size in the range of the lab scale product (35-70 nm). Differences were found in the size as a function of circulation time (size increase or size redn. with time) and the no. of cycles required (1 or 5) for the optimal product. The stavudine SLN formulation (2% lipid content, high surfactant to lipid ratio) showed a different behavior to conventional higher concd. SLN suspensions or nanoemulsions (10% or 20% lipid/oil, low surfactant to lipid ratio). In general, smallest sizes were obtained in the discontinuous mode after just one homogenization cycle. The continuous prodn. mode was only efficient with a 10 kg batch size using the LAB 60. In addn., the long-term stability over 1 yr was monitored at refrigeration, room temp. and at 40° to assess a potential effect of the homogenizer type on stability. All batches at room temp. and below were stable, only a negligible increase in size was obsd.
- 81Farhood, H.; Gao, X.; Son, K.; Yang, Y. Y.; Lazo, J. S.; Huang, L.; Barsoum, J.; Bottega, R.; Epand, R. M. Cationic liposomes for direct gene transfer in therapy of cancer and other diseases. Ann. N.Y. Acad. Sci. 1994, 716, 23– 34, discussion 34–25 DOI: 10.1111/j.1749-6632.1994.tb21701.xGoogle Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmslSrurk%253D&md5=03f357282c1dbd19dfe656c60df2e5eeCationic liposomes for direct gene transfer in therapy of cancer and other diseasesFarhood, Hassan; Gao, Xiang; Son, Kyonghee; Yang, Ya-Yun; Lazo, John S.; Huang, Leaf; Barsoum, James; Bottega, Remo; Epand, Richard M.Annals of the New York Academy of Sciences (1994), 716 (GENE THERAPY FOR NEOPLASTIC DISEASES), 23-35CODEN: ANYAA9; ISSN:0077-8923.A review with 29 refs. Efficiency of gene delivery, decrease in the toxicity of DNA carrier, gene therapy of cis-platin-resistant tumors and the use of cationic liposomes for treatment of malignant tumors in an immunotherapy approach are discussed.
- 82Araujo, V. H. S.; Delello Di Filippo, L.; Duarte, J. L.; Spósito, L.; Camargo, B. A. F.; da Silva, P. B.; Chorilli, M. Exploiting solid lipid nanoparticles and nanostructured lipid carriers for drug delivery against cutaneous fungal infections. Crit Rev. Microbiol 2021, 47 (1), 79– 90, DOI: 10.1080/1040841X.2020.1843399Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1yjt7jK&md5=a8c6f491b85b684a22c4ba8633becea1Exploiting solid lipid nanoparticles and nanostructured lipid carriers for drug delivery against cutaneous fungal infectionsAraujo, Victor Hugo Sousa; Delello Di Filippo, Leonardo; Duarte, Jonatas Lobado; Sposito, Larissa; Camargo, Bruna Almeida Furquim de; da Silva, Patricia Bento; Chorilli, MarlusCritical Reviews in Microbiology (2021), 47 (1), 79-90CODEN: CRVMAC; ISSN:1040-841X. (Taylor & Francis Ltd.)Several types of cutaneous fungal infections can affect the population worldwide, such as dermatophytosis, cutaneous candidiasis, onychomycosis, and sporotrichosis. However, oral treatments have pronounced adverse effects, making the topical route an alternative to avoid this disadvantage. On the other hand, currently available pharmaceutical forms designed for topical application, such as gels and creams, do not demonstrate effective retention of biomols. in the upper layers of the skin. An interesting approach to optimize biomols.' activity in the skin is the use of nanosystems for drug delivery, esp. solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), which in the past decade has shown advantages like increased adhesiveness, great occlusive properties and higher biomol. deposition in stratum corneum when designed for topical application. Considering the demand for more effective therapeutic alternatives and the promising characteristics of SLN and NLC for topical application, the present study sought to gather studies that investigated the potential of using SLN and NLC for the treatment of cutaneous fungal infections. Studies demonstrated that these nanosystems showed optimization, mostly, of the effectiveness of biomols. besides other biopharmaceutical properties, in addn. to offering potential occlusion and hydration of the applied region.
- 83Hao, J.; Wang, F.; Wang, X.; Zhang, D.; Bi, Y.; Gao, Y.; Zhao, X.; Zhang, Q. Development and optimization of baicalin-loaded solid lipid nanoparticles prepared by coacervation method using central composite design. Eur. J. Pharm. Sci. 2012, 47 (2), 497– 505, DOI: 10.1016/j.ejps.2012.07.006Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1Kku7zP&md5=bb30a8f0c7331472fd39e09862359902Development and optimization of baicalin-loaded solid lipid nanoparticles prepared by coacervation method using central composite designHao, Jifu; Wang, Fugang; Wang, Xiaodan; Zhang, Dianrui; Bi, Yanping; Gao, Yunsheng; Zhao, Xuemei; Zhang, QiangEuropean Journal of Pharmaceutical Sciences (2012), 47 (2), 497-505CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)The objective of this study was to design and optimize a novel baicalin-loaded solid lipid nanoparticles (SLNs) carrier system composed of a stearic acid alk. salt as lipid matrix and prepd. as per the coacervation method in which fatty acids pptd. from their sodium salt micelles in the presence of polymeric nonionic surfactants. A 2-factor 5-level central composite design (CCD) was introduced to perform the expts. A quadratic polynomial model was generated to predict and evaluate the independent variables with respect to the dependent variables. The compn. of optimal formulation was detd. as 0.69% (w/v) lipid and 26.64% (wt./wt.) drug/lipid ratio. The results showed that the optimal formulation of baicalin-loaded SLN had entrapment efficiency (EE) of 88.29%, particle size of 347.3 nm and polydispersity index (PDI) of 0.169. The morphol. of nanoparticles was found to be nearly spherical in shape by SEM observation. The differential scanning calorimetry (DSC) anal. indicated that the drug incorporated into SLN was not in an amorphous form but in a cryst. state. The Cmax, MRT, AUMC0→(infinity symbol) and AUC0→infinity symbol) values of SLN were approx. 1.6-fold, 1.9-fold, 5.0-fold and 2.6-fold greater than that of ref. prepn., resp.
- 84Badawi, N.; El-Say, K.; Attia, D.; El-Nabarawi, M.; Elmazar, M.; Teaima, M. Development of Pomegranate Extract-Loaded Solid Lipid Nanoparticles: Quality by Design Approach to Screen the Variables Affecting the Quality Attributes and Characterization. ACS Omega 2020, 5 (34), 21712– 21721, DOI: 10.1021/acsomega.0c02618Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsF2msr3J&md5=9d3a442d1a103ef3be014bc2152c8bd5Development of Pomegranate Extract-Loaded Solid Lipid Nanoparticles: Quality by Design Approach to Screen the Variables Affecting the Quality Attributes and CharacterizationBadawi, Noha; El-Say, Khalid; Attia, Dalia; El-Nabarawi, Mohamed; Elmazar, Mohey; Teaima, MahmoudACS Omega (2020), 5 (34), 21712-21721CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)The aim of this work was to study the influence of process variables on the quality attributes of pomegranate ext. loaded solid lipid nanoparticles (PE-SLNs) using Plackett-Burman design. PE-SLN formulations were prepd. by hot homogenization followed by ultra-sonication technique and evaluated based on the dependent variables that were analyzed utilizing Statgraphics Centurion XV software. The lipid and surfactant (type and concn.), co-surfactant concn., sonication time, and amplitude were selected as the independent variables (X1-X7). The dependent parameters were particle size, polydispersity index, zeta potential, entrapment efficiency, and cumulative drug release (Y1-Y5). Response surface plots, Pareto charts, and math. equations were generated to study the influence of independent variables on the dependent quality parameters. Out of seven variables, X1, X2, and X6 have the main significant (p value < 0.05) effect on the entrapment efficiency, the cumulative drug release, the polydispersity index, resp., while particle size was mainly affected by X3, X6 and zeta potential by X1, X3, and X4. Consequently, this screening study revealed that stearic acid as lipid, Tween 80 as surfactant, as well as sonication with short time and high amplitude can be selected for the development of PE-SLN formulation with min. particle size, max. zeta potential, highest entrapment, and sustained drug release behavior. Meanwhile, concns. of lipid, surfactant, and co-surfactant are planned to be scaled up for further optimization study. In conclusion, the Plackett-Burman design verified its influence and significance in detg. and understanding both process and formulation variables affecting the quality of PE-SLNs.
- 85Ostrosky-Zeichner, L.; Marr, K. A.; Rex, J. H.; Cohen, S. H. Amphotericin B: Time for a New ″Gold Standard″. Clin. Infect. Dis. 2003, 37 (3), 415, DOI: 10.1086/376634Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1yktLc%253D&md5=43f208c366ac0f4d5e4e6b6e0f8f226cAmphotericin B: time for a new "gold standard"Ostrosky-Zeichner, Luis; Marr, Kieren A.; Rex, John H.; Cohen, Stuart H.Clinical Infectious Diseases (2003), 37 (3), 415-425CODEN: CIDIEL; ISSN:1058-4838. (University of Chicago Press)A review. When introduced in 1959, amphotericin B deoxycholate (AmBD) was clearly a life-saving drug. Randomized studies demonstrating its efficacy were not thought to be necessary, and it was granted indications for many invasive fungal infections. Despite its formidable toxicities, AmBD is thus often used as the primary comparator in studies of invasive fungal infections. Safer lipid-based versions of amphotericin B (AmB) have been introduced, but difficulties with studying these agents generally led to licensure for salvage therapy, not primary therapy. However, the cumulative clin. experience to date with the lipid-based prepns. is now adequate to demonstrate that these agents are no less active than AmBD, and, for some infections, it can now be stated that specific lipid-based prepns. of AmB are superior to AmBD. Given their superior safety profiles, these prepns. can now be considered suitable replacements for AmBD for primary therapy for many invasive fungal infections in clin. practice and research.
- 86FDA approves DaunoXome as first-line therapy for Kaposi’s sarcoma. Food and Drug Administration. J. Int. Assoc Physicians AIDS Care 1996, 2 (5), 50– 51.Google ScholarThere is no corresponding record for this reference.
- 87Guo, P.; Hsu, T. M.; Zhao, Y.; Martin, C. R.; Zare, R. N. Preparing amorphous hydrophobic drug nanoparticles by nanoporous membrane extrusion. Nanomedicine (Lond) 2013, 8 (3), 333– 341, DOI: 10.2217/nnm.12.119Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjslKhs7k%253D&md5=e54efa26bf30b5456dcbeca18a6b3c00Preparing amorphous hydrophobic drug nanoparticles by nanoporous membrane extrusionGuo, Peng; Hsu, Tammy M.; Zhao, Yaping; Martin, Charles R.; Zare, Richard N.Nanomedicine (London, United Kingdom) (2013), 8 (3), 333-341CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)The aim of the present study was to develop a simple and straightforward method for formulating hydrophobic drugs into nanoparticulate form in a scalable and inexpensive manner. The nanoporous membrane extrusion (NME) method was used to prep. hydrophobic drug nanoparticles. NME is based on the induced pptn. of drug-loaded nanoparticles at the exits of nanopores. Three common hydrophobic drug models (silymarin, β-carotene and butylated hydroxytoluene) were tested. The authors carefully investigated the morphol., crystallinity and dissoln. profile of the resulting nanoparticles. Using NME, the authors successfully prepd. rather uniform drug nanoparticles (∼100 nm in diam.). These nanoparticles were amorphous and show an improved dissoln. profile compared with untreated drug powders. These studies suggest that NME could be used as a general method to produce nanoparticles of hydrophobic drugs. Original submitted 8 June 2011; Revised submitted 7 May 2012; Published online 3 Sept. 2012.
- 88FDA Fast Track Designation for Myocet for Metastatic Breast Cancer. Oncology Times 2010, 32 (3), 24. DOI: 10.1097/01.COT.0000368457.66658.a6Google ScholarThere is no corresponding record for this reference.
- 89FDA Approves Onivyde Combo Regimen for Advanced Pancreatic Cancer. Oncology Times 2015, 37 (22), 8. DOI: 10.1097/01.COT.0000475247.29686.b2Google ScholarThere is no corresponding record for this reference.
- 90Venkatakrishnan, K.; Liu, Y.; Noe, D.; Mertz, J.; Bargfrede, M.; Marbury, T.; Farbakhsh, K.; Oliva, C.; Milton, A. Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment. Br. J. Clin. Pharmacol. 2014, 77 (6), 998– 1010, DOI: 10.1111/bcp.12261Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXos1agsbc%253D&md5=a2e3b1c95edd18abbd4418db93f8d38bPharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairmentVenkatakrishnan, Karthik; Liu, Yi; Noe, Dennis; Mertz, Jaime; Bargfrede, Michael; Marbury, Thomas; Farbakhsh, Kambiz; Oliva, Cristina; Milton, AshleyBritish Journal of Clinical Pharmacology (2014), 77 (6), 998-1010CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Aims : To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, wt.- and sex-matched healthy subjects with normal hepatic function. Methods : Subjects received a 4 mg dose of liposomal mifamurtide via 1 h i.v. infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumor necrosis factor-α and C-reactive protein). Results : Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6-132%) and 119% (90% confidence interval, 94.1-151%), resp., which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumor necrosis factor-α concns. were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered mifamurtide (4 mg). Conclusions : These results support the conclusion that mild or moderate hepatic impairment does not produce clin. meaningful effects on the clin. pharmacokinetics or pharmacodynamics of mifamurtide; no dose modifications are needed in these special patient populations based on clin. pharmacol. considerations.
- 91Galmarini, C. M.; Mackey, J. R.; Dumontet, C. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol 2002, 3 (7), 415– 424, DOI: 10.1016/S1470-2045(02)00788-XGoogle Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xls1Wisrw%253D&md5=605a00f19023e972fdc7b9fd2b0381bbNucleoside analogues and nucleobases in cancer treatmentGalmarini, Carlos M.; Mackey, John R.; Dumontet, CharlesLancet Oncology (2002), 3 (7), 415-424CODEN: LOANBN; ISSN:1470-2045. (Lancet Publishing Group)A review. Cytotoxic nucleoside analogs and nucleobases were among the first chemotherapeutic agents to be introduced for the medical treatment of cancer. This family of compds. has grown to include a variety of purine and pyrimidine nucleoside derivs. with activity in both solid tumors and malignant disorders of the blood. These agents behave as antimetabolites, compete with physiol. nucleosides, and interact with a large no. of intracellular targets to induce cytotoxicity. Progress has recently been made in the identification and characterization of nucleoside transporters and the enzymes of nucleoside metab. In addn., there is now greater understanding of the mol. mechanisms of anticancer nucleoside activity, which provides opportunities for potentiating their antitumor effects. Strategies to optimize intracellular analog accumulation and to enhance cancer-cell selectivity are proving beneficial in clin. trials.
- 92O’Brien, S.; Schiller, G.; Lister, J.; Damon, L.; Goldberg, S.; Aulitzky, W.; Ben-Yehuda, D.; Stock, W.; Coutre, S.; Douer, D. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J. Clin Oncol 2013, 31 (6), 676– 683, DOI: 10.1200/JCO.2012.46.2309Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVGmtbg%253D&md5=114161a66b2efb6bf463752ec7bff04dHigh-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemiaO'Brien, Susan; Schiller, Gary; Lister, John; Damon, Lloyd; Goldberg, Stuart; Aulitzky, Walter; Ben-Yehuda, Dina; Stock, Wendy; Coutre, Steven; Douer, Dan; Heffner, Leonard T.; Larson, Melissa; Seiter, Karen; Smith, Scott; Assouline, Sarit; Kuriakose, Philip; Maness, Lori; Nagler, Arnon; Rowe, Jacob; Schaich, Markus; Shpilberg, Ofer; Yee, Karen; Schmeider, Guenter; Silverman, Jeffrey A.; Thomas, Deborah; Deitcher, Steven R.; Kantarjian, HagopJournal of Clinical Oncology (2013), 31 (6), 676-683CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Relapsed adult acute lymphoblastic leukemia (ALL) is assocd. with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -neg. ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Patients and Methods Sixty-five adults with Ph-neg. ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. I.v. VSLI 2.25 mg/m2, without dose capping, was administered once per wk until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematol. recovery (CRi). Results The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 wk (range, 5 to 66 wk); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and assocd. with a low 30-day mortality rate (12%). Conclusion High-dose VSLI monotherapy resulted in meaningful clin. outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to std. VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.
- 93Berger, N.; Sachse, A.; Bender, J.; Schubert, R.; Brandl, M. Filter extrusion of liposomes using different devices: comparison of liposome size, encapsulation efficiency, and process characteristics. Int. J. Pharm. 2001, 223 (1–2), 55– 68, DOI: 10.1016/S0378-5173(01)00721-9Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXkvFynsr4%253D&md5=17211f68779121aa8414deb64139aec9Filter extrusion of liposomes using different devices: comparison of liposome size, encapsulation efficiency, and process characteristicsBerger, N.; Sachse, A.; Bender, J.; Schubert, R.; Brandl, M.International Journal of Pharmaceutics (2001), 223 (1-2), 55-68CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)Liposomes were prepd. by stepwise extrusion through 5, 1, 0.4, 0.2, 0.1 and 0.05 μm pore sizes using two different filter-extruders, the continuous high pressure device Dispex Maximato (CE) or alternatively the discontinuous Avestin LiposoFast (DE). The liposome dispersions obtained were compared in terms of particle size, lamellarity and encapsulation efficiency of calcein. The liposomes were smaller with CE than DE at all stages due to higher flow rates and pressure drops, except for final filter pore size (0.05 μm) where both prepns. had similar sizes. The particle size anal. technique itself had a strong influence on the liposome sizes measured. For bigger liposomes (extruded through 0.4 μm filters) the Nicomp 370 revealed bigger vol.-based mean particle sizes along with more stringent differences between vol.-based and no.-based diams. than the Malvern Zetasizer. In contrast, for small liposomes extruded through 0.05 μm filters, similar liposome sizes were found no matter which of the two PCS techniques or cryo-TEM was used. In congruence to the liposome sizes measured, encapsulation efficiencies were smaller for CE than DE at all filter stages except the final (0.05 μm). No lipid loss occurred and lysophosphatidylcholine formation was negligible irresp. of which extrusion technique was used.
- 94Gradishar, W. J.; Tjulandin, S.; Davidson, N.; Shaw, H.; Desai, N.; Bhar, P.; Hawkins, M.; O’Shaughnessy, J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J. Clin Oncol 2005, 23 (31), 7794– 7803, DOI: 10.1200/JCO.2005.04.937Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1Cqs7nK&md5=c8a43467ef442663d22e169364f717c4Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancerGradishar, William J.; Tjulandin, Sergei; Davidson, Neville; Shaw, Heather; Desai, Neil; Bhar, Paul; Hawkins, Michael; O'Shaughnessy, JoyceJournal of Clinical Oncology (2005), 23 (31), 7794-7803CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Purpose: ABI-007, the first biol. interactive albumin-bound paclitaxel in a nanometer particle, free of solvents, was compared with polyethylated castor oil-based std. paclitaxel in patients with metastatic breast cancer (MBC). This phase III study was performed to confirm preclin. studies demonstrating superior efficacy and reduced toxicity of ABI-007 compared with std. paclitaxel. Patients and Methods: Patients were randomly assigned to 3-wk cycles of either ABI-007 260 mg/m2 i.v. without premedication (n = 229) or std. paclitaxel 175 mg/m2 i.v. with premedication (n = 225). Results: ABI-007 demonstrated significantly higher response rates compared with std. paclitaxel (33% v 19%, resp.; P = .001) and significantly longer time to tumor progression (23.0 v 16.9 wk, resp.; hazard ratio = 0.75; P = .006). The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with std. paclitaxel (9% v 22%, resp.; P < .001) despite a 49% higher paclitaxel dose. Febrile neutropenia was uncommon (< 2%), and the incidence did not differ between the two study arms. Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the std. paclitaxel arm (10% v 2%, resp.; P < .001) but was easily managed and improved rapidly (median, 22 days). No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time. Conclusion: ABI-007 demonstrated greater efficacy and a favorable safety profile compared with std. paclitaxel in this patient population. The improved therapeutic index and elimination of corticosteroid premedication required for solvent-based taxanes make the novel albumin-bound paclitaxel ABI-007 an important advance in the treatment of MBC.
- 95Yardley, D. A. nab-Paclitaxel mechanisms of action and delivery. J. Controlled Release 2013, 170 (3), 365– 372, DOI: 10.1016/j.jconrel.2013.05.041Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ems7vO&md5=57303f72f8914a2ee07428d2a530b196nab-Paclitaxel mechanisms of action and deliveryYardley, Denise A.Journal of Controlled Release (2013), 170 (3), 365-372CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Taxanes are a key chemotherapy component for several malignancies, including metastatic breast cancer (MBC), ovarian cancer, and advanced non-small cell lung cancer (NSCLC). Despite the clin. benefit achieved with solvent-based (sb) taxanes, these agents can be assocd. with significant and severe toxicities. Albumin-bound paclitaxel (Abraxane; nab-Paclitaxel), a novel solvent-free taxane, has demonstrated higher response rates and improved tolerability when compared with solvent-based formulations in patients with advanced MBC and NSCLC. The technol. used to create nab-paclitaxel utilizes albumin to deliver paclitaxel, resulting in an advantageous pharmacokinetic (PK) profile. This review discusses the proposed mechanism of delivery of nab-paclitaxel, including an examn. into a hypothesized greater ability to leverage albumin-based transport relative to sb-paclitaxel. An advantageous PK profile and the more efficient use of albumin-based transport may contribute to the preclin. finding that nab-paclitaxel achieves a 33% higher tumor uptake relative to sb-paclitaxel. Another possible contributing factor to the tumor accumulation of nab-paclitaxel is the binding of albumin to secreted protein acidic and rich in cysteine (SPARC), although the data supporting this relationship between SPARC and nab-paclitaxel remain largely correlative at this point. Recent data also suggest that nab-paclitaxel may enhance tumor accumulation of gemcitabine in pancreatic cancer treated with both agents. Addnl., a possible mechanistic synergy between nab-paclitaxel and capecitabine was cited as the rationale to combine the 2 agents for MBC treatment. Thus, nab-paclitaxel appears to interact with tumors in a no. of interesting, but not fully understood, ways. Continued preclin. and clin. research across a range of tumor types is warranted to answer the questions that remain on the mechanisms of delivery and antitumor activity of nab-paclitaxel.
- 96Ran, R.; Sun, Q.; Baby, T.; Wibowo, D.; Middelberg, A. P.; Zhao, C.-X. J. C. E. S. Multiphase microfluidic synthesis of micro-and nanostructures for pharmaceutical applications 2017, 169, 78– 96, DOI: 10.1016/j.ces.2017.01.008Google ScholarThere is no corresponding record for this reference.
- 97Adedoyin, A.; Bernardo, J. F.; Swenson, C. E.; Bolsack, L. E.; Horwith, G.; DeWit, S.; Kelly, E.; Klasterksy, J.; Sculier, J. P.; DeValeriola, D. Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies. Antimicrob. Agents Chemother. 1997, 41 (10), 2201– 2208, DOI: 10.1128/AAC.41.10.2201Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXms1Sns70%253D&md5=4c23bd70c7fde8bbc54c5e94975c85fdPharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studiesAdedoyin, Adedayo; Bernardo, Jose F.; Swenson, Christine E.; Bolsack, Lois E.; Horwith, Gary; Dewit, Stephane; Kelly, Edward; Klasterksy, J.; Sculier, J. P.; Devaleriola, D.; Anaissie, Elias; Lopez-Berestein, Gabriel; Llanos-Cuentas, Alejandro; Boyle, Anthony; Branch, Robert A.Antimicrobial Agents and Chemotherapy (1997), 41 (10), 2201-2208CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examd. in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concn. performed by high-pressure liq. chromatog. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger vol. of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and vol. of distribution were increased with dose, peak and trough concns. after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estd. half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concns. in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.
- 98Stone, N. R.; Bicanic, T.; Salim, R.; Hope, W. Liposomal Amphotericin B (AmBisome((R))): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions. Drugs 2016, 76 (4), 485– 500, DOI: 10.1007/s40265-016-0538-7Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVSqt7k%253D&md5=451c195f502d6ba1d7b514f5c95f432dLiposomal Amphotericin B (AmBisome): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future DirectionsStone, Neil R. H.; Bicanic, Tihana; Salim, Rahuman; Hope, WilliamDrugs (2016), 76 (4), 485-500CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Liposomal amphotericin B (AmBisome; LAmB) is a unique lipid formulation of amphotericin B. LAmB is a std. of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clin. use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clin. setting. The mol. pharmacol., preclin. and clin. pharmacokinetics, and clin. experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, exptl. animal models and human clin. trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclin. models and in clin. trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients.
- 99Clemons, K. V.; Stevens, D. A. Comparison of fungizone, Amphotec, AmBisome, and Abelcet for treatment of systemic murine cryptococcosis. Antimicrob. Agents Chemother. 1998, 42 (4), 899– 902, DOI: 10.1128/AAC.42.4.899Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXisFGmtrY%253D&md5=d96d32b3d478b806ef8d55ce25737dfaComparison of Fungizone, Amphotec, AmBisome, and Abelcet for treatment of systemic murine cryptococcosisClemons, Karl V.; Stevens, David A.Antimicrobial Agents and Chemotherapy (1998), 42 (4), 899-902CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Three lipid-based formulations of amphotericin B have been approved for use in various countries. The aim of this study was to compare Amphotec (I; Sequus), AmBisome (II; Nexstar), Abelcet (III; The Liposome Co.), and conventional deoxycholate amphotericin B (Fungizone; Bristol Meyers Squibb) for the treatment of exptl. systemic cryptococcosis. A model was established in 10-wk-old female CD-1 mice by i.v. injection of 6.25 × 105 viable Cryptococcus neoformans yeast cells. Therapy began 4 days later, with i.v. administration three times per wk for 2 wk. Mice received either no treatment, 1 mg of Fungizone per kg of body wt., or 1, 5, or 10 mg of I, II, or III per kg. Ninety percent of control mice died between days 15 and 34. All treatment regimens except III at 1 mg/kg prolonged survival compared with no treatment (P < 0.01 to 0.001). All mice receiving 5 or 10 mg of I or II per kg and 90% of mice given 10 mg of III per kg survived, whereas ≤50% of those given other treatment regimens survived. Fungizone was the least effective of the four formulations, with 5 or 10 mg of I, II, or III per kg resulting in a significantly better outcome than Fungizone (P < 0.001). Among the three formulations, I and II were equally effective, both being better than III at equal 5- or 10-mg/kg doses (P < 0.001). Comparison of residual infectious burdens in various organs showed that each drug had some dose-responsive efficacy in three or more organs at escalating doses. In the brain, I or II at 5 or 10 mg/kg or III at 10 mg/kg was more effective than Fungizone at 1 mg/kg or no treatment, while I or II at 1 mg/kg was as effective as III at 10 mg/kg. Similar results were obtained for the kidneys and lungs. In the spleen, I at 10 mg/kg cured all mice of infection and was superior to all other regimens. In the liver, II at 5 mg/kg was superior to an equal dose of I or III. Overall, the efficacies of I and II were equal to that of Fungizone at 1 mg/kg and were about 10-fold better than that of III, particularly in the brain; a comparative rank order of efficacies was I ≈ II > III » Fungizone. This is the first study that compared all four amphotericin B formulations.
- 100Bovier, P. A. Epaxal: a virosomal vaccine to prevent hepatitis A infection. Expert Rev. Vaccines 2008, 7 (8), 1141– 1150, DOI: 10.1586/14760584.7.8.1141Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1Glu7jE&md5=9268a04795bbbbee9d216fb1f80b1a92Epaxal: a virosomal vaccine to prevent hepatitis A infectionBovier, Patrick A.Expert Review of Vaccines (2008), 7 (8), 1141-1150CODEN: ERVXAX; ISSN:1476-0584. (Expert Reviews Ltd.)A review. Over the last few decades, different types of inactivated hepatitis A virus (HAV) vaccines have been developed: several aluminum-adjuvanted vaccines and an aluminum-free, virosome-formulated vaccine. Both types of vaccines are whole-virus prepns. that are produced by growth of HAV strains in human diploid cell cultures and are subsequently inactivated with formaldehyde. This review summarizes all published papers on a virosome-formulated vaccine, Epaxal, based on formalin inactivated HAV (strain RG-SB) adsorbed to the surface of special liposomes (virosomes), that replace aluminum hydroxide as the adjuvant principle. A single injection of virosomal HAV vaccine is well tolerated and highly immunogenic, with 88-97% of seroprotection 2 wk after a first dose. HAV virosomal vaccine can be administered concomitantly with other vaccines, without inducing antigenic competition. Direct comparison with aluminum-adsorbed vaccine has shown that the immunogenicity was similar, but fewer local reactions were reported with Epaxal. Recent studies in children have demonstrated that Epaxal Junior is also an excellent HAV vaccine for mass vaccination programs.
- 101Herzog, C.; Hartmann, K.; Kunzi, V.; Kursteiner, O.; Mischler, R.; Lazar, H.; Gluck, R. Eleven years of Inflexal V-a virosomal adjuvanted influenza vaccine. Vaccine 2009, 27 (33), 4381– 4387, DOI: 10.1016/j.vaccine.2009.05.029Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotFCrtr8%253D&md5=b3184686147d5dee75395860b6ae4eceEleven years of Inflexal V-a virosomal adjuvanted influenza vaccineHerzog, Christian; Hartmann, Katharina; Kuenzi, Valerie; Kuersteiner, Oliver; Mischler, Robert; Lazar, Hedvika; Glueck, ReinhardVaccine (2009), 27 (33), 4381-4387CODEN: VACCDE; ISSN:0264-410X. (Elsevier Ltd.)A review. Since the introduction to the Swiss market in 1997, Crucell (former Berna Biotech Ltd.), has sold over 41 million doses worldwide of the virosomal adjuvanted influenza vaccine, Inflexal V. Since 1992, 29 company sponsored clin. studies investigating the efficacy and safety of Inflexal V have been completed in which 3920 subjects participated. During its decade on the market, Inflexal V has shown an excellent tolerability profile due to its biocompatibility and purity. The vaccine contains no thiomersal or formaldehyde and its purity is reflected in the low ovalbumin content. By mimicking natural infection, the vaccine is highly efficacious. Inflexal V is the only adjuvanted influenza vaccine licensed for all age groups and shows a good immunogenicity in both healthy and immunocompromised elderly, adults and children. This review presents and discusses the experience with Inflexal V during the past decade.
- 102Cheng, X.; Gao, J.; Ding, Y.; Lu, Y.; Wei, Q.; Cui, D.; Fan, J.; Li, X.; Zhu, E.; Lu, Y. Multi-Functional Liposome: A Powerful Theranostic Nano-Platform Enhancing Photodynamic Therapy. Adv. Sci. (Weinh) 2021, 8 (16), e2100876 DOI: 10.1002/advs.202100876Google ScholarThere is no corresponding record for this reference.
- 103Mayer, M.; Doenicke, A.; Nebauer, A. E.; Hepting, L. Propofol and etomidate-Lipuro for induction of general anesthesia. Hemodynamics, vascular compatibility, subjective findings and postoperative nausea. Anaesthesist 1996, 45 (11), 1082– 1084, DOI: 10.1007/s001010050343Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s7itFOlug%253D%253D&md5=a388ba81663d51f7e80844f5f593fe4bPropofol and etomidate-Lipuro for induction of general anesthesia. Hemodynamics, vascular compatibility, subjective findings and postoperative nauseaMayer M; Doenicke A; Nebauer A E; Hepting LDer Anaesthesist (1996), 45 (11), 1082-4 ISSN:0003-2417.UNLABELLED: Etomidate has become an important induction agent in high-risk patients because of its cardiovascular stability. Its unwanted side-effects such as pain on injection and thrombophlebitis could be significantly reduced by a new (medium chain triglyceride and soya bean) emulsion formulation. Propofol is solved in a mixture of long chain triglyceride and soya bean emulsion. In this double-blind, randomized study we compared the haemodynamic effects, the patients' sensations, signs of thrombophlebitis and postoperative nausea and vomiting (PONV) following injection of both drugs. METHODS: Following premedication with 2 mg Lormetazepam p.o. in 50 patients per group, anaesthesia was induced with either 0.51 mg etomidate in lipid emulsion or 3.04 mg propofol per kg bw. No opioid or benzdiazepine was given i.v. before induction. After injection of the tested drug, the cannula was removed. Changes in blood pressure and heart rate were recorded as well as signs of discomfort during and after injection (pain, burning, tension, cold). Venous sequelae were assessed for 5 days after injection to register signs of thrombophlebitis. RESULTS: Demographic data showed no difference between the two groups. After propofol more often a fall in blood pressure was seen. Pain (25 vs 1 pt), burning 19 vs 1), tension 15 vs 3), cold (35 vs 17) after injection was registered significantly more often in the propofol group, whereas myocloni predominated in the etomidate group (13 vs 6) P < 0.05, chi-squared-test). No difference was seen in PONV in either groups. CONCLUSION: Etomidate formulated in a medium chain lipid emulsion causes significant less discomfort for the patients than propofol, which is solved in a long chain formulation. Myocloni, however, occur significantly more frequently after etomidate than after propofol.
- 104Patel, H. H.; P, M.; Patel, P. M.; Roth, D. M. General Anesthetics and Therapeutic Gases; McGraw Hill.Google ScholarThere is no corresponding record for this reference.
- 105Bakshi, P.; Jiang, Y.; Nakata, T.; Akaki, J.; Matsuoka, N.; Banga, A. K. Formulation Development and Characterization of Nanoemulsion-Based Formulation for Topical Delivery of Heparinoid. J. Pharm. Sci. 2018, 107 (11), 2883– 2890, DOI: 10.1016/j.xphs.2018.07.015Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslals73N&md5=c25e65a47954af1cdde91d374b204f86Formulation development and characterization of nanoemulsion-based formulation for topical delivery of heparinoidBakshi, Pooja; Jiang, Ying; Nakata, Takahiro; Akaki, Junji; Matsuoka, Nobuya; Banga, Ajay K.Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2018), 107 (11), 2883-2890CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)Heparinoid is commonly used for the treatment of superficial thrombophlebitis, a condition wherein inflammation and clotting occurs in the veins below the skin surface. However, stratum corneum is a major barrier that limits the delivery of hydrophilic heparinoid, in and across the skin. The aim of the present study was to develop a nonirritant topical formulation for heparinoid incorporating chem. penetration enhancers and investigate the delivery of heparinoid across the human epidermis using in vitro vertical Franz diffusion cells. The developed oil-in-water nanoemulsions (NEs; NE-1 and NE-2) delivered higher amt. of heparinoid (91.58 ± 25.75 μg/sq.cm and 62.67 ± 5.66 μg/sq.cm, resp.) after 72 h compared with the other developed formulations, which in turn also delivered significantly higher amt. compared with com. formulations: cream (1.78 ± 0.07 μg/sq.cm), ointment (9.95 ± 4.41 μg/sq.cm), and gel (0 μg/sq.cm) (p <0.05). Transmission electron microscopy, polarizing light microscopy, and dynamic light scattering studies were performed to characterize the microstructure of these NEs with chem. enhancers. NE-1 was tested to be nonirritant with cell viability greater than 50% and a minimal release of IL-1α by using the "in vitro Epiderm tissue" model. Our results demonstrate that NE formulations represent a potential strategy for providing a localized therapy for the treatment of superficial thrombophlebitis.
- 106Salim, N.; Jose García-Celma, M.; Escribano, E.; Nolla, J.; Llinàs, M.; Basri, M.; Solans, C.; Esquena, J.; Tadros, T. F. Formation of Nanoemulsion Containing Ibuprofen by PIC Method for Topical Delivery. Materials Today: Proceedings 2018, 5, S172– S179, DOI: 10.1016/j.matpr.2018.08.062Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVShtbbJ&md5=99272ba91fedb3827fe0cb4bab32e09eFormation of Nanoemulsion Containing Ibuprofen by PIC Method for Topical DeliverySalim, Norazlinaliza; Jose Garcia-Celma, Maria; Escribano, Elvira; Nolla, Jordi; Llinas, Meritxell; Basri, Mahiran; Solans, Conxita; Esquena, Jordi; Tadros, Tharwat F.Materials Today: Proceedings (2018), 5 (Suppl._2), S172-S179CODEN: MTPAC4; ISSN:2214-7853. (Elsevier Ltd.)This study reports the formation of nanoemulsions from palm-kernel oil esters (PKOE)/Cremophor EL/water systems intended for topical administration of a non-steroidal anti-inflammatory drug, ibuprofen. Nanoemulsions contg. 2% ibuprofen, various oil:surfactant ratios (10:90, 20:80 and 30:70) and 80% of water were selected from the ternary system of PKOE/Cremophor EL/water and prepd. by the phase inversion compn. (PIC) method. The characterization of the nanoemulsions such as droplet size, polydispersity index, zeta potential, stability and the permeation of ibuprofen from nanoemulsions were evaluated. The prepd. nanoemulsions exhibited good stability without any phase sepn., sedimentation or creaming for the period of tested exptl. time (6 mo). The permeation study of ibuprofen was performed on Franz type-diffusion cells through human abdominal skin. The median values of the fluxes obtained as well as the median of the percentage of permeated amt. at 24h were not statistically different. The mean profiles of permeated ibuprofen vs. time from PKOE was greater (p < 0.05) than those obtained from Miglyol 812.
- 107Stahelin, H. F. The history of cyclosporin A (Sandimmune) revisited: another point of view. Experientia 1996, 52 (1), 5– 13, DOI: 10.1007/BF01922409Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK287mt1yrug%253D%253D&md5=f3a516187852962c4eaba0314266eb6bThe history of cyclosporin A (Sandimmune) revisited: another point of viewStahelin H FExperientia (1996), 52 (1), 5-13 ISSN:0014-4754.The immunosuppressant cyclosporin A (Sandimmune) has become the first line treatment for preventing rejection of transplanted organs and for certain autoimmune diseases. The discovery of that drug and its preclinical development are described, and it is shown that most earlier accounts of the history of this compound are, in important respects, incorrect and misleading.
- 108Dickman, D. A. Process Chemistry Development of the HIV Protease Inhibitor Drug Kaletra: A Mixture of Ritonavir and Lopinavir 2022, 57, DOI: 10.1002/9781119847281.ch4Google ScholarThere is no corresponding record for this reference.
- 109Zhou, Q.; Sun, X.; Zeng, L.; Liu, J.; Zhang, Z. A randomized multicenter phase II clinical trial of mitoxantrone-loaded nanoparticles in the treatment of 108 patients with unresected hepatocellular carcinoma. Nanomedicine 2009, 5 (4), 419– 423, DOI: 10.1016/j.nano.2009.01.009Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXls1ekug%253D%253D&md5=11012837af694f1074293276a5c69b2cA randomized multicenter phase II clinical trial of mitoxantrone-loaded nanoparticles in the treatment of 108 patients with unresected hepatocellular carcinomaZhou, Qinghua; Sun, Xun; Zeng, Lingyuan; Liu, Jie; Zhang, ZhirongNanomedicine (New York, NY, United States) (2009), 5 (4), 419-423CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Previous studies have demonstrated that i.v. administration of mitoxantrone-loaded polybutylcyanoacrylate nanoparticles (DHAD-PBCA-NPs) could allow increased cytotoxicity in hepatic tumors. Therefore, the authors evaluated the activity and toxicity of DHAD-PBCA-NPs and DHAD injection in individuals with unresected hepatocellular carcinoma. For the DHAD-PBCA-NPs arm the objective response rate was 10.5%, 61.4% patients had stable disease, and 28.1% patients had progression. For the DHAD injection arm no objective response was found, 45.1% patients had stable disease, and 54.9% patients had progression. There were significant differences in both stable disease and progressive disease between the 2 groups (P<.05). The median survival periods of the DHAD-PBCA-NPs group and the DHAD injection group were 5.46 mo and 3.23 mo, resp. Leukopenia was obsd. in 47.4% and 74.5% of the DHAD-PBCA-NPs arm and the DHAD injection arm, resp. Meanwhile, anemia was noted in 65% and 37.3% of the DHAD-PBCA-NPs arm and the DHAD injection arm, resp.
- 110Holtze, C. Large-scale droplet production in microfluidic devices─an industrial perspective. J. Phys. D: Appl. Phys. 2013, 46 (11), 114008, DOI: 10.1088/0022-3727/46/11/114008Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvVansr4%253D&md5=659b7701a8041aa71f5f214c5e10e43fLarge-scale droplet production in microfluidic devices - an industrial perspectiveHoltze, ChristianJournal of Physics D: Applied Physics (2013), 46 (11), 114008, 9 pp.CODEN: JPAPBE; ISSN:0022-3727. (IOP Publishing Ltd.)Microfluidic emulsification yields droplets with extremely narrow size distribution, multiple emulsions with a precisely controlled no. of inner droplets, and higher order emulsions ranging from double to quintuple emulsions. However, prodn. rates are inherently small and scale-up can be achieved by massive parallelization only. Can the control that microfluidic emulsification offers for drop prodn. nevertheless be used for the prodn. of materials. What will it take to develop it into an industrial process. Many obstacles need to be addressed ranging from technol., and com. issues to a fragmented and confusing conference and supplier landscape. This contribution gives a large chem. industry perspective on formulating materials in massively parallelized microfluidic processes.
- 111Maeki, M.; Okada, Y.; Uno, S.; Sugiura, K.; Suzuki, Y.; Okuda, K.; Sato, Y.; Ando, M.; Yamazaki, H.; Takeuchi, M. Mass production system for RNA-loaded lipid nanoparticles using piling up microfluidic devices. Applied Materials Today 2023, 31, 101754, DOI: 10.1016/j.apmt.2023.101754Google ScholarThere is no corresponding record for this reference.
- 112Carvajal-Vidal, P.; Gonzalez-Pizarro, R.; Araya, C.; Espina, M.; Halbaut, L.; Gomez de Aranda, I.; Garcia, M. L.; Calpena, A. C. Nanostructured lipid carriers loaded with Halobetasol propionate for topical treatment of inflammation: Development, characterization, biopharmaceutical behavior and therapeutic efficacy of gel dosage forms. Int. J. Pharm. 2020, 585, 119480, DOI: 10.1016/j.ijpharm.2020.119480Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtV2ru7nN&md5=40217b25e5d1c2dd4dd1071d761cbcafNanostructured lipid carriers loaded with Halobetasol propionate for topical treatment of inflammation: Development, characterization, biopharmaceutical behavior and therapeutic efficacy of gel dosage formsCarvajal-Vidal, Paulina; Gonzalez-Pizarro, Roberto; Araya, Carolina; Espina, Marta; Halbaut, Lyda; Gomez de Aranda, Immaculada; Garcia, M. Luisa; Calpena, Ana C.International Journal of Pharmaceutics (Amsterdam, Netherlands) (2020), 585 (), 119480CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)The aim of this research was the development and characterization of three gel dosage forms of Halobetasol propionate loaded lipid nanoparticles (HB-NLC) for the treatment of inflammatory skin diseases. A Pluronic gel (Pl-HB-NLC), a Carbopol gel (Cb-HB-NLC) and a Cremigel (Cg-HB-NLC), were characterized for stability, swelling, degrdn., porosity and rheol. The biopharmaceutical behavior of in vitro release and ex vivo permeation, along with microbiol. stability were also evaluated. Tolerance and therapeutic efficacy were detd. in vivo. The gels proved to have eudermic pH and to be effective to improve HB-NLC stability for more than 6 mo. In vitro drug release profiles were adjusted to a first order (Pl-HB-NLC, Cg-HB-NLC) and hyperbola (Cb-HB-NLC) kinetic models, revealing sustained drug release. Ex vivo biopharmaceutical behavior showed slow drug penetration through skin, delaying the drug entrance into systemic circulation. The formulations were effective in reducing inflammation with a lower drug dose in comparison with existing treatments, obtaining the fastest effect when using Pl-HB-NLC. After application of the formulations in volunteers, no irritation, redness or edema reactions were detected, plus, an enhancement of the biomech. properties of the skin was evidenciated. Therefore, the results indicate that these formulations are a suitable alternative to current treatments.
- 113Luzzati, V.; Tardieu, A.; Gulik-Krzywicki, T. Polymorphism of lipids. Nature 1968, 217 (5133), 1028– 1030, DOI: 10.1038/2171028a0Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1cXktl2mtrg%253D&md5=8b1800b2ec47e559683bc879f6bcbb48Polymorphism of lipidsLuzzati, Vittorio; Tardieu, A.; Gulik-Krzywicki, T.Nature (London, United Kingdom) (1968), 217 (5133), 1028-30CODEN: NATUAS; ISSN:0028-0836.The high temp. phases of the anhyd. soaps of the divalent cations of Group II seem to be constructed according to the same principle. The polar groups are clustered in rod-like regions and the rods, all identical and crystallographically equiv., are organized in either a 2- or 3-dimensional lattice. Structure H consists of infinitely long isolated rods (1-dimensional network) arranged in a hexagonal 2-dimensional lattice; structures R and T consist of rods of finite length, linked 3 by 3 or 4 by 4, resp., forming 2-dimensional hexagonal or rectangular networks which are stacked regularly into 3-dimensional lattices. Structure Q consists of rods joining 3 by 3 and forming 2 interwoven 3-dimensional networks. The highly developed organization of all these phases is achieved in spite of great disorder of the paraffin chains. The correlation between chem. compn. of the lipid and the class of the structures must be sought in the organization of the polar groups.
- 114Agrawal, Y.; Petkar, K. C.; Sawant, K. K. Development, evaluation and clinical studies of Acitretin loaded nanostructured lipid carriers for topical treatment of psoriasis. Int. J. Pharm. 2010, 401 (1–2), 93– 102, DOI: 10.1016/j.ijpharm.2010.09.007Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlGmsbvE&md5=224e32a46063efa12aa664fcb35e684dDevelopment, evaluation and clinical studies of Acitretin loaded nanostructured lipid carriers for topical treatment of psoriasisAgrawal, Yogeeta; Petkar, Kailash C.; Sawant, Krutika K.International Journal of Pharmaceutics (2010), 401 (1-2), 93-102CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)The objective of the present study was to formulate and characterize acitretin-loaded nanostructured lipid carriers (ActNLCs), to understand in vitro drug release and clin. evaluate the role of the developed gel in the topical treatment of psoriasis. ActNLCs were prepd. by solvent diffusion technique using 32 full factorial design. The mean diam. and surface morphol. of ActNLC was evaluated. ActNLCs were lyophilized and crystallinity of NLC was characterized by DSC and powder x-ray diffraction (XRD). The NLCs were incorporated in 1% wt./wt. Carbopol 934P gel base and in vitro skin deposition studies in human cadaver skin and double-blind clin. studies in psoriatic patients were conducted. The optimized ActNLCs were spherical in shape, with av. particle size of 223 nm, zeta potential of -26.4 mV and EE of 63.0%. DSC and XRD data confirmed the formation of NLCs. Significantly higher deposition of acitretin was found in human cadaver skin from ActNLC gel (81.38%) as compared to Act plain gel (47.28). Clin. studies demonstrated significant improvement in therapeutic response and redn. in local side effects with ActNLCs loaded gel indicated its effectiveness in the topical treatment of psoriasis.
- 115Charoenputtakun, P.; Pamornpathomkul, B.; Opanasopit, P.; Rojanarata, T.; Ngawhirunpat, T. Terpene composited lipid nanoparticles for enhanced dermal delivery of all-trans-retinoic acids. Biol. Pharm. Bull. 2014, 37 (7), 1139– 1148, DOI: 10.1248/bpb.b14-00015Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFalu73J&md5=fc37d033044bad53eee18724433c0e5cTerpene composited lipid nanoparticles for enhanced dermal delivery of all-trans-retinoic acidsCharoenputtakun, Ponwanit; Pamornpathomkul, Boonnada; Opanasopit, Praneet; Rojanarata, Theerasak; Ngawhirunpat, TanasaitBiological & Pharmaceutical Bulletin (2014), 37 (7), 1139-1148CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)In the present study, terpene composited lipid nanoparticles and lipid nanoparticles were developed and evaluated for dermal delivery of all-trans-retinoic acids (ATRA). Terpene composited lipid nanoparticles and lipid nanoparticles were investigated for size, size distribution, zeta potential, entrapment efficiency, photostability, and cytotoxicity. In vitro skin permeation of ATRA lipid formulations were also evaluated. To explore the ability of lipid nanocarriers to target the skin, the distribution of rhodamine B base in the skin was investigated using confocal laser scanning microscopy (CLSM). The results indicated that the physicochem. characteristics of terpene composited lipid nanoparticles influenced skin permeability. All lipid nanocarriers significantly protected ATRA from photodegrdn. and were non-toxic to normal human foreskin fibroblast cells in vitro. Solid lipid nanoparticles contg. 10% limonene (10% L-SLN) had the highest ATRA skin permeability. Terpene composited SLN and nanostructured lipid carriers (NLC) showed higher epidermal permeation of rhodamine B across the skin based on CLSM image anal. Our study suggests that terpene composited SLN and NLC can be potentially used as dermal drug delivery carriers for ATRA.
- 116El-Salamouni, N. S.; Farid, R. M.; El-Kamel, A. H.; El-Gamal, S. S. Effect of sterilization on the physical stability of brimonidine-loaded solid lipid nanoparticles and nanostructured lipid carriers. Int. J. Pharm. 2015, 496 (2), 976– 983, DOI: 10.1016/j.ijpharm.2015.10.043Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGlsrbO&md5=61b63f423cbcf8bd06689591df4882d8Effect of sterilization on the physical stability of brimonidine-loaded solid lipid nanoparticles and nanostructured lipid carriersEl-Salamouni, Noha S.; Farid, Ragwa M.; El-Kamel, Amal H.; El-Gamal, Safaa S.International Journal of Pharmaceutics (Amsterdam, Netherlands) (2015), 496 (2), 976-983CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)Nanoparticulate delivery systems have recently been under consideration for topical ophthalmic drug delivery. Brimonidine base-loaded solid lipid nanoparticles and nanostructured lipid carrier formulations were prepd. using glyceryl monostearate as solid lipid and were evaluated for their phys. stability following sterilization by autoclaving at 121 °C for 15 min. The objective of this work was to evaluate the effect of autoclaving on the phys. appearance, particle size, polydispersity index, zeta potential, entrapment efficiency and particle morphol. of the prepd. formulations, compared to non-autoclaved ones. Results showed that, autoclaving at 121 °C for 15 min allowed the prodn. of phys. stable formulations in nanometric range, below 500 nm suitable for ophthalmic application. Moreover, the autoclaved samples appeared to be superior to non-autoclaved ones, due to their increased zeta potential values, indicating a better phys. stability. As well as, increased amt. of brimonidine base entrapped in the tested formulations.
- 117Hadinoto, K.; Sundaresan, A.; Cheow, W. S. Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: A review. Eur. J. Pharm. Biopharm. 2013, 85 (3, Part A), 427– 443, DOI: 10.1016/j.ejpb.2013.07.002Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlWhtLrI&md5=0a197b42f477e861ff74a33a4d7f5e39Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: A reviewHadinoto, Kunn; Sundaresan, Ajitha; Cheow, Wean SinEuropean Journal of Pharmaceutics and Biopharmaceutics (2013), 85 (3PA), 427-443CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)A review. Lipid-polymer hybrid nanoparticles (LPNs) are core-shell nanoparticle structures comprising polymer cores and lipid/lipid-PEG shells, which exhibit complementary characteristics of both polymeric nanoparticles and liposomes, particularly in terms of their phys. stability and biocompatibility. Significantly, the LPNs have recently been demonstrated to exhibit superior in vivo cellular delivery efficacy compared to that obtained from polymeric nanoparticles and liposomes. Since their inception, the LPNs have advanced significantly in terms of their prepn. strategy and scope of applications. Their prepn. strategy has undergone a shift from the conceptually simple two-step method, involving preformed polymeric nanoparticles and lipid vesicles, to the more principally complex, yet easier to perform, one-step method, relying on simultaneous self-assembly of the lipid and polymer, which has resulted in better products and higher prodn. throughput. The scope of LPNs' applications has also been extended beyond single drug delivery for anticancer therapy, to include combinatorial and active targeted drug deliveries, and deliveries of genetic materials, vaccines, and diagnostic imaging agents. This review details the current state of development for the LPNs prepn. and applications from which we identify future research works needed to bring the LPNs closer to its clin. realization.
- 118Baden, L. R.; El Sahly, H. M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, D.; Spector, S. A.; Rouphael, N.; Creech, C. B. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J. Med. 2021, 384 (5), 403– 416, DOI: 10.1056/NEJMoa2035389Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjvFSmsrc%253D&md5=9b0c79f3e3fd2ea452a3fbf57281720fEfficacy and safety of the mRNA-1273 SARS-CoV-2 vaccineBaden, L. R.; El Sahly, H. M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, D.; Spector, S. A.; Rouphael, N.; Creech, C. B.; McGettigan, J.; Khetan, S.; Segall, N.; Solis, J.; Brosz, A.; Fierro, C.; Schwartz, H.; Neuzil, K.; Corey, L.; Gilbert, P.; Janes, H.; Follmann, D.; Marovich, M.; Mascola, J.; Polakowski, L.; Ledgerwood, J.; Graham, B. S.; Bennett, H.; Pajon, R.; Knightly, C.; Leav, B.; Deng, W.; Zhou, H.; Han, S.; Ivarsson, M.; Miller, J.; Zaks, T.New England Journal of Medicine (2021), 384 (5), 403-416CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two i.m. injections of mRNA-1273 (100μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serol., virol., or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified.
- 119Polack, F. P.; Thomas, S. J.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Perez, J. L.; Perez Marc, G.; Moreira, E. D.; Zerbini, C. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J. Med. 2020, 383 (27), 2603– 2615, DOI: 10.1056/NEJMoa2034577Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXotFSjuw%253D%253D&md5=08cb7204334ed37c7949dfcdfe5af75cSafety and efficacy of the BNT162b2 mRNA Covid-19 vaccinePolack, Fernando P.; Thomas, Stephen J.; Kitchin, Nicholas; Absalon, Judith; Gurtman, Alejandra; Lockhart, Stephen; Perez, John L.; Marc, Gonzalo Perez; Moreira, Edson D.; Zerbini, Cristiano; Bailey, Ruth; Swanson, Kena A.; Roychoudhury, Satrajit; Koury, Kenneth; Li, Ping; Kalina, Warren V.; Cooper, David; Frenck, Robert W., Jr.; Hammitt, Laura L.; Tureci, Ozlem; Nell, Haylene; Schaefer, Axel; Unal, Serhat; Tresnan, Dina B.; Mather, Susan; Dormitzer, Philip R.; Sahin, Ugur; Jansen, Kathrin U.; Gruber, William C.New England Journal of Medicine (2020), 383 (27), 2603-2615CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)A review. Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30μg per dose). BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against lab.-confirmed Covid-19 and safety. results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was obsd. across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 mo was similar to that of other viral vaccines.
- 120Song, S. Y.; Kim, K. P.; Jeong, S. Y.; Park, J.; Park, J.; Jung, J.; Chung, H. K.; Lee, S. W.; Seo, M. H.; Lee, J. S. Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model. Oncotarget 2016, 7 (47), 77348– 77357, DOI: 10.18632/oncotarget.12668Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srksFWnuw%253D%253D&md5=6c7f63bb7c6a4e2c01e46f4fbffcfd05Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer modelSong Si Yeol; Choi Eun Kyung; Song Si Yeol; Jeong Seong-Yun; Park Jin; Park Jaesook; Lee Jung-Shin; Choi Eun Kyung; Kim Kyu-Pyo; Lee Jung-Shin; Jung Kyung Hae; Jeong Seong-Yun; Park Jin; Park Jaesook; Jung Joohee; Chung Hye Kyung; Lee Sa-Won; Seo Min HyoOncotarget (2016), 7 (47), 77348-77357 ISSN:.We assessed the efficacy of the polymeric nanoparticle containing docetaxel (PNP-DTX) in preclinical mouse models and determined the maximum tolerated dose (MTD) through clinical study. Subcutaneous and orthotopic mouse models were dedicated. Tumor growth delay in orthotopic model and quantification of in vivo imaging in orthotopic model were evaluated. Phase I clinical study was a single-center, prospective, open-label trial in advanced solid tumors. PNP-DTX was injected intravenously and the starting dose was 20 mg/m2 escalated to 35 mg/m2, 45 mg/m2, 60 mg/m2 and 75 mg/m2. Pharmacokinetics, tumor response, toxicities were evaluated. Preclinical result revealed the more potent cytotoxic effect of PNP-DTX than docetaxel (DTX). However, there was no difference between PNP-DTX and DTX in subcutaneous model. Tubulin polymerization assay showed that PNP-DTX preserved original mode of action of DTX. For phase I clinical trial, 18 patients were analyzed. The dose of 75 mg/m2 was tentatively determined as the MTD and the most common toxicity was grade 4 neutropenia not lasting over 7days. The Cmax of 60 mg/m2 PNP-DTX and AUClast of 45 mg/m2 PNP-DTX were measured to be comparable to those of 75 mg/m2 DTX. Partial remission (PR) was achieved in 4 (22%) patients. The potency of PNP-DTX was revealed especially in orthotopic mouse model. The MTD of PNP-DTX could not be confirmed, but 75 mg/m2 was tentatively determined. The PNP-DTX of 45 mg/m2 had the same pharmacokinetic profile with that of 75 mg/m2 DTX.
- 121Vetten, M. A.; Yah, C. S.; Singh, T.; Gulumian, M. Challenges facing sterilization and depyrogenation of nanoparticles: effects on structural stability and biomedical applications. Nanomedicine 2014, 10 (7), 1391– 1399, DOI: 10.1016/j.nano.2014.03.017Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntl2gtb8%253D&md5=b914dc444c7c2dcdc37a1218de6ecbefChallenges facing sterilization and depyrogenation of nanoparticles: Effects on structural stability and biomedical applicationsVetten, Melissa A.; Yah, Clarence S.; Singh, Tanusha; Gulumian, MaryNanomedicine (New York, NY, United States) (2014), 10 (7), 1391-1399CODEN: NANOBF; ISSN:1549-9634. (Elsevier)This review outlines and compares techniques that are currently available for the sterilization of nanoparticles and addresses the topic of endotoxin contamination. Several techniques are available for the removal of microbial contamination from nanoparticles developed for use in nanomedicine applications. These techniques include filtration, autoclaving and irradn., as well as formaldehyde, ethylene oxide and gas plasma treatments. Of these sterilization methodologies, filtration may potentially remove microbial contamination without altering the physicochem. properties of the carrier nanoparticles, nor affecting their toxicity and functionality. However, no single process may be applied to all nanoparticle prepns. and, therefore, it is recommended that each nanoparticle-drug system be validated on a case-by-case basis.This comprehensive review covers the currently available methods for removal of microbial contaminations from nanoparticles for nanomedicine applications. The review highlights the pros and cons of each available method. Authors conclude that there is no single best method and recommend a customized approach for each nanoparticle system.
- 122Packer, M.; Gyawali, D.; Yerabolu, R.; Schariter, J.; White, P. A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems. Nat. Commun. 2021, 12 (1), 6777, DOI: 10.1038/s41467-021-26926-0Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisFClsLzL&md5=9ea94bb1f8267764266f7419475c1255A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systemsPacker, Meredith; Gyawali, Dipendra; Yerabolu, Ravikiran; Schariter, Joseph; White, PhilNature Communications (2021), 12 (1), 6777CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)Lipid nanoparticle (LNP)-formulated mRNA vaccines were rapidly developed and deployed in response to the SARS-CoV-2 pandemic. Due to the labile nature of mRNA, identifying impurities that could affect product stability and efficacy is crucial to the long-term use of nucleic-acid based medicines. Herein, reversed-phase ion pair high performance liq. chromatog. (RP-IP HPLC) was used to identify a class of impurity formed through lipid:mRNA reactions; such reactions are typically undetectable by traditional mRNA purity anal. techniques. The identified modifications render the mRNA untranslatable, leading to loss of protein expression. Specifically, electrophilic impurities derived from the ionizable cationic lipid component are shown to be responsible. Mechanisms implicated in the formation of reactive species include oxidn. and subsequent hydrolysis of the tertiary amine. It thus remains crit. to ensure robust anal. methods and stringent manufg. control to ensure mRNA stability and high activity in LNP delivery systems.
- 123Autio, K. A.; Dreicer, R.; Anderson, J.; Garcia, J. A.; Alva, A.; Hart, L. L.; Milowsky, M. I.; Posadas, E. M.; Ryan, C. J.; Graf, R. P. Safety and Efficacy of BIND-014, a Docetaxel Nanoparticle Targeting Prostate-Specific Membrane Antigen for Patients With Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Clinical Trial. JAMA Oncol 2018, 4 (10), 1344– 1351, DOI: 10.1001/jamaoncol.2018.2168Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c%252FltlGisw%253D%253D&md5=13681c92391bfd3f76c3d25c4f9e7c2aSafety and Efficacy of BIND-014, a Docetaxel Nanoparticle Targeting Prostate-Specific Membrane Antigen for Patients With Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Clinical TrialAutio Karen A; Anderson Justine; Schreiber Nicole A; Morris Michael J; Scher Howard I; Autio Karen A; Morris Michael J; Scher Howard I; Dreicer Robert; Garcia Jorge A; Alva Ajjai; Hart Lowell L; Milowsky Matthew I; Posadas Edwin M; Ryan Charles J; Graf Ryon P; Dittamore Ryan; Summa Jason M; Youssoufian HagopJAMA oncology (2018), 4 (10), 1344-1351 ISSN:.Importance: Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)-targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring. Objective: To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration-resistant prostate cancer (mCRPC). Design, Setting, and Participants: A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016. Intervention: Treatment with BIND-014 at a dosage of 60 mg/m2 was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred. Main Outcomes and Measures: The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (≥50% reduction from baseline) and changes in CTC number (from ≥5 to <5 cells per 7.5 mL of blood) (CellSearch). Changes in CTC number based on PSMA expression levels on CTCs were also evaluated (Epic Sciences). Results: Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]). Conclusions and Relevance: These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated. Trial Registration: ClinicalTrials.gov Identifier: NCT01812746.
- 124Lobovkina, T.; Jacobson, G. B.; Gonzalez-Gonzalez, E.; Hickerson, R. P.; Leake, D.; Kaspar, R. L.; Contag, C. H.; Zare, R. N. In vivo sustained release of siRNA from solid lipid nanoparticles. ACS Nano 2011, 5 (12), 9977– 9983, DOI: 10.1021/nn203745nGoogle Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVKiur%252FK&md5=7e39aaa90f295e81f8e64f7de88d4e1fIn Vivo Sustained Release of siRNA from Solid Lipid NanoparticlesLobovkina, Tatsiana; Jacobson, Gunilla B.; Gonzalez-Gonzalez, Emilio; Hickerson, Robyn P.; Leake, Devin; Kaspar, Roger L.; Contag, Christopher H.; Zare, Richard N.ACS Nano (2011), 5 (12), 9977-9983CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with a challenge of being delivered in a sustained manner. Nanoparticle drug delivery systems allow for incorporating and controlled release of therapeutic payloads. We demonstrate that solid lipid nanoparticles can incorporate and provide sustained release of siRNA. Tristearin solid lipid nanoparticles, made by nanopptn., were loaded with siRNA (4.4-5.5 wt. % loading ratio) using a hydrophobic ion pairing approach that employs the cationic lipid DOTAP. Intradermal injection of these nanocarriers in mouse footpads resulted in prolonged siRNA release over a period of 10-13 days. In vitro cell studies showed that the released siRNA retained its activity. Nanoparticles developed in this study offer an alternative approach to polymeric nanoparticles for encapsulation and sustained delivery of siRNA with the advantage of being prepd. from physiol. well-tolerated materials.
- 125Salvi, V. R.; Pawar, P. Nanostructured lipid carriers (NLC) system: A novel drug targeting carrier. Journal of Drug Delivery Science and Technology 2019, 51, 255– 267, DOI: 10.1016/j.jddst.2019.02.017Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkvFWhtbg%253D&md5=62ac986050fd98c87b454350a205c6abNanostructured lipid carriers (NLC) system: A novel drug targeting carrierSalvi, Vedanti R.; Pawar, PravinJournal of Drug Delivery Science and Technology (2019), 51 (), 255-267CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)Lipid nanocarriers are developed as an alternative to polymeric nanoparticles, liposomes and emulsions. Further, Nanostructured Lipid Nanocarriers are the second generation lipid carriers developed to overcome problems assocd. with Solid Lipid Nanoparticles and are utilized in various therapeutic approaches. NLCs were primarily considered for the delivery of lipophilic drugs but their suitability for hydrophilic drugs is now well established. Biocompatible nature of lipids is responsible for its development as a promising drug delivery. It was found to be having superior characteristics over other lipid formulations. This article describes the NLC with respect to structures, methods of prepn., characterization, stability and its advantages over first generation lipid nanoparticles. Review mainly focuses on the various therapeutic applications of NLCs and their specificity for different physiol. proximities. Due to their biol. non-toxic, non-immunogenic and compatible nature, NLCs are going to be the widely explored lipid nanocarrier systems.
- 126Chauhan, I.; Yasir, M.; Verma, M.; Singh, A. P. Nanostructured Lipid Carriers: A Groundbreaking Approach for Transdermal Drug Delivery. Adv. Pharm. Bull. 2020, 10 (2), 150– 165, DOI: 10.34172/apb.2020.021Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlGitLvM&md5=962b6f1b7182995e18923ef72c505702Nanostructured lipid carriers: a groundbreaking approach for transdermal drug deliveryChauhan, Iti; Yasir, Mohd; Verma, Madhu; Singh, Alok PratapAdvanced Pharmaceutical Bulletin (2020), 10 (2), 150-165CODEN: APBDCL; ISSN:2251-7308. (Tabriz University of Medical Sciences)Nanostructured lipid carriers (NLCs) are novel pharmaceutical formulations which are composed of physiol. and biocompatible lipids, surfactants and co-surfactants. Over time, as a second generation lipid nanocarrier NLC has emerged as an alternative to first generation nanoparticles. This review article highlights the structure, compn., various formulation methodologies, and characterization of NLCs which are prerequisites in formulating a stable drug delivery system. NLCs hold an eminent potential in pharmaceuticals and cosmetics market because of extensive beneficial effects like skin hydration, occlusion, enhanced bioavailability, and skin targeting. This article aims to evoke an interest in the current state of art NLC by discussing their promising assistance in topical drug delivery system. The key attributes of NLC that make them a promising drug delivery system are ease of prepn., biocompatibility, the feasibility of scale up, non-toxicity, improved drug loading, and stability.
- 127Izza, N.; Suga, K.; Okamoto, Y.; Watanabe, N.; Bui, T. T.; Wibisono, Y.; Fadila, C. R.; Umakoshi, H. Systematic Characterization of Nanostructured Lipid Carriers from Cetyl Palmitate/Caprylic Triglyceride/Tween 80 Mixtures in an Aqueous Environment. Langmuir 2021, 37 (14), 4284– 4293, DOI: 10.1021/acs.langmuir.1c00270Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXnslCnu7c%253D&md5=ae6349e5759713b87c7793a18bbb1dfdSystematic Characterization of Nanostructured Lipid Carriers from Cetyl Palmitate/Caprylic Triglyceride/Tween 80 Mixtures in an Aqueous EnvironmentIzza, Ni'matul; Suga, Keishi; Okamoto, Yukihiro; Watanabe, Nozomi; Bui, Tham Thi; Wibisono, Yusuf; Fadila, Cut Rifda; Umakoshi, HiroshiLangmuir (2021), 37 (14), 4284-4293CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)Nanostructured lipid carriers (NLCs) are gaining attention as the new generation of lipid vehicles. These carriers consist of satd. lipids with small drops of liq. oil dispersed into the inner lipid matrix and are stabilized by a surfactant. Conventionally, NLC-based drug delivery systems have been widely studied, and many researchers are looking into the compn. of NLC properties to improve the performance of NLCs. The membrane fluidity and polarity of self-assembling lipids are also essential properties that must be affected by membrane compns.; however, such fundamental characteristics have not been studied yet. In this study, NLCs were prepd. from cetyl palmitate (CP), caprylic triglyceride (CaTG), and Tween 80 (T80). Structural properties, such as particle size and ζ-potential of the CP/CaTG/T80 ternary mixts., were investigated. Then, the systematic characterization of self-assembly properties using fluorescence-based anal. was applied for the first time to the NLC system. As a final step, the ternary diagram was developed based on the self-assembly properties to summarize the possible structures formed at different compns. The results showed four states: micelle-like, oil-in-water (O/W) emulsion-like, solid lipid nanoparticle-like, and intermediate (solid-liq. coexistence). For the purpose of making the lipid matrix more liquefied, the heterogeneous state and the disordered state of the O/W emulsion-like structure might fulfill the criteria of NLCs. Finally, the ternary diagram provides new information about the assembly state of NLC constituents that could become an important ref. for developing high-performance NLCs.
- 128Ortiz, A. C.; Yanez, O.; Salas-Huenuleo, E.; Morales, J. O. Development of a Nanostructured Lipid Carrier (NLC) by a Low-Energy Method, Comparison of Release Kinetics and Molecular Dynamics Simulation. Pharmaceutics 2021, 13 (4), 531, DOI: 10.3390/pharmaceutics13040531Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvF2gtb7M&md5=47c2b2bbb6dbd3e8043ea1cef7b95410Development of a nanostructured lipid carrier (NLC) by a low-energy method, comparison of release kinetics and molecular dynamics simulationOrtiz, Andrea C.; Yanez, Osvaldo; Salas-Huenuleo, Edison; Morales, Javier O.Pharmaceutics (2021), 13 (4), 531CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)Lipid nanocarriers have a great potential for improving the physicochem. characteristics and behavior of poorly water-sol. drugs, such as aq. dispersibility and oral bioavailability. This investigation presents a novel nanostructured lipid carrier (NLC) based on a mixt. of solid lipid glycerides, fatty acid esters of PEG 1500 (Gelucire 44/14), and an oil mix composed of capric and caprylic triglycerides (Miglyol 812). These NLCs were developed by a simple lowenergy method based on melt emulsification to yield highly encapsulating and narrowly distributed nanoparticles (~ 100 nm, PdI = 0.1, and zeta potential = ~ -10 mV). Rhodamine 123 was selected as a poorly water-sol. drug model and owing to its spectroscopic properties. The novel NLCs were characterized by dynamic light scattering (DLS), zeta potential, nanoparticle tracking anal. (NTA), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and colloidal stability. The drug release was detd. through a dialysis bag and vertical Franzs' cells to provide insights about the methods' suitability, revealing similar performance regardless of their different fluid dynamics. Rhodamine 123 followed a characteristic biphasic release profile owing to the swelling of the hydrophilic polymer coating and diffusion process from the lipid core as revealed by the Korsmeyers-Peppas kinetic modeling. Moreover, to elucidate the formation and incorporation of Rhodamine 123 into the NLC core, several mol. dynamics simulations were conducted. The temp. was shown to be an important condition to improve the formation of the nanoparticles. In addn., the liq. lipid incorporation to the formulation forms nanoparticles with imperfect centers, in contrast to nanoparticles without it. Moreover, Miglyol 812 improves hydrophobic mol. soly. These results suggest the potential of novel NLC as a drug delivery system for poorly water-sol. drugs.
- 129Beloqui, A.; Solinis, M. A.; Rodriguez-Gascon, A.; Almeida, A. J.; Preat, V. Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine 2016, 12 (1), 143– 161, DOI: 10.1016/j.nano.2015.09.004Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1ChtbnN&md5=54a53749143ad60e738d1e3277a83d2aNanostructured lipid carriers: Promising drug delivery systems for future clinicsBeloqui, Ana; Solinis, Maria Angeles; Rodriguez-Gascon, Alicia; Almeida, Antonio J.; Preat, VeroniqueNanomedicine (New York, NY, United States) (2016), 12 (1), 143-161CODEN: NANOBF; ISSN:1549-9634. (Elsevier)During the past decade, the no. of studies describing nanostructured lipid carriers (NLCs)-based formulations has been dramatically increased. The raise in NLC exploitation is essentially due to defeated barriers within the technol. process of lipid-based nanoparticles' formulation and increased knowledge of the underlying mechanisms of transport of NLCs via different routes of administration. This review article aims to give an overview on the current state of the art of NLC as controlled drug delivery systems for future clinics through novel NLC applications providing examples of successful outcomes. The reported data clearly illustrate the promise of these nanoparticles for novel treatments in the near future.
- 130Carvajal-Vidal, P.; Fabrega, M. J.; Espina, M.; Calpena, A. C.; Garcia, M. L. Development of Halobetasol-loaded nanostructured lipid carrier for dermal administration: Optimization, physicochemical and biopharmaceutical behavior, and therapeutic efficacy. Nanomedicine 2019, 20, 102026, DOI: 10.1016/j.nano.2019.102026Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1Wqt7zP&md5=665bdf52f48abaebe093fa535a99616eDevelopment of Halobetasol-loaded nanostructured lipid carrier for dermal administration: Optimization, physicochemical and biopharmaceutical behavior, and therapeutic efficacyCarvajal-Vidal, Paulina; Fabrega, Maria-Jose; Espina, Marta; Calpena, Ana Cristina; Garcia, M. LuisaNanomedicine (New York, NY, United States) (2019), 20 (), 102026CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Halobetasol propionate (HB) is considered a super potent drug in the group of topical corticosteroids. HB has anti-inflammatory activity, vasoconstriction properties, and due to its high skin penetration, it can cause systemic side effects. To improve its characteristics, enhance topical effectiveness and reduce penetration to systemic circulation, a study to optimize and characterize a HB-loaded lipid nanocarrier (HB-NLC) has been made by high-pressure homogenization method. The formulation is composed by HB, surfactant, glyceryl distearate and capric glycerides. The optimized HB-NLC contg. 0.01% of HB and 3% of total lipid shows an av. size below 200 nm with a polydispersity index «0.2 and an encapsulation efficiency »90%. The in vitro and in vivo tests indicate that the HB-NLC is not toxic, is well tolerated and has an anti-inflammatory effect because they decrease the prodn. of Interleukins in keratinocytes and monocytes. HB-NLC is considered an alternative treatment for skin inflammatory disorders.
- 131Cirri, M.; Maestrini, L.; Maestrelli, F.; Mennini, N.; Mura, P.; Ghelardini, C.; Di Cesare Mannelli, L. Design, characterization and in vivo evaluation of nanostructured lipid carriers (NLC) as a new drug delivery system for hydrochlorothiazide oral administration in pediatric therapy. Drug Deliv 2018, 25 (1), 1910– 1921, DOI: 10.1080/10717544.2018.1529209Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1aqtr3I&md5=d011eeeda87c4594414361e1a3df1039Design, characterization and in vivo evaluation of nanostructured lipid carriers (NLC) as a new drug delivery system for hydrochlorothiazide oral administration in pediatric therapyCirri, Marzia; Maestrini, Lavinia; Maestrelli, Francesca; Mennini, Natascia; Mura, Paola; Ghelardini, Carla; Di Cesare Mannelli, LorenzoDrug Delivery (2018), 25 (1), 1910-1921CODEN: DDELEB; ISSN:1071-7544. (Taylor & Francis Ltd.)Effectiveness of strategy based on development of nanostructured lipid carriers as innovative oral pediatric formulation of HCT with improved therapeutic efficacy. Performance of various synthetic and natural liq. lipids was examd. and two different prepn. methods were employed, i.e. homogenization-ultrasonication and microemulsion, to evaluate their influence on NLC properties in terms of size, polydispersity index, Ζ-potential, entrapment efficiency, gastric stability, and drug release properties. PrecirolATO5 was used as solid lipid and Tween80 and PluronicF68 as surfactants, formerly selected in previous study focused on development of HCT-solid lipid nanoparticles. The presence of PluronicF68 did not allow ME formation. On the contrary, using Tween80, the ME method enabled a higher entrapment efficiency than the HU. Regardless of the prepn. method, NLCs exhibited great entrapment efficiency values clearly higher than previous SLNs. Moreover, NLC-ME formulations provided a prolonged release, which lasted for 6 h. In particular, NLC-ME contg. Tween20 as Co-Surfactant showed the best performances, giving rise to a complete drug release, never achieved with previous SLN formulations, despite their successful results. In vivo studies on rats confirmed these results, displaying their best diuretic profile. Moreover, all HCT-loaded NLC formulations showed higher stability than the corresponding SLNs.
- 132Sun, M.; Nie, S.; Pan, X.; Zhang, R.; Fan, Z.; Wang, S. Quercetin-nanostructured lipid carriers: characteristics and anti-breast cancer activities in vitro. Colloids Surf. B Biointerfaces 2014, 113, 15– 24, DOI: 10.1016/j.colsurfb.2013.08.032Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVWms77N&md5=3188a99f5b4e2ce7246716928d93b0e1Quercetin-nanostructured lipid carriers: Characteristics and anti-breast cancer activities in vitroSun, Ming; Nie, Shufang; Pan, Xuan; Zhang, Ruiwen; Fan, Zhaoyang; Wang, ShuColloids and Surfaces, B: Biointerfaces (2014), 113 (), 15-24CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)Quercetin (Q), a common dietary flavonoid, has gained research attention in cancer chemo-prevention, but its low level of aq. soly., stability, cellular bioavailability has limited its application. We have synthesized biocompatible and biodegradable Q-nanostructured lipid carriers (Q-NLC) using a novel phase inversion-based process method. The av. size of Q-NLC was 32 nm in diam. Q-NLC had good chem. and phys. stability, and showed a sustained release pattern. The encapsulation efficiency and loading capacity of Q-NLC were 95% and 11%, resp. The aq. soly. of Q was dramatically improved by at least 1000 folds. The results from Raman spectroscopy, powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) demonstrated that Q presented in NLC as an encapsulated mol. form. As compared to native Q, Q-NLC dramatically increased cytotoxicity in a dose-dependent manner (1-50 μM) and induced apoptosis at 20 μM in MCF-7 and MDA-MB-231 breast cancer cells. The enhanced cytotoxicity and apoptosis were parallel to increased Q uptake by those cancer cells. Void NLC did not change the viability and apoptosis of those cancer cells as compared to phosphate buffered saline. In conclusion, Q-NLC dramatically enhanced the anti-cancer activities of Q, which were assocd. with enhanced Q soly. and stability, and increased Q content in those cancer cells. Q-NLC have a potential for chemo-preventive use in breast cancer.
- 133Jaiswal, P.; Gidwani, B.; Vyas, A. Nanostructured lipid carriers and their current application in targeted drug delivery. Artif Cells Nanomed Biotechnol 2016, 44 (1), 27– 40, DOI: 10.3109/21691401.2014.909822Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12qs7w%253D&md5=dcbdd59bad3a7d15a84120562f881f06Nanostructured lipid carriers and their current application in targeted drug deliveryJaiswal, Piyush; Gidwani, Bina; Vyas, AmberArtificial Cells, Nanomedicine, and Biotechnology (2016), 44 (1), 27-40CODEN: ACNBCI; ISSN:2169-141X. (Taylor & Francis Ltd.)A review. In the last few decades, various drug-delivery technologies have emerged and a fascinating part of this has been the development of nanoscale drug delivery devices. Nanoparticles (NPs) and other colloidal drug-delivery systems modify the kinetics, drug distribution in the body and release profile of an assocd. drug. Nanostructured lipid carriers (NLCs) have been reported to be an alternative system to emulsions, liposomes, microparticles, solid lipid nanoparticles (SLNs) and their polymeric counterparts due to their numerous advantages. This paper basically reviews the types of NLCs, mechanism of skin penetration, stability related issues along with their prodn. techniques, characterization and applications towards targeted drug delivery.
- 134Zhang, L. I.; Zhang, L. Lipid-Polymer Hybrid Nanoparticles: Synthesis, Characterization and Applications. Nano LIFE 2010, 01 (01n02), 163– 173, DOI: 10.1142/S179398441000016XGoogle Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisVGhtb4%253D&md5=0b72de834d6c67f728e29cb74dc4a7d5Lipid-polymer hybrid nanoparticles: synthesis, characterization and applicationsZhang, Li; Zhang, LiangfangNano LIFE (2010), 1 (1 & 2), 163-173CODEN: NLAIA8; ISSN:1793-9844. (World Scientific Publishing Co. Pte. Ltd.)A review. Nanotechnol. has been extensively explored in the past decade to develop a myriad of functional nanostructures to facilitate the delivery of therapeutic and imaging agents for various medical applications. Liposomes and polymeric nanoparticles represent two primary delivery vehicles that are currently under investigation. While many advantages of these two particle platforms have been disclosed, some intrinsic limitations remain to limit their applications at certain extent. Recently, a new type of nanoparticle platform, named lipid-polymer hybrid nanoparticle, has been developed that combines the pos. attributes of both liposomes and polymeric nanoparticles while excluding some of their shortages. This new nanoparticle consists of a hydrophobic polymeric core, a lipid shell surrounding the polymeric core, and a hydrophilic polymer stealth layer outside the lipid shell. In this review, we first introduce the synthesis and surface functionalization techniques of the lipid-polymer hybrid nanoparticle, followed by a review of typical characterization of the particles. We then summarize the current and potential medical applications of this new nanoparticle as a delivery vehicle of therapeutic and imaging agents. Finally we highlight some challenges faced in further developing this robust delivery platform.
- 135Shafique, M.; Ur Rehman, M.; Kamal, Z.; Alzhrani, R. M.; Alshehri, S.; Alamri, A. H.; Bakkari, M. A.; Sabei, F. Y.; Safhi, A. Y.; Mohammed, A. M. Formulation development of lipid polymer hybrid nanoparticles of doxorubicin and its in-vitro, in-vivo and computational evaluation. Front Pharmacol 2023, 14, 1025013, DOI: 10.3389/fphar.2023.1025013Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXkvV2lsLk%253D&md5=9146938f02bc4fce18425e2c3256556cFormulation development of lipid polymer hybrid nanoparticles of doxorubicin and its in-vitro, in-vivo and computational evaluationShafique, Muhammad; Rehman, Maqsood Ur; Kamal, Zul; Alzhrani, Rami M.; Alshehri, Sameer; Alamri, Ali H.; Bakkari, Mohammed Ali; Sabei, Fahad Y.; Safhi, Awaji Y.; Mohammed, Ahmed M.; El Hamd, Mohamed A.; Almawash, SaudFrontiers in Pharmacology (2023), 14 (), 1025013CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)The purpose of this study was to assess the parameters of doxorubicin (DOX) loaded lipid polymer hybrid nanoparticles (LPHNs) formulation development, and then the bioavailability of DOX were detd. in the rabbit model, in order to evaluate the intrinsic outcome of dosage form improvement after the oral administration. LPHNs were prepd. by combine approach, using both magnetic stirring and probe sonication followed by its characterization in terms of size-distribution (Zeta Size), entrapment efficiency (EE), loading capacity, and the kinetics of DOX. LPHNPs were further characterized by using SEM (SEM), powder X-Ray diffractometry (P-XRD), Fourier transform IR spectroscopy (FT-IR), differential scanning calorimetry (DSC), in vitro and in vivo studies. The mol. modeling was detd. through the d. functional theory (DFT) simulations and interactions. DOX loaded and unloaded LPHNs were administered orally to the rabbits for bioavailability and pharmacokinetic parameters detns. The plasma concn. of DOX was detd. through high performance liq. chromatog. (HPLC). The av. size of DOX-loaded LPHNs was 121.90 ± 3.0 nm. The drug loading of DOX was 0.391% ± 0.01 of aq. dispersion, where its encapsulation efficiency was 95.5% ± 1.39. After oral administration of the DOX-LPHNs, the area under the plasma drug concn.-time curve (AUC) improved about 2-folds comparatively (p < 0.05). DFT simulations were used to understand the interactions of polymers with different sites of DOX mol. The larger neg. binding energies (-9.33 to -18.53 kcal/mol) of the different complexes evince that the polymers have stronger affinity to bind with the DOX mol. while the neg. values shows that the process is spontaneous, and the synthesis of DOX-LPHNs is energetically favorable. It was concluded that DOX-LPHNs provides a promising new formulation that can enhance the oral bioavailability, which have optimized compatibilities and improve the pharmacokinetic of DOX after oral administration.
- 136Hadinoto, K.; Sundaresan, A.; Cheow, W. S. Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: a review. Eur. J. Pharm. Biopharm 2013, 85 (3 Pt A), 427– 443, DOI: 10.1016/j.ejpb.2013.07.002Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlWhtLrI&md5=0a197b42f477e861ff74a33a4d7f5e39Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: A reviewHadinoto, Kunn; Sundaresan, Ajitha; Cheow, Wean SinEuropean Journal of Pharmaceutics and Biopharmaceutics (2013), 85 (3PA), 427-443CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)A review. Lipid-polymer hybrid nanoparticles (LPNs) are core-shell nanoparticle structures comprising polymer cores and lipid/lipid-PEG shells, which exhibit complementary characteristics of both polymeric nanoparticles and liposomes, particularly in terms of their phys. stability and biocompatibility. Significantly, the LPNs have recently been demonstrated to exhibit superior in vivo cellular delivery efficacy compared to that obtained from polymeric nanoparticles and liposomes. Since their inception, the LPNs have advanced significantly in terms of their prepn. strategy and scope of applications. Their prepn. strategy has undergone a shift from the conceptually simple two-step method, involving preformed polymeric nanoparticles and lipid vesicles, to the more principally complex, yet easier to perform, one-step method, relying on simultaneous self-assembly of the lipid and polymer, which has resulted in better products and higher prodn. throughput. The scope of LPNs' applications has also been extended beyond single drug delivery for anticancer therapy, to include combinatorial and active targeted drug deliveries, and deliveries of genetic materials, vaccines, and diagnostic imaging agents. This review details the current state of development for the LPNs prepn. and applications from which we identify future research works needed to bring the LPNs closer to its clin. realization.
- 137Musielak, E.; Feliczak-Guzik, A.; Nowak, I. Synthesis and Potential Applications of Lipid Nanoparticles in Medicine. Materials (Basel) 2022, 15 (2), 682, DOI: 10.3390/ma15020682Google ScholarThere is no corresponding record for this reference.
- 138Bazylińska, U.; Lewińska, A.; Lamch, L.; Wilk, K. A. Polymeric nanocapsules and nanospheres for encapsulation and long sustained release of hydrophobic cyanine-type photosensitizer. Colloids Surf., A 2014, 442, 42– 49, DOI: 10.1016/j.colsurfa.2013.02.023Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktFWhtLc%253D&md5=fc0d24baf9803e95b65d834b0ae23005Polymeric nanocapsules and nanospheres for encapsulation and long sustained release of hydrophobic cyanine-type photosensitizerBazylinska, Urszula; Lewinska, Agnieszka; Lamch, Lukasz; Wilk, Kazimiera A.Colloids and Surfaces, A: Physicochemical and Engineering Aspects (2014), 442 (), 42-49CODEN: CPEAEH; ISSN:0927-7757. (Elsevier B.V.)Owing to the nanopptn. methodol. IR-780 loaded PLA and PCL nanospheres and nanocapsules (stabilized by Cremophor EL and contg., in the case of nanocapsules, coconut oil as the liq. core) were fabricated and their colloidal stability, encapsulated cargo release and photoactivity were assessed. DLS measurements and AFM confirmed, resp., the obtained nanoparticles diam. below 150 nm as well as their morphol. and shape. Doppler electrophoresis provided the ζ-potential of the studied nanoobjects while UV-vis spectroscopy made it possible to det. the encapsulation efficiency (about 90%) of IR-780 and to establish its release characteristics. Nanofiltration and freeze drying approaches prior to storage in the dark provided the best conditions' parameters for the near monodispersed nanocarriers of cyanine. In order to evaluate the photoactivity of IR-780, both as native and encapsulated in the obtained nanocarriers, photobleaching and ROS detection (by means of spectrophotometrical measurements) were successfully performed. The applied methodologies made it possible to obtain successfully stable and long sustained IR-780 loaded monodispersed oil-cored nanocapsules and nanospheres both under physiol. conditions, and after freeze drying procedure.
- 139Siqueira-Moura, M. P.; Primo, F. L.; Espreafico, E. M.; Tedesco, A. C. Development, characterization, and photocytotoxicity assessment on human melanoma of chloroaluminum phthalocyanine nanocapsules. Mater. Sci. Eng. C Mater. Biol. Appl. 2013, 33 (3), 1744– 1752, DOI: 10.1016/j.msec.2012.12.088Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFSlurw%253D&md5=e4e38235e6f6c2144cc97280c14ce50aDevelopment, characterization, and photocytotoxicity assessment on human melanoma of chloroaluminum phthalocyanine nanocapsulesSiqueira-Moura, Marigilson P.; Primo, Fernando L.; Espreafico, Enilza M.; Tedesco, Antonio C.Materials Science & Engineering, C: Materials for Biological Applications (2013), 33 (3), 1744-1752CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)In this work the authors have developed nanocapsules contg. chloroaluminum phthalocyanine (ClAlPc) and assessed their phototoxic action on WM1552C, WM278, and WM1617 human melanoma cell lines. The ClAlPc-loaded nanocapsules were prepd. by the nanopptn. method and optimized by a 23 full factorial design. The ClAlPc nanocapsules were characterized by particle size and distribution, zeta potential, morphol., encapsulation efficiency, singlet oxygen prodn., stability, and phototoxic action on melanoma cells. Both the development and optimization studies revealed that stable colloidal formulations could be obtained by 1.75% (w/v) soybean lecithin, 1.25% (w/v) Poloxamer 188, 2.5% (vol./vol.) soybean oil, and 0.75% (w/v) poly(D,L-lactide-co-glycolide). The nanocapsules had a mean diam. of 230 nm, homogeneous size distribution (polydispersity index < 0.3), and neg. zeta potential (about - 30 mV). Their morphol. was spherical, with evident polymer membrane coating droplet. The encapsulation efficiency was 70%, as expected for hydrophobic drugs, and the nanoencapsulated ClAlPc was able to produce high singlet oxygen quantum yield. ClAlPc nanocapsules exhibited good phys. stability over a 12-mo period. WM1552C primary melanoma cells were more sensitive (p < 0.05) to the phototoxic effect elicited by ClAlPc nanocapsules (0.3 μg ml-1) under light irradn. at 20 mJ cm-2. On the other hand, the cell survival percentage for all the melanoma cell lines treated with the highest light dose (150 mJ cm-2) was lower than 10%. In summary, ClAlPc nanoencapsulation could enable application of this hydrophobic photosensitizer in the treatment of malignant melanoma with the use of both low sensitizer drug concn. and light dose.
- 140Mazzarino, L.; Travelet, C.; Ortega-Murillo, S.; Otsuka, I.; Pignot-Paintrand, I.; Lemos-Senna, E.; Borsali, R. Elaboration of chitosan-coated nanoparticles loaded with curcumin for mucoadhesive applications. J. Colloid Interface Sci. 2012, 370 (1), 58– 66, DOI: 10.1016/j.jcis.2011.12.063Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhsleqt7w%253D&md5=4451a176ddfcc725c8cdfb5e12b5ef91Elaboration of chitosan-coated nanoparticles loaded with curcumin for mucoadhesive applicationsMazzarino, Leticia; Travelet, Christophe; Ortega-Murillo, Sonia; Otsuka, Issei; Pignot-Paintrand, Isabelle; Lemos-Senna, Elenara; Borsali, RedouaneJournal of Colloid and Interface Science (2012), 370 (1), 58-66CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)Polycaprolactone (PCL) nanoparticles decorated with a mucoadhesive polysaccharide chitosan (CS) contg. curcumin were developed aiming the buccal delivery of this drug. These nanoparticles were prepd. by the nanopptn. method using different molar masses and concns. of chitosan and concns. of triblock surfactant poloxamer (PEO-PPO-PEO), to optimize the prepn. conditions. Chitosan-coated nanoparticles showed pos. surface charge and a mean particle radius ranging between 114 and 125 nm, confirming the decoration of the nanoparticles with the mucoadhesive polymer, through hydrogen bonds between ether and amino groups from PEO and CS, resp. Dynamic Light Scattering (DLS) studies at different scattering angles and concns. showed that the nanoparticles are monodisperse (polydispersity indexes were <0.3). The nanoparticle systems were also examd. with Nanoparticle Tracking Anal. (NTA), and the results were in good agreement with those obtained by DLS. Colloidal systems showed mean drug content ∼460 μg/mL and encapsulation efficiency >99%. Finally, when coated with chitosan, these nanoparticles show a great ability to interact with mucin indicating also their suitability for mucoadhesive applications.
- 141Katara, R.; Majumdar, D. K. Eudragit RL 100-based nanoparticulate system of aceclofenac for ocular delivery. Colloids Surf. B Biointerfaces 2013, 103, 455– 462, DOI: 10.1016/j.colsurfb.2012.10.056Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlalu74%253D&md5=aaafd497f5c06b293e5eb5e32ed8a857Eudragit RL 100-based nanoparticulate system of aceclofenac for ocular deliveryKatara, Rajesh; Majumdar, Dipak K.Colloids and Surfaces, B: Biointerfaces (2013), 103 (), 455-462CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)The purpose of this study was to prep. Eudragit RL 100-based nanoparticles of aceclofenac by nanopptn. and evaluate the particle size, zeta potential, drug entrapment, particle morphol.; in vitro drug release and in vivo efficacy. Change in drug-polymer ratio from 1:5 to 1:20 increased the particle size and entrapment efficiency. The particles showed sustained in vitro drug release which followed the Higuchi square-root kinetics. The results indicate that the nanoparticles release the drug by a combination of dissoln. and diffusion. Based on the particle size (134.97 nm) and entrapment efficiency (95.73%), the formulation made with 1:10 drug-polymer ratio was selected for further studies. The particles were spherical with a polydispersity index of 0.186 and zeta potential of +30.5 mV. Powder X-ray diffraction and differential scanning calorimetry indicated decrease in crystallinity of drug in the nanoparticle formulation. In the in vitro permeation study, the nanoparticle formulation showed 2-fold higher permeation of drug through excised cornea compared to an aq. soln. of drug with no signs of corneal damage. The in vivo studies involving arachidonic acid-induced ocular inflammation in rabbits revealed significantly higher inhibition of polymorphonuclear leukocytes migration (p < 0.05) and lid closure scores by the nanoparticle formulation compared with the aq. soln. The formulation was quite stable to ensure 2 yr shelf life at room temp.
- 142Dong, Y.; Ng, W. K.; Shen, S.; Kim, S.; Tan, R. B. Solid lipid nanoparticles: continuous and potential large-scale nanoprecipitation production in static mixers. Colloids Surf. B Biointerfaces 2012, 94, 68– 72, DOI: 10.1016/j.colsurfb.2012.01.018Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvV2lsLc%253D&md5=7fc4b84734b9e1a136275b450d2491acSolid lipid nanoparticles: Continuous and potential large-scale nanoprecipitation production in static mixersDong, Yuancai; Ng, Wai Kiong; Shen, Shoucang; Kim, Sanggu; Tan, Reginald B. H.Colloids and Surfaces, B: Biointerfaces (2012), 94 (), 68-72CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)This work aimed at developing continuous and scalable nanopptn. synthesis of solid lipid nanoparticles (SLN) by mixing lipids acetonic soln. with water using static mixers. The developed platform exhibited good control over the nanopptn. process and enabled the prodn. of SLN below 200 nm at a throughput of 37.5-150 g/h (for 25 mg/mL lipid soln. at a flow rate of 25-100 mL/min). Among the several process parameters investigated, the lipid concn. played primary role in influencing the size of the SLN and higher lipid concn. resulted in relatively larger particles. Fenofibrate, a model drug, has been successfully loaded into the SLN. Our work demonstrates the potential of applying static mixing-nanopptn. for continuous and large scale prodn. of SLN.
- 143Riewe, J.; Erfle, P.; Melzig, S.; Kwade, A.; Dietzel, A.; Bunjes, H. Antisolvent precipitation of lipid nanoparticles in microfluidic systems - A comparative study. Int. J. Pharm. 2020, 579, 119167, DOI: 10.1016/j.ijpharm.2020.119167Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkslarurk%253D&md5=0756f182c3c4e28d2b13b6485bf09677Antisolvent precipitation of lipid nanoparticles in microfluidic systems - A comparative studyRiewe, Juliane; Erfle, Peer; Melzig, Sebastian; Kwade, Arno; Dietzel, Andreas; Bunjes, HeikeInternational Journal of Pharmaceutics (Amsterdam, Netherlands) (2020), 579 (), 119167CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)Microsystems offer promising possibilities to produce nanoparticles which can be used as carriers for poorly water-sol. active substances. The aim of the present study was to compare the prepn. of lipid nanoparticles by pptn. in different microsystems: A segmented-flow micromixer, a high-pressure micromixer and the com. NanoAssemblrTM platform with a staggered herringbone micromixer. A batch set-up served as ref. expt. Castor oil nanoemulsions prepd. with polysorbate 80 as surfactant in the aq. phase were in the size range of 36-160 nm. The particle sizes could be reduced to 43-93 nm when the surfactant was processed via the ethanolic phase. Furthermore, glycerol monooleate nanodispersions (65-141 nm) were manufd. with poloxamer 407 added as stabilizer via the aq. phase. Deposition of lipid material in the segmented-flow micromixer could be reduced by a modification of the design. Prepn. in the high-pressure mixer and in the herringbone mixer at high total flow rates resulted in the smallest particles for castor oil emulsions, but with bimodal distributions. The particle size of glycerol monooleate dispersions was smallest when prepd. in the high-pressure micromixer and in the herringbone micromixer at a higher flow rate. In conclusion, microfluidic systems can be a useful tool to produce lipid nanoparticles.
- 144Streck, S.; Neumann, H.; Nielsen, H. M.; Rades, T.; McDowell, A. Comparison of bulk and microfluidics methods for the formulation of poly-lactic-co-glycolic acid (PLGA) nanoparticles modified with cell-penetrating peptides of different architectures. International journal of pharmaceutics: X 2019, 1, 100030, DOI: 10.1016/j.ijpx.2019.100030Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1WmtrfF&md5=74432ed416ae6ee0976ef6a0caa3141eComparison of bulk and microfluidics methods for the formulation of poly-lactic-co-glycolic acid (PLGA) nanoparticles modified with cell-penetrating peptides of different architecturesStreck, Sarah; Neumann, Henriette; Nielsen, Hanne Moerck; Rades, Thomas; McDowell, ArleneInternational Journal of Pharmaceutics: X (2019), 1 (), 100030CODEN: IJPXAP; ISSN:2590-1567. (Elsevier B.V.)The efficient and reproducible prodn. of nanoparticles using bulk nanopptn. methods is still challenging because of low batch to batch reproducibility. Here, we optimize a bulk nanopptn. method using design of expts. and translate to a microfluidic device to formulate surface-modified poly-lactic-co-glycolic (PLGA) nanoparticles. Cell-penetrating peptides (CPPs) with a short, long linear or branched architecture were used for the surface modification of PLGA nanoparticles. The microfluidics method was more time efficient than the bulk nanopptn. method and allowed the formulation of uniform PLGA nanoparticles with a size of 150 nm, a polydispersity index below 0.150 and with better reproducibility in comparison to the bulk nanopptn. method. After surface modification the size of CPP-tagged PLGA nanoparticles increased to 160-180 nm and the surface charge of the CPP-tagged PLGA nanoparticles varied between -24 mV and +3 mV, depending on the architecture and concn. of the conjugated CPP. Covalent attachment of CPPs to the PLGA polymer was confirmed with FTIR by identifying the formation of an amide bond. The conjugation efficiency of CPPs to the polymeric PLGA nanoparticles was between 32 and 80%. The development and design of reproducible nanoformulations with tuneable surface properties is crucial to understand interactions at the nano-bio interface.
- 145Gupta, A.; Eral, H. B.; Hatton, T. A.; Doyle, P. S. Nanoemulsions: formation, properties and applications. Soft Matter 2016, 12 (11), 2826– 2841, DOI: 10.1039/C5SM02958AGoogle Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjtVCgur8%253D&md5=157b13b11410fded750c89ed10060261Nanoemulsions: formation, properties and applicationsGupta, Ankur; Eral, H. Burak; Hatton, T. Alan; Doyle, Patrick S.Soft Matter (2016), 12 (11), 2826-2841CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)Nanoemulsions are kinetically stable liq.-in-liq. dispersions with droplet sizes on the order of 100 nm. Their small size leads to useful properties such as high surface area per unit vol., robust stability, optically transparent appearance, and tunable rheol. Nanoemulsions are finding application in diverse areas such as drug delivery, food, cosmetics, pharmaceuticals, and material synthesis. Addnl., they serve as model systems to understand nanoscale colloidal dispersions. High and low energy methods are used to prep. nanoemulsions, including high pressure homogenization, ultrasonication, phase inversion temp. and emulsion inversion point, as well as recently developed approaches such as bubble bursting method. In this review article, we summarize the major methods to prep. nanoemulsions, theories to predict droplet size, phys. conditions and chem. additives which affect droplet stability, and recent applications.
- 146Ganesan, P.; Narayanasamy, D. Lipid nanoparticles: Different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery. Sustainable Chemistry and Pharmacy 2017, 6, 37– 56, DOI: 10.1016/j.scp.2017.07.002Google ScholarThere is no corresponding record for this reference.
- 147Battaglia, L.; Trotta, M.; Gallarate, M.; Carlotti, M. E.; Zara, G. P.; Bargoni, A. Solid lipid nanoparticles formed by solvent-in-water emulsion-diffusion technique: development and influence on insulin stability. J. Microencapsul 2007, 24 (7), 672, DOI: 10.1080/02652040701532981Google ScholarThere is no corresponding record for this reference.
- 148Vandergraaf, S.; Schroen, C.; Boom, R. Preparation of double emulsions by membrane emulsification?a review. J. Membr. Sci. 2005, 251 (1–2), 7– 15, DOI: 10.1016/j.memsci.2004.12.013Google ScholarThere is no corresponding record for this reference.
- 149Gibaud, S.; Attivi, D. Microemulsions for oral administration and their therapeutic applications. Expert Opin Drug Deliv 2012, 9 (8), 937– 951, DOI: 10.1517/17425247.2012.694865Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVOmsbjF&md5=93b937adcb32da97471c95f55b9833c2Microemulsions for oral administration and their therapeutic applicationsGibaud, Stephane; Attivi, DavidExpert Opinion on Drug Delivery (2012), 9 (8), 937-951CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)A review. Introduction: The microemulsion concept was introduced in 1943 by Hoar and Schulman. Self-microemulsifying drug delivery systems (S(M)EDDS) are much more recent and can be described as isotropic solns. of oils and surfactants that form oil-in-water O/W microemulsions when they are poured into an aq. medium. When they are presented as soft capsules for oral delivery, S(M)EDDS have the ability to considerably improve the intestinal absorption of agents that are incorporated into the S(M)EDDS. Forty percent of newly discovered drug candidates have little or no water soly. and therefore have low and/or variable bioavailability profiles. Many of these drugs are good candidates for formulation into S(M)EDDS.Areas covered: This paper describes the prepn. and assessment of these formulations and their current applications. The characterization of this type of formulation has improved, and in vitro models (Caco-2 cell cultures, Ussing chambers, the everted sac technique, etc.) can be used for screening different formulations. It describes also marketed formulations (i.e., cyclosporin and saquinavir S(M)EDDS) and some other formulations.Expert opinion: Actual applications of S(M)EDDS remain rare. The first drug marketed as a S(M)EDDS was cyclosporin, and it had significantly improved bioavailability compared with the conventional soln. In the last decade, several S(M)EDDS loaded with antiviral drugs (e.g., ritonavir, saquinavir) were tested for treatment of HIV infection, but the relative improvement in clin. benefit was not significant. The S(M)EDDS formulation of Norvir (soft capsules) has been withdrawn in some countries.
- 150Trotta, M.; Debernardi, F.; Caputo, O. Preparation of solid lipid nanoparticles by a solvent emulsification-diffusion technique. Int. J. Pharm. 2003, 257 (1–2), 153– 160, DOI: 10.1016/S0378-5173(03)00135-2Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjtVemsrY%253D&md5=8a2b5dc89012f6f86bc183085cf9eeacPreparation of solid lipid nanoparticles by a solvent emulsification-diffusion techniqueTrotta, Michele; Debernardi, Francesca; Caputo, OttoInternational Journal of Pharmaceutics (2003), 257 (1-2), 153-160CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)A prepn. method for nanoparticles based on the emulsification of a Bu lactate or benzyl alc. soln. of a solid lipid in an aq. soln. of different emulsifiers, followed by diln. of the emulsion with water, was used to prep. glyceryl monostearate nanodispersions with narrow size distribution. To increase the lipid load the process was conducted at 47±2 °C and to reach submicron size a high-shear homogenizer was used. Particle size of the solid lipid nanoparticles (SLN) was affected by different emulsifiers and different lipid loads. By using lecithin and taurodeoxycholic acid sodium salt, on increasing the GMS percentage from 2.5 to 10% an increase of the mean diam. from 205 to 695 nm and from 320 to 368 nm was obsd. for the SLN prepd. using benzyl alc. and Bu lactate, resp. Transmission electron micrographs of SLN reveal nanospheres with a smooth surface.
- 151Sjöström, B.; Bergenståhl, B. Preparation of submicron drug particles in lecithin-stabilized o/w emulsions I. Model studies of the precipitation of cholesteryl acetate. Int. J. Pharm. 1992, 88 (1–3), 53– 62, DOI: 10.1016/0378-5173(92)90303-JGoogle ScholarThere is no corresponding record for this reference.
- 152Trotta, M.; Gallarate, M.; Pattarino, F.; Morel, S. Emulsions containing partially water-miscible solvents for the preparation of drug nanosuspensions. J. Controlled Release 2001, 76 (1–2), 119– 128, DOI: 10.1016/S0168-3659(01)00432-1Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmt1Glsrc%253D&md5=f3bd861120446da46a04c1e3329f4422Emulsions containing partially water-miscible solvents for the preparation of drug nanosuspensionsTrotta, M.; Gallarate, M.; Pattarino, F.; Morel, S.Journal of Controlled Release (2001), 76 (1-2), 119-128CODEN: JCREEC; ISSN:0168-3659. (Elsevier Science Ireland Ltd.)The aim of this study was to investigate the feasibility of partially water-miscible solvents, such as benzyl alc., Bu lactate and triacetin, to prep. drug nanosuspensions by a solvent quenching technique. Mitotane, which possesses very poor water soly. and low bioavailability, was used as model drug. Prepn. was by emulsifying an org. soln. of the drug in an aq. soln. of a stabilizing agent followed by rapid displacement of the solvent from the internal into the external phase, provoking solid particle formation. To verify the influence of emulsion droplet size on the drug particle size, 0.1 or 0.2% of different emulsifiers (Tween 80, caprylyl-capryl glucoside or lecithin) and different homogenization conditions (Ultra Turrax or a high pressure homogenizer at 200 or 1000 bar for three cycles) were used. In general, emulsion droplet size decreased with high pressure homogenization and on increasing the no. of cycles. The size of drug particles, obtained after adding water at a const. rate, was dependent on the droplet size in the emulsion. Drug particles of ∼80 nm were obtained using Bu lactate, supporting the hypothesis that drug particle formation by the emulsification diffusion process involves generating regions of local supersatn. Because of the increase in available surface area, the dissoln. rate of diaultrafiltrated suspensions increased greatly compared to com. product.
- 153Gamal, A.; Gad, S.; Gardouh, A. Formulation and pharmacokinetic evaluation of rifampicin solid lipid nanoparticles. J. Res. Pharmacy 2020, 24, 539, DOI: 10.35333/jrp.2020.202Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitlSlurfE&md5=64ba9a508ebb8de3e0b459d4a43d1b4dFormulation and pharmacokinetic evaluation of rifampicin solid lipid nanoparticlesGardouh, Ahmed; Gamal, Alshimaa; Gad, ShadeedJournal of Research in Pharmacy (2020), 24 (4), 539-551CODEN: JRPOBW; ISSN:2630-6344. (Marmara University Press)RIF loaded SLNs were formulated by a modified micro emulsionbased technique using two different lipids (Cetyl palmitate and Glyceryl monostearate) and two different surfactants (Tween 80 and Poloxamer 188). Particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (E.E), drug loading capacity (L.C), in vitro drug release, differential scanning calorimetry (DSC), Fourier transform IR spectroscopy (FTIR) and transmission electron microscopy (TEM) were detd. for RIF loaded SLNs formulas. Pharmacokinetic study was performed on optimized RIF-SLNs, marketed RIF and pure drug suspension in Wistar rats. The particle size, PDI, E.E% and L.C% of optimized formula were recorded as 0.183μm, 0.420, -34.7 mV, 80.8% and 0.216%, resp. In vitro release studies suggested that all SLNs formulas possessed a burst release created from the unloaded drug and adsorbed drug mols. at SLNs surface then sustained release due to diffusion of drug from lipid matrix over a period of 120 h. From the release kinetics data, the release rate of RIF from all formulas fitted into Higuchi's diffusion model. Pharmacokinetic study showed significant enhancement in RIF-SLNs relative bioavailability 5.86 and 2.33 folds in comparison with pure RIF suspension and marketed RIF. RIF loaded SLNs were formulated successfully by a modified micro emulsion-based method. Also, oral drug delivery can be enhanced by SLNs which showed improvement in the oral bioavailability of the drug.
- 154Roumi, S.; Tabrizi, M. H.; Eshaghi, A.; Abbasi, N. Teucrium polium extract-loaded solid lipid nanoparticles: A design and in vitro anticancer study. J. Food Biochem 2021, 45 (9), e13868 DOI: 10.1111/jfbc.13868Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsl2mtrfF&md5=11ecc6d1c392c2553c6101456207f5beTeucrium polium extract-loaded solid lipid nanoparticles: A design and in vitro anticancer studyRoumi, Sana; Tabrizi, Masoud Homayouni; Eshaghi, Ali; Abbasi, NafasJournal of Food Biochemistry (2021), 45 (9), e13868CODEN: JFBIDW; ISSN:0145-8884. (Wiley-Blackwell)Teucrium polium ext. (TPE) is a natural product with potent anticancer activity because of its terpenoid and flavonoid content. The aim of this study was to synthesize solid lipid nanoparticles (SLN) contg. T. polium ext. (TPE-SLNs) and to evaluate its anti-cancer effect. Formulations of TPE-SLNs were prepd. using high-shear homogenization followed by the ultra-sonication technique. Then the TPE-SLNs were characterized by dynamic light scattering (DLS), Zetasizer and field-emission SEM (FESEM), and Fourier transform IR spectroscopy methods. After confirming the presence of nanoparticles, its anti-proliferative activity was evaluated on Ntra-2 cancer cells and compared to human foreskin fibroblasts (HFF) as a normal cell line by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The pro-apoptotic (flow cytometry) and quant. PCR (qPCR) and anti-angiogenic (chick chorioallantoic membrane (CAM)) and anti-inflammatory (qPCR) effects of TPE-SLNs were assessed by various methods. TPE-SLNs (85.5 nm, PDI: 0.39, and zeta potential: -25.5 mv) were inhibited by the proliferation of Ntra-2 cancer cells with half-maximal inhibitory concn. (IC50; 106.58μg/mL). Moreover, by increasing the expression of caspase-3,9 and decreasing the expression of interleukin 6 (IL-6), IL-1b, and Bcl-2 genes, apoptosis and anti-inflammatory effects were obsd. Redn. of angiogenesis was obsd. by the redn. of genes involved in angiogenesis and redn. of vascular and embryonic factors in the CAM assay. Activation of various mechanisms of inhibiting cancer cells in the treatment of nanoparticles was demonstrated in the present study. Therefore, these nanoparticles can be recommended for therapeutic purposes. Practical applications : Solid lipid nanoparticles (SLNs) are composed of pure solid fats and have been researched for many applications. Advantages such as high safety, low toxicity, control of drug release, and increase in chem. stability of loaded drugs distinguish these systems from other colloidal systems. According to the results of this study, solid lipid nanoparticles (SLN) contg. T. polium ext. showed their anti-cancer effects through various strategies such as inhibiting angiogenesis, inhibiting inflammation, and inducing apoptosis on Ntra-2 cells. These results make it possible to apply these nanocarriers in the loading and transport of drugs to treat various diseases such as cancer.
- 155Subramanian, P. Lipid-Based Nanocarrier System for the Effective Delivery of Nutraceuticals. Molecules 2021, 26 (18), 5510, DOI: 10.3390/molecules26185510Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitl2hurzE&md5=0569516c7aad966547faef44667cad12Lipid-Based Nanocarrier System for the Effective Delivery of NutraceuticalsSubramanian, ParthasarathiMolecules (2021), 26 (18), 5510CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Nutraceuticals possess several health benefits and functions; however, most nutraceuticals are prone to degrdn. in the gastrointestinal environment and have poor bioavailability. Application of a novel carrier system is of increasing importance to overcome obstacles and provide efficient applicability. Lipid-based nanocarriers provide a large surface-to-mass ratio, enhanced intestinal absorption by solubilization in the intestinal milieu, intestinal lymphatic transport, and altering enterocyte-based transport. A crit. overview of the current limitation, prepn., and application of lipid-based nanocarriers (liposomes and niosomes) and lipid nanoparticles (SLNs and NLCs) is discussed. Phys. and gastrointestinal stability and bioavailability of nanoencapsulated nutraceuticals are considered as well.
- 156Das, S.; Ng, W. K.; Kanaujia, P.; Kim, S.; Tan, R. B. Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: effects of process variables. Colloids Surf. B Biointerfaces 2011, 88 (1), 483– 489, DOI: 10.1016/j.colsurfb.2011.07.036Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtV2qtbrN&md5=58bf1dba1d1e497ec64d362957f20308Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: Effects of process variablesDas, Surajit; Ng, Wai Kiong; Kanaujia, Parijat; Kim, Sanggu; Tan, Reginald B. H.Colloids and Surfaces, B: Biointerfaces (2011), 88 (1), 483-489CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)This study aimed to prep. solid lipid nanoparticles (SLNs) of a hydrophobic drug, tretinoin, by emulsification-ultrasonication method. Soly. of tretinoin in the solid lipids was examd. Effects of process variables were investigated on particle size, polydispersity index (PI), zeta potential (ZP), drug encapsulation efficiency (EE), and drug loading (L) of the SLNs. Shape and surface morphol. of the SLNs were investigated by cryogenic field emission SEM (cryo-FESEM). Complete encapsulation of drug in the nanoparticles was checked by cross-polarized light microscopy and differential scanning calorimetry (DSC). Crystallinity of the formulation was analyzed by DSC and powder x-ray diffraction (PXRD). In addn., drug release and stability studies were also performed. The results indicated that 10 mg tretinoin was sol. in 0.45 ± 0.07 g Precirol ATO5 and 0.36 ± 0.06 g Compritol 888ATO, resp. Process variables exhibited significant influence in producing SLNs. SLNs with <120 nm size, <0.2 PI, >I30I mV ZP, >75% EE, and ∼0.8% L can be produced following the appropriate formulation conditions. Cryo-FESEM study showed spherical particles with smooth surface. Cross-polarized light microscopy study revealed that drug crystals in the external aq. phase were absent when the SLNs were prepd. at ≤0.05% drug concn. DSC and PXRD studies indicated complete drug encapsulation within the nanoparticle matrix as amorphous form. The drug release study demonstrated sustained/prolonged drug release from the SLNs. Furthermore, tretinoin-loaded SLNs were stable for 3 mo at 4 °C. Hence, the developed SLNs can be used as drug carrier for sustained/prolonged drug release and/or to improve oral absorption/bioavailability.
- 157Khairnar, S. V.; Pagare, P.; Thakre, A.; Nambiar, A. R.; Junnuthula, V.; Abraham, M. C.; Kolimi, P.; Nyavanandi, D.; Dyawanapelly, S. Review on the Scale-Up Methods for the Preparation of Solid Lipid Nanoparticles. Pharmaceutics 2022, 14 (9), 1886, DOI: 10.3390/pharmaceutics14091886Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XisFKksL3I&md5=148972b772693d2be68888f9f43f16fcReview on the Scale-Up Methods for the Preparation of Solid Lipid NanoparticlesKhairnar, Sakshi V.; Pagare, Pritha; Thakre, Aditya; Nambiar, Aswathy Rajeevan; Junnuthula, Vijayabhaskarreddy; Abraham, Manju Cheripelil; Kolimi, Praveen; Nyavanandi, Dinesh; Dyawanapelly, SathishPharmaceutics (2022), 14 (9), 1886CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)Solid lipid nanoparticles (SLNs) are an alternate carrier system to liposomes, polymeric nanoparticles, and inorg. carriers. SLNs have attracted increasing attention in recent years for delivering drugs, nucleic acids, proteins, peptides, nutraceuticals, and cosmetics. These nanocarriers have attracted industrial attention due to their ease of prepn., physicochem. stability, and scalability. These characteristics make SLNs attractive for manuf. on a large scale. Currently, several products with SLNs are in clin. trials, and there is a high possibility that SLN carriers will quickly increase their presence in the market. A large-scale manufg. unit is required for com. applications to prep. enough formulations for clin. studies. Furthermore, continuous processing is becoming more popular in the pharmaceutical sector to reduce product batch-to-batch differences. This review paper discusses some conventional methods and the rationale for large-scale prodn. It further covers recent progress in scale-up methods for the synthesis of SLNs, including high-pressure homogenization (HPH), hot melt extrusion coupled with HPH, microchannels, nanopptn. using static mixers, and microemulsion-based methods. These scale-up technologies enable the possibility of commercialization of SLNs. Furthermore, ongoing studies indicate that these technologies will eventually reach the pharmaceutical market.
- 158Ding, S.; Anton, N.; Vandamme, T. F.; Serra, C. A. Microfluidic nanoprecipitation systems for preparing pure drug or polymeric drug loaded nanoparticles: an overview. Expert Opin Drug Deliv 2016, 13 (10), 1447– 1460, DOI: 10.1080/17425247.2016.1193151Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptlCrsbc%253D&md5=615aac651de01ac777a334de22c54b92Microfluidic nanoprecipitation systems for preparing pure drug or polymeric drug loaded nanoparticles: an overviewDing, Shukai; Anton, Nicolas; Vandamme, Thierry F.; Serra, Christophe A.Expert Opinion on Drug Delivery (2016), 13 (10), 1447-1460CODEN: EODDAW; ISSN:1742-5247. (Taylor & Francis Ltd.)This review gives an overview of the different microfluidic setups used to produce either pure drug or drug-loaded polymeric nanoparticles. We propose a description of the different fluidic principles reported in the literature, explaining their resp. design and configuration in parallel with the tech. challenges related to the nanopptn. of the polymer, in relation with the results obtained, e.g., particle size, distribution and productivity. This review is mostly intended for a broad readership and provides key tools regarding the choice of microfluidic setups, tailored to given specifications. We discuss the specificities and geometries of the microfluidic devices intended to nanopptn., advantages, drawbacks and limitations.
- 159Liu, Y.; Yang, G.; Hui, Y.; Ranaweera, S.; Zhao, C. X. Microfluidic Nanoparticles for Drug Delivery. Small 2022, 18 (36), e2106580 DOI: 10.1002/smll.202106580Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpvFKjs70%253D&md5=37e1e608e094927e4a30c17e64c6dad0Microfluidic Nanoparticles for Drug DeliveryLiu, Yun; Yang, Guangze; Hui, Yue; Ranaweera, Supun; Zhao, Chun-XiaSmall (2022), 18 (36), 2106580CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Nanoparticles (NPs) have attracted tremendous interest in drug delivery in the past decades. Microfluidics offers a promising strategy for making NPs for drug delivery due to its capability in precisely controlling NP properties. The recent success of mRNA vaccines using microfluidics represents a big milestone for microfluidic NPs for pharmaceutical applications, and its rapid scaling up demonstrates the feasibility of using microfluidics for industrial-scale manufg. This article provides a crit. review of recent progress in microfluidic NPs for drug delivery. First, the synthesis of org. NPs using microfluidics focusing on typical microfluidic methods and their applications in making popular and clin. relevant NPs, such as liposomes, lipid NPs, and polymer NPs, as well as their synthesis mechanisms are summarized. Then, the microfluidic synthesis of several representative inorg. NPs (e.g., silica, metal, metal oxide, and quantum dots), and hybrid NPs is discussed. Lastly, the applications of microfluidic NPs for various drug delivery applications are presented.
- 160Pourabed, A.; Younas, T.; Liu, C.; Shanbhag, B. K.; He, L.; Alan, T. High throughput acoustic microfluidic mixer controls self-assembly of protein nanoparticles with tuneable sizes. J. Colloid Interface Sci. 2021, 585, 229– 236, DOI: 10.1016/j.jcis.2020.11.070Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisVyitbnM&md5=0bc10544f1190df48cb0758a7e1223d8Acoustic microfluidic mixer controls self-assembly of protein nanoparticles with tuneable sizesPourabed, Amir; Younas, Tayyaba; Liu, Chang; Shanbhag, Bhuvana K.; He, Lizhong; Alan, TuncayJournal of Colloid and Interface Science (2021), 585 (), 229-236CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)Protein nanoparticles have attracted increased interest due to their broad applications ranging from drug delivery and vaccines to biocatalysts and biosensors. The morphol. and the size of the nanoparticles play a crucial role in detg. their suitability for different applications. Yet, effectively controlling the size of the nanoparticles is still a significant challenge in their manuf. The hypothesis of this paper is that the assembly conditions and size of protein particles can be tuned via a mech. route by simply modifying the mixing time and strength, while keeping the chem. parameters const. We use an acoustically actuated, high throughput, ultrafast, microfluidic mixer for the assembly of protein particles with tuneable sizes. The performance of the acoustic micro-mixer is characterized via Laser Doppler Vibrometry and image processing. The assembly of protein nanoparticles is monitored by dynamic light scattering (DLS) and transmission electron microscopy (TEM). By changing actuation parameters, the turbulence and mixing in the microchannel can be precisely varied to control the initiation of protein particle assembly while the soln. conditions of assembly (pH and ionic strength) are kept const. Importantly, mixing times as low as 6 ms can be achieved for triggering protein assembly in the microfluidic channel. In comparison to the conventional batch process of assembly, the acoustic microfluidic mixer approach produces smaller particles with a more uniform size distribution, promising a new way to manuf. protein particles with controllable quality.
- 161Maeki, M.; Kimura, N.; Sato, Y.; Harashima, H.; Tokeshi, M. Advances in microfluidics for lipid nanoparticles and extracellular vesicles and applications in drug delivery systems. Adv. Drug Delivery Rev. 2018, 128, 84– 100, DOI: 10.1016/j.addr.2018.03.008Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnslOhur4%253D&md5=dc9cec6c06ac9a634c91657fac1a5a53Advances in microfluidics for lipid nanoparticles and extracellular vesicles and applications in drug delivery systemsMaeki, Masatoshi; Kimura, Niko; Sato, Yusuke; Harashima, Hideyoshi; Tokeshi, ManabuAdvanced Drug Delivery Reviews (2018), 128 (), 84-100CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Lipid-based nanobiomaterials as liposomes and lipid nanoparticles (LNPs) are the most widely used nanocarriers for drug delivery systems (DDSs). Extracellular vesicles (EVs) and exosomes are also expected to be applied as DDS nanocarriers. The performance of nanomedicines relies on their components such as lipids, targeting ligands, encapsulated DNA, encapsulated RNA, and drugs. Recently, the importance of the nanocarrier sizes smaller than 100 nm is attracting attention as a means to improve nanomedicine performance. Microfluidics and lab-on-a chip technologies make it possible to produce size-controlled LNPs by a simple continuous flow process and to sep. EVs from blood samples by using a surface marker, ligand, or elec. charge or by making a mass or particle size discrimination. Here, we overview recent advances in microfluidic devices and techniques for liposomes, LNPs, and EVs and their applications for DDSs.
- 162Maeki, M.; Uno, S.; Niwa, A.; Okada, Y.; Tokeshi, M. Microfluidic technologies and devices for lipid nanoparticle-based RNA delivery. J. Controlled Release 2022, 344, 80– 96, DOI: 10.1016/j.jconrel.2022.02.017Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XkvFegu7Y%253D&md5=e624cf5c2755bdc9c99670fc161e2d9cMicrofluidic technologies and devices for lipid nanoparticle-based RNA deliveryMaeki, Masatoshi; Uno, Shuya; Niwa, Ayuka; Okada, Yuto; Tokeshi, ManabuJournal of Controlled Release (2022), 344 (), 80-96CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. In 2021, mRNA vaccines against COVID-19 were approved by the Food and Drug Administration. The mRNA vaccines are important for preventing severe COVID-19 and returning to normal life. The development of RNA-delivery technol., including mRNA vaccines, has been investigated worldwide for ∼30 yr. Lipid nanoparticles (LNPs) are a breakthrough technol. that stably delivers RNA to target organs, and RNA-loaded LNP-based nanomedicines have been studied for the development of vaccines and nanomedicines for RNA-, gene-, and cell-based therapies. Recently, microfluidic devices and technologies have attracted attention for the prodn. of LNPs, particularly RNA-loaded LNPs. Microfluidics provides many advantages for RNA-loaded LNP prodn., including precise LNP size controllability, high reproducibility, high-throughput optimization of LNP formulation, and continuous LNP-prodn. processes. We summarize microfluidic-based RNA-loaded LNP prodn. and its applications in RNA-based therapy and genome editing.
- 163Shepherd, S. J.; Issadore, D.; Mitchell, M. J. Microfluidic formulation of nanoparticles for biomedical applications. Biomaterials 2021, 274, 120826, DOI: 10.1016/j.biomaterials.2021.120826Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVelurzK&md5=ae122491b0d19caeef1d84096567d2e6Microfluidic formulation of nanoparticles for biomedical applicationsShepherd, Sarah J.; Issadore, David; Mitchell, Michael J.Biomaterials (2021), 274 (), 120826CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)A review. Nanomedicine has made significant advances in clin. applications since the late-20th century, in part due to its distinct advantages in biocompatibility, potency, and novel therapeutic applications. Many nanoparticle (NP) therapies have been approved for clin. use, including as imaging agents or as platforms for drug delivery and gene therapy. However, there are remaining challenges that hinder translation, such as non-scalable prodn. methods and the inefficiency of current NP formulations in delivering their cargo to their target. To address challenges with existing formulation methods that have batch-to-batch variability and produce particles with high dispersity, microfluidics-devices that manipulate fluids on a micrometer scale-have demonstrated enormous potential to generate reproducible NP formulations for therapeutic, diagnostic, and preventative applications. Microfluidic-generated NP formulations have been shown to have enhanced properties for biomedical applications by formulating NPs with more controlled phys. properties than is possible with bulk techniques-such as size, size distribution, and loading efficiency. In this review, we highlight advances in microfluidic technologies for the formulation of NPs, with an emphasis on lipid-based NPs, polymeric NPs, and inorg. NPs. We provide a summary of microfluidic devices used for NP formulation with their advantages and resp. challenges. Addnl., we provide our anal. for future outlooks in the field of NP formulation and microfluidics, with emerging topics of prodn. scale-independent formulations through device parallelization and multi-step reactions within droplets.
- 164Baby, T.; Liu, Y.; Middelberg, A. P.; Zhao, C.-X. J. C. E. S. Fundamental studies on throughput capacities of hydrodynamic flow-focusing microfluidics for producing monodisperse polymer nanoparticles 2017, 169, 128– 139, DOI: 10.1016/j.ces.2017.04.046Google ScholarThere is no corresponding record for this reference.
- 165Shepherd, S. J.; Warzecha, C. C.; Yadavali, S.; El-Mayta, R.; Alameh, M. G.; Wang, L. L.; Weissman, D.; Wilson, J. M.; Issadore, D.; Mitchell, M. J. Scalable mRNA and siRNA Lipid Nanoparticle Production Using a Parallelized Microfluidic Device. Nano Lett. 2021, 21 (13), 5671– 5680, DOI: 10.1021/acs.nanolett.1c01353Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVams7%252FM&md5=2c12a37ac4867a7c202bdd97b98ccfceScalable mRNA and siRNA Lipid Nanoparticle Production Using a Parallelized Microfluidic DeviceShepherd, Sarah J.; Warzecha, Claude C.; Yadavali, Sagar; El-Mayta, Rakan; Alameh, Mohamad-Gabriel; Wang, Lili; Weissman, Drew; Wilson, James M.; Issadore, David; Mitchell, Michael J.Nano Letters (2021), 21 (13), 5671-5680CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)A major challenge to advance lipid nanoparticles (LNPs) for RNA therapeutics is the development of formulations that can be produced reliably across the various scales of drug development. Microfluidics can generate LNPs with precisely defined properties, but have been limited by challenges in scaling throughput. To address this challenge, we present a scalable, parallelized microfluidic device (PMD) that incorporates an array of 128 mixing channels that operate simultaneously. The PMD achieves a >100x prodn. rate compared to single microfluidic channels, without sacrificing desirable LNP phys. properties and potency typical of microfluidic-generated LNPs. In mice, we show superior delivery of LNPs encapsulating either Factor VII siRNA or luciferase-encoding mRNA generated using a PMD compared to conventional mixing, with a 4-fold increase in hepatic gene silencing and 5-fold increase in luciferase expression, resp. These results suggest that this PMD can generate scalable and reproducible LNP formulations needed for emerging clin. applications, including RNA therapeutics and vaccines.
- 166Hood, R. R.; DeVoe, D. L.; Atencia, J.; Vreeland, W. N.; Omiatek, D. M. A facile route to the synthesis of monodisperse nanoscale liposomes using 3D microfluidic hydrodynamic focusing in a concentric capillary array. Lab Chip 2014, 14 (14), 2403– 2409, DOI: 10.1039/C4LC00334AGoogle Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVajtb3F&md5=2e16dd9844cd8733e7af993030773435A facile route to the synthesis of monodisperse nanoscale liposomes using 3D microfluidic hydrodynamic focusing in a concentric capillary arrayHood, Renee R.; DeVoe, Don L.; Atencia, Javier; Vreeland, Wyatt N.; Omiatek, Donna M.Lab on a Chip (2014), 14 (14), 2403-2409CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)A novel microscale device has been developed to enable the one-step continuous flow assembly of monodisperse nanoscale liposomes using three-dimensional microfluidic hydrodynamic focusing (3D-MHF) in a concentric capillary array. The 3D-MHF flow technique displays patent advantages over conventional methods for nanoscale liposome manuf. (i.e., bulk-scale alc. injection and/or sonication) through the on-demand synthesis of consistently uniform liposomes without the need for post-processing strategies. Liposomes produced by the 3D-MHF device are of tunable size, have a factor of two improvement in polydispersity, and a prodn. rate that is four orders of magnitude higher than previous MHF methods, which can be attributed to entirely radially sym. diffusion of alc.-solvated lipid into an aq. flow stream. Moreover, the 3D-MHF platform is simple to construct from low-cost, com.-available components, which obviates the need for advanced microfabrication strategies necessitated by previous MHF nanoparticle synthesis platforms.
- 167Ahn, G. Y.; Choi, I.; Ryu, T. K.; Ryu, Y. H.; Oh, D. H.; Kang, H. W.; Kang, M. H.; Choi, S. W. Continuous production of lipid nanoparticles by multiple-splitting in microfluidic devices with chaotic microfibrous channels. Colloids Surf. B Biointerfaces 2023, 224, 113212, DOI: 10.1016/j.colsurfb.2023.113212Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXjs1Gktrw%253D&md5=7445c643caca29e993df70783922085cContinuous production of lipid nanoparticles by multiple-splitting in microfluidic devices with chaotic microfibrous channelsAhn, Guk-Young; Choi, Inseong; Ryu, Tae-Kyung; Ryu, Young-Hyun; Oh, Do-Hyun; Kang, Hye-Won; Kang, Min-Ho; Choi, Sung-WookColloids and Surfaces, B: Biointerfaces (2023), 224 (), 113212CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier B.V.)Polydimethylsiloxane (PDMS) microfluidic devices with chaotic microfibrous channels were fabricated for the continuous prodn. of lipid nanoparticles (LNPs). Electrospun poly(ε-caprolactone) (PCL) microfibrous matrixes with different diams. (3.6 ± 0.3, 6.3 ± 0.4, and 12.2 ± 0.8μm) were used as a template to develop microfibrous channels. The lipid soln. (in ethanol) and water phase were introduced into the microfluidic device as the discontinuous and continuous phases, resp. The smaller diam. of microfibrous channels and the higher flow rate of the continuous phase resulted in the smaller LNPs with a narrower size distribution. The multiple-splitting of the discontinuous phase and the microscale contact between the two phases in the microfibrous channels were the key features of the LNP prodn. in our approach. The LNPs contg. doxorubicin with different av. sizes (89.7 ± 35.1 and 190.4 ± 66.4 nm) were prepd. using the microfluidic devices for the potential application in tumor therapy. In vitro study revealed higher cellular uptake efficiency and cytotoxicity of the smaller LNPs, esp. in the HepG2 cells. The microfluidic devices with microfibrous channels can be widely used as a continuous and high-throughput platform for the prodn. of LNPs contg. various active agents.
- 168Abstiens, K.; Goepferich, A. M. Microfluidic manufacturing improves polydispersity of multicomponent polymeric nanoparticles. Journal of Drug Delivery Science and Technology 2019, 49, 433– 439, DOI: 10.1016/j.jddst.2018.12.009Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFGhsr7N&md5=a058531d29d589c97c1763aa51943ed7Microfluidic manufacturing improves polydispersity of multicomponent polymeric nanoparticlesAbstiens, Kathrin; Goepferich, Achim M.Journal of Drug Delivery Science and Technology (2019), 49 (), 433-439CODEN: JDDSAL; ISSN:1773-2247. (Elsevier B.V.)A key challenge in manufg. of multicomponent polymeric colloids is obtaining monodisperse nanoparticles (NPs) with reproducible characteristics. Herein, NP formulations with varying core to shell ratios were either prepd. by bulk nanopptn. or microfluidic synthesis and evaluated regarding their size and polydispersity. Microfluidic process parameters, such as the total flow rate (TFR) and the flow rate ratio (FRR) of the aq. phase and the org. polymer soln., were varied to tune particle size and further improve size distribution. In general, bulk nanopptn. resulted in formation of larger particles (52-65 nm) with a wide size distribution, whereas particles were significantly smaller in size (24-43 nm) and displayed a rather monodisperse size distribution when they were manufd. with a microfluidic system. The FRR was identified to be the key factor for improving the size distribution of NPs with a high ratio of PLA-PEG to PLGA, whereas it had only minor impact on particle characteristics of formulations with a lower copolymer ratio. Polydispersity of different NP formulations was successfully improved by microfluidic manufg., demonstrating that this technol. is a valuable tool that allows for reproducible and scalable manufg. of multicomponent NPs with precisely tunable quality attributes.
- 169Precision Nanosystems. NxGen TM - A Disruptive Technology Enabling Transformative Medicine. https://www.precisionnanosystems.com/platform-technologies/nxgen.Google ScholarThere is no corresponding record for this reference.
- 170Hao, Y.; Seo, J. H.; Hu, Y.; Mao, H. Q.; Mittal, R. Flow physics and mixing quality in a confined impinging jet mixer. AIP Adv. 2020, 10 (4), 045105, DOI: 10.1063/5.0002125Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpt1Gms7g%253D&md5=ff621b7eefa501289ca894ba074db301Flow physics and mixing quality in a confined impinging jet mixerHao, Yue; Seo, Jung-Hee; Hu, Yizong; Mao, Hai-Quan; Mittal, RajatAIP Advances (2020), 10 (4), 045105CODEN: AAIDBI; ISSN:2158-3226. (American Institute of Physics)Due to their ability to provide efficient mixing at small scales, confined impinging jet mixers (CIJMs) are employed widely in nanoparticle assembly processes such as flash nanopptn. and flash nanocomplexation, which require rapid mixing. In this mixing device, two jets from opposite directions impinge directly on each other forming a thin shear layer that breaks down rapidly into small flow structures. This enables effective mixing of the species transported by each jet by drastically reducing the diffusion distance. In the present study, the mixing performance of a commonly used cylindrical CIJM is examd. by direct numerical simulations. Anal. of the simulation results indicates that the interaction of the shear layer with the inner walls of the CIJM is crit. in inducing a range of instabilities in the impinging jet flow. By examg. flow structures, statistical quantities, and metrics, we have characterized and quantified the mixing quality of a binary mixt. in the CIJM. Product uniformity in processes such as pptn. and complexation is expected to depend on the residence time of the constituents, and this quantity is also calcd. and compared for the cases with different jet Reynolds nos. The jet Reynolds nos. of Re = 200, 600, and 1000 are considered, and the simulation results show that the CIJM achieves very good mixing for the Re = 600 and Re = 1000 cases. It is also found that the Re = 600 case performs slightly better than the other cases in terms of uniformity of the residence time. These quant. analyses offer useful insights into the mechanism of nanoparticle size control and uniformity afforded by the unique flow physics and mixing characteristics in the CIJMs. (c) 2020 American Institute of Physics.
- 171Tao, J.; Chow, S. F.; Zheng, Y. Application of flash nanoprecipitation to fabricate poorly water-soluble drug nanoparticles. Acta Pharm. Sin B 2019, 9 (1), 4– 18, DOI: 10.1016/j.apsb.2018.11.001Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cfjslejsQ%253D%253D&md5=2303a329485b629dcba254d79167db0eApplication of flash nanoprecipitation to fabricate poorly water-soluble drug nanoparticlesTao Jinsong; Zheng Ying; Chow Shing FungActa pharmaceutica Sinica. B (2019), 9 (1), 4-18 ISSN:2211-3835.Nanoparticles are considered to be a powerful approach for the delivery of poorly water-soluble drugs. One of the main challenges is developing an appropriate method for preparation of drug nanoparticles. As a simple, rapid and scalable method, the flash nanoprecipitation (FNP) has been widely used to fabricate these drug nanoparticles, including pure drug nanocrystals, polymeric micelles, polymeric nanoparticles, solid lipid nanoparticles, and polyelectrolyte complexes. This review introduces the application of FNP to produce poorly water-soluble drug nanoparticles by controllable mixing devices, such as confined impinging jets mixer (CIJM), multi-inlet vortex mixer (MIVM) and many other microfluidic mixer systems. The formation mechanisms and processes of drug nanoparticles by FNP are described in detail. Then, the controlling of supersaturation level and mixing rate during the FNP process to tailor the ultrafine drug nanoparticles as well as the influence of drugs, solvent, anti-solvent, stabilizers and temperature on the fabrication are discussed. The ultrafine and uniform nanoparticles of poorly water-soluble drug nanoparticles prepared by CIJM, MIVM and microfluidic mixer systems are reviewed briefly. We believe that the application of microfluidic mixing devices in laboratory with continuous process control and good reproducibility will be benefit for industrial formulation scale-up.
- 172Knauer. Impingement Jets Mixing Skids for high-flow production of nanoparticles (LNP, microemulsions, etc.) , 2022. https://www.knauer.net/en/Systems-Solutions/LNP_lipid_nanoparticles/impingement-jets-mixing-skids-for-high-flow-production-of-nanoparticles (accessed 21 Mar 2023).Google ScholarThere is no corresponding record for this reference.
- 173Warne, N.; Ruesch, M.; Siwik, P.; Mensah, P.; Ludwig, J.; Hripcsak, M.; Godavarti, R.; Prigodich, A.; Dolsten, M. Delivering 3 billion doses of Comirnaty in 2021. Nat. Biotechnol. 2023, 41 (2), 183– 188, DOI: 10.1038/s41587-022-01643-1Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXis1Sjs7o%253D&md5=c0125b7d1eb92de3d174e35c99a37aecDelivering 3 billion doses of Comirnaty in 2021Warne, Nicholas; Ruesch, Margaret; Siwik, Pamela; Mensah, Paul; Ludwig, John; Hripcsak, Michael; Godavarti, Ranga; Prigodich, Andrew; Dolsten, MikaelNature Biotechnology (2023), 41 (2), 183-188CODEN: NABIF9; ISSN:1087-0156. (Nature Portfolio)Pfizer created a 'light-speed' approach to meet the challenge of vaccinating the world against COVID-19. It involved developing new strategies for all aspects of vaccine development, from sourcing materials and scaling up manufg. to transportation and dosing.
- 174Siekmann, B.; Westesen, K. Thermoanalysis of the recrystallization process of melt-homogenized glyceride nanoparticles. Colloids Surf., B 1994, 3 (3), 159– 175, DOI: 10.1016/0927-7765(94)80063-4Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXivVKmu7w%253D&md5=c7066fd7fdd1c09a2d4d1d181101acf2Thermoanalysis of the recrystallization process of melt-homogenized glyceride nanoparticlesSiekmann, Britta; Westesen, KirstenColloids and Surfaces, B: Biointerfaces (1994), 3 (3), 159-75CODEN: CSBBEQ; ISSN:0927-7765. (Elsevier)The recrystn. behavior, the time course of polymorphic transitions, and the degree of crystallinity of melt-homogenized glyceride nanoparticle dispersions were investigated by differential scanning calorimetry (DSC). The results suggest that these properties of the nanoparticles are different from those of the glyceride bulk materials. Crystn. of the molten emulsified glycerides tripalmitate and hard fat in the dispersed state occurs about 20°C lower than in the bulk. The melting temp. of the colloidal cryst. particles is lowered as much as 12°C. Unambiguous interpretation of DSC thermograms is only possible using the information about the cryst. modification of the glyceride nanoparticles obtained by X-ray diffraction studies. The lower degree of crystallinity of the dispersed lipids compared to bulk materials is reflected in the reduced heat of fusion of the glyceride nanoparticles. The polymorphic transitions are accelerated in glyceride nanoparticles as compared to their bulk materials and the effect depends on the emulsifier and its concn. The crystallinity index of hard fat nanoparticles is lower than that of tripalmitate nanoparticles. Incorporation of the model drug ubidecarenone into different lipid matrixes resulted in a decreased crystallinity as well as in a delayed transition of residual α-polymorphic material into the stable β-polymorph. The latter effect was also obsd. for incorporation of glycerol monostearate. The DSC results can be explained in terms of the colloidal nature of the dispersions and the influence of foreign compds. such as emulsifiers, drugs and impurities.
- 175Battaglia, L.; Gallarate, M. Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery. Expert Opinion on Drug Delivery 2012, 9 (5), 497– 508, DOI: 10.1517/17425247.2012.673278Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlvVGrt7g%253D&md5=2291ffdfea37d3020960774d4f68bd87Lipid nanoparticles: state of the art, new preparation methods and challenges in drug deliveryBattaglia, Luigi; Gallarate, MarinaExpert Opinion on Drug Delivery (2012), 9 (5), 497-508CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)A review. Introduction: Nanoparticles are rapidly developing as drug carriers because of their size-dependent properties. Lipid nanoparticles (LNPs) are widely employed in drug delivery because of the biocompatibility of the lipid matrix. Areas covered: Many different types of LNPs have been engineered in the last 20 years, the most important being solid lipid nanoparticles (SLNs), nanostrucured lipid carriers (NLCs), lipid-drug conjugates (LDCs) and lipid nanocapsules (LNCs). This review gives an overview of LNPs, including their physico-chem. properties and pharmacol. uses. Moreover, it highlights the most important innovations in the prepn. techniques of LNPs, aimed to encapsulate different mols. within the lipid matrix. Finally, it gives a short perspective on the challenges of drug delivery, which are a potential field of application for LNPs: cancer therapy, overcoming the blood-brain barrier and gene and protein delivery. Expert opinion: LNPs are a safe and versatile vehicles for drug and active delivery, suitable for different administration routes. New technologies have been developed for LNP prepn. and studies are currently underway in order to obtain the encapsulation of different drugs and to deliver the active mol. to the site of action.
- 176Souto, E. B.; Müller, R. H. Cosmetic features and applications of lipid nanoparticles (SLN, NLC). Int. J. Cosmet Sci. 2008, 30 (3), 157– 165, DOI: 10.1111/j.1468-2494.2008.00433.xGoogle Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXns1alsLw%253D&md5=034525f1e7b6ee45b189d0902f117795Cosmetic features and applications of lipid nanoparticles (SLN , NLC)Souto, E. B.; Muller, R. H.International Journal of Cosmetic Science (2008), 30 (3), 157-165CODEN: IJCMDW; ISSN:0142-5463. (Blackwell Publishing Ltd.)A detailed review of the literature is presented in attempts to emphasize several advantages of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for cosmetic applications. Examples of several actives are given and the main features of the solid core of SLN and NLC for topical delivery of cosmetics are discussed. Lipid nanoparticles have been more and more explored in pharmaceutical technol., showing superior advantages for topical purposes over conventional colloidal carriers.
- 177Bunjes, H.; Westesen, K.; Koch, M. H. J. Crystallization tendency and polymorphic transitions in triglyceride nanoparticles. Int. J. Pharm. 1996, 129 (1), 159– 173, DOI: 10.1016/0378-5173(95)04286-5Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XitVSqsro%253D&md5=57d33bcf6ed743196866516eeea8740fCrystallization tendency and polymorphic transitions in triglyceride nanoparticlesBunjes, Heike; Westesen, Kirsten; Koch, Michel H. J.International Journal of Pharmaceutics (1996), 129 (1,2), 159-73CODEN: IJPHDE; ISSN:0378-5173. (Elsevier)The ability of tristearin, tripalmitin, trimyristin and trilaurin to form solid lipid nanoparticles after melt-homogenization was investigated by DSC and x-ray diffraction. Upon storage at common temps. after prepn. solid nanoparticles were formed in tristearin and tripalmitin dispersions. In contrast to literature reports, colloidal dispersions of trilaurin did not form solid particles under those conditions. They should, therefore, be regarded as emulsions of supercooled melts rather than as nanosuspensions. Trimyristin nanoparticles which can be obtained in solid or liq. form had a larger incorporation capacity for the lipophilic model drug menadione in the liq. than in the solid state. The kinetics of polymorphic transitions after crystn. of triglyceride nanoparticles were slower for longer-chain than for shorter-chain triglycerides. Addn. of tristearin raises the crystn. temp. of colloidally dispersed trimyristin and trilaurin facilitating solidification during prodn. The structure and melting behavior of the resulting mixed nanoparticles are more complex than those of nanoparticles prepd. from the simple triglycerides. Depending on the mixing ratio, the time-course of polymorphic transitions after crystn. may also be altered significantly. The melting enthalpy of the mixed nanoparticle dispersions is usually not significantly different from that of dispersions of the simple triglycerides.
- 178Youshia, J.; Kamel, A. O.; El Shamy, A.; Mansour, S. Gamma sterilization and in vivo evaluation of cationic nanostructured lipid carriers as potential ocular delivery systems for antiglaucoma drugs. Eur. J. Pharm. Sci. 2021, 163, 105887, DOI: 10.1016/j.ejps.2021.105887Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtlSrtrbO&md5=be0e049fceb9e4dca48212832c7855baGamma sterilization and in vivo evaluation of cationic nanostructured lipid carriers as potential ocular delivery systems for antiglaucoma drugsYoushia, John; Kamel, Amany O.; El Shamy, Abdelhameed; Mansour, SamarEuropean Journal of Pharmaceutical Sciences (2021), 163 (), 105887CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)Solid lipid nanoparticles and nanostructured lipid carriers showed promising results for enhancement of ocular bioavailability of drugs with poor corneal permeability. One of these drugs is methazolamide, which is an orally administered carbonic anhydrase inhibitor for glaucoma treatment. However, sterilization by autoclaving may result in loss of the phys. properties of lipid nanoparticles such as particle size and surface charge. Here, we evaluated gamma radiation as an alternative sterilization method. Methazolamide loaded nanostructured lipid carriers were optimized using 23 factorial design. Optimized formulations contained 6% lipid (85% solid lipid (Cetostearyl alc. and glyceryl behenate) and 15% oil either medium chain triglycerides or iso-Pr myristate) stabilized by 2% polysorbate 80 and 0.15% stearylamine. Nanoparticles were cationic, smaller than 500 nm, and had an entrapment efficiency of about 30%. They released methazolamide within 8 h and showed a 5-fold enhanced redn. in intraocular pressure compared to methazolamide soln. Gamma sterilization was superior to autoclaving in preserving entrapped methazolamide, size, and surface charge of lipid nanoparticles. These findings demonstrate that gamma radiation is a viable alternative to autoclaving for sterilizing lipid nanoparticles. Moreover, this proves that nanostructured lipid carriers enhance pharmacol. response of topically administered methazolamide for treating glaucoma.
- 179Gokce, E. H.; Sandri, G.; Bonferoni, M. C.; Rossi, S.; Ferrari, F.; Guneri, T.; Caramella, C. Cyclosporine A loaded SLNs: evaluation of cellular uptake and corneal cytotoxicity. Int. J. Pharm. 2008, 364 (1), 76– 86, DOI: 10.1016/j.ijpharm.2008.07.028Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1yktbvJ&md5=b7167326c976a5293b1c1e9b645bcb21Cyclosporine A loaded SLNs: Evaluation of cellular uptake and corneal cytotoxicityGokce, Evren H.; Sandri, Giuseppina; Bonferoni, M. Cristina; Rossi, Silvia; Ferrari, Franca; Gueneri, Tamer; Caramella, CarlaInternational Journal of Pharmaceutics (2008), 364 (1), 76-86CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)Cyclosporine A (CsA) loaded solid lipid nanoparticles (SLNs) for topical ophthalmic applications were prepd. by high shear homogenization and ultrasound method using Compritol 888 ATO, Poloxamer 188 and Tween 80, to investigate the cellular uptake of rabbit corneal epithelial cells (RCE) and to evaluate the cytotoxicity. The size of the optimized formulation was 225.9 ± 5.5 nm with a polydispersity index of 0.253 ± 0.05. The zeta potential and entrapment efficiency was detected as -16.9 ± 0.7 mV and 95.6%, resp. The CsA release was found to be enzyme (lipase/co-lipase complex) dependent. SLNs were sterilized at 110 and 121 °C. The cytotoxicity was evaluated in vitro by RCE cells and was higher at 121 °C sterilization temp., probably due to a supposed leakage of Tween 80 following lipid re-crystn. The permeation and penetration of CsA across/into the corneal cells were evaluated using in vitro and ex vivo expts. The cellular uptake was investigated by replacing CsA with the fluorescent dye Rhodamine B. The penetration enhancement properties were supported by confocal laser scanning microscopy anal. The internalization of SLNs in cornea and in RCE cell lines was confirmed, pointing out the possibility of CsA targeting to the cornea.
- 180Hou, X.; Zaks, T.; Langer, R.; Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 2021, 6 (12), 1078– 1094, DOI: 10.1038/s41578-021-00358-0Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhslOnsr3N&md5=651ec4d4569c58d0ad34c9215c02fd38Lipid nanoparticles for mRNA deliveryHou, Xucheng; Zaks, Tal; Langer, Robert; Dong, YizhouNature Reviews Materials (2021), 6 (12), 1078-1094CODEN: NRMADL; ISSN:2058-8437. (Nature Portfolio)A review. MRNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degrdn. and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle-mRNA vaccines are now in clin. use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we discuss the design of lipid nanoparticles for mRNA delivery and examine physiol. barriers and possible administration routes for lipid nanoparticle-mRNA systems. We then consider key points for the clin. translation of lipid nanoparticle-mRNA formulations, including good manufg. practice, stability, storage and safety, and highlight preclin. and clin. studies of lipid nanoparticle-mRNA therapeutics for infectious diseases, cancer and genetic disorders. Finally, we give an outlook to future possibilities and remaining challenges for this promising technol.
- 181Ma, G. J.; Yoon, B. K.; Sut, T. N.; Yoo, K. Y.; Lee, S. H.; Jeon, W. Y.; Jackman, J. A.; Ariga, K.; Cho, N. J. Lipid coating technology: A potential solution to address the problem of sticky containers and vanishing drugs. View 2022, 3 (3), 20200078, DOI: 10.1002/VIW.20200078Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhvFaksrvE&md5=9da00fd914fd8f479b00998c3778847fLipid coating technology: A potential solution to address the problem of sticky containers and vanishing drugsMa, Gamaliel Junren; Yoon, Bo Kyeong; Sut, Tun Naw; Yoo, Ki Yeol; Lee, Seung Hwa; Jeon, Won-Yong; Jackman, Joshua A.; Ariga, Katsuhiko; Cho, Nam-JoonView (2022), 3 (3), 20200078CODEN: VIEWC3; ISSN:2688-268X. (John Wiley & Sons, Inc.)A review. Pharmaceutical drugs and vaccines require the use of material containers for protection, storage, and transportation. Glass and plastic materials are widely used for packaging, and a longstanding challenge in the field is the nonspecific adsorption of pharmaceutical drugs to container walls - the so-called "sticky containers, vanishing drugs" problem - that effectively reduces the active drug concn. and can cause drug denaturation. This challenge has been frequently discussed in the case of the anticancer drug, paclitaxel, and the ongoing coronavirus disease 2019 (COVID-19) pandemic has brought renewed attention to this material science challenge in light of the need to scale up COVID-19 vaccine prodn. and to secure sufficient quantities of packaging containers. To reduce nonspecific adsorption on inner container walls, various strategies based on siliconization and thin polymer films have been explored, while it would be advantageous to develop mass-manufacturable, natural material solns., esp. ones involving pharmaceutical grade excipients. Inspired by how lipid nanoparticles have revolutionized the vaccine field, in this perspective, we discuss the prospects for developing lipid bilayer coatings to prevent nonspecific adsorption of pharmaceutical drugs and vaccines and how recent advances in lipid bilayer coating fabrication technologies are poised to accelerate progress in the field. We critically discuss recent examples of how lipid bilayer coatings can prevent nonspecific sticking of proteins and vaccines to relevant material surfaces and examine future translational prospects.
- 182Schoenmaker, L.; Witzigmann, D.; Kulkarni, J. A.; Verbeke, R.; Kersten, G.; Jiskoot, W.; Crommelin, D. J. A. mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. Int. J. Pharm. 2021, 601, 120586, DOI: 10.1016/j.ijpharm.2021.120586Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXovFSjsbY%253D&md5=7c669d60f3b3864bf9fc4b24eb2f75cemRNA-lipid nanoparticle COVID-19 vaccines: Structure and stabilitySchoenmaker, Linde; Witzigmann, Dominik; Kulkarni, Jayesh A.; Verbeke, Rein; Kersten, Gideon; Jiskoot, Wim; Crommelin, Daan J. A.International Journal of Pharmaceutics (Amsterdam, Netherlands) (2021), 601 (), 120586CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)A review. A drawback of the current mRNA-lipid nanoparticle (LNP) COVID-19 vaccines is that they have to be stored at (ultra)low temps. Understanding the root cause of the instability of these vaccines may help to rationally improve mRNA-LNP product stability and thereby ease the temp. conditions for storage. We discuss proposed structures of mRNA-LNPs, factors that impact mRNA-LNP stability and strategies to optimize mRNA-LNP product stability. Anal. of mRNA-LNP structures reveals that mRNA, the ionizable cationic lipid, and water are present in the LNP core. The neutral helper lipids are mainly positioned in the outer, encapsulating, wall. The mRNA hydrolysis is the detg. factor for mRNA-LNP instability. It is currently unclear how water in the LNP core interacts with the mRNA and to what extent the degrdn. prone sites of mRNA are protected through a coat of ionizable cationic lipids. To improve the stability of mRNA-LNP vaccines, optimization of the mRNA nucleotide compn. should be prioritized. Secondly, a better understanding of the milieu the mRNA is exposed to in the core of LNPs may help to rationalize adjustments to the LNP structure to preserve mRNA integrity. Moreover, drying techniques, such as lyophilization, are promising options still to be explored.
- 183Jakubek, Z. J.; Chen, S.; Zaifman, J.; Tam, Y. Y. C.; Zou, S. Lipid Nanoparticle and Liposome Reference Materials: Assessment of Size Homogeneity and Long-Term −70 degrees C and 4 degrees C Storage Stability. Langmuir 2023, 39 (7), 2509– 2519, DOI: 10.1021/acs.langmuir.2c02657Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXis1Witbg%253D&md5=a15acae19bb17cc1500c6f0ac62a9260Lipid Nanoparticle and Liposome Reference Materials: Assessment of Size Homogeneity and Long-Term -70°C and 4°C Storage StabilityJakubek, Zygmunt J.; Chen, Sam; Zaifman, Josh; Tam, Yuen Yi C.; Zou, ShanLangmuir (2023), 39 (7), 2509-2519CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)With recent advances and anticipated proliferation of lipid nanoparticle (LNP)-delivered vaccines and therapeutics, there is a need for the availability of internationally recognized ref. materials of LNP systems. Accordingly, we developed six LNP and liposome (anionic, neutral, and cationic each) candidate ref. material formulations and thoroughly characterized by dynamic light scattering their particle hydrodynamic size (Z-avr) and polydispersity. We also evaluated the particle size homogeneity and long-term -70°C and 4°C storage stability using multiple large sets of randomly selected vials for each formulation. The formulations stored at -70°C remained stable and homogeneous for a min. of 9 mo. The Z-avr relative combined uncertainty and the long-term variability were both <1.3% for liposome formulations and anionic LNPs, (3.9% and 1.7%) for neutral LNPs, and (6.7% and 4.4%) for cationic LNPs. An inadvertent few-hour-long storage temp. increase to -35°C due to a freezer malfunction resulted in a small change of the size and size distribution of anionic liposomes and LNPs but, unexpectedly, a larger size increase of the neutral and cationic liposomes (≤5%) and LNPs (≤25%). The mean Z-avr values of the LNPs stored at 4°C appeared to slowly increase with t1/3, where t is the storage time, and the Z-avr between-vial heterogeneity and mean polydispersity index values appeared to decrease; no change was obsd. for liposomes. The size and size distribution evolution of LNPs stored at 4°C was attributed to an incomplete equilibration of the formulations following the addn. of sucrose prior to the initial freezing. Such a process of size increase and size distribution narrowing has not been previously discussed nor obsd. in the context of LNPs.