Dual Thermo- and pH-Responsive Polymer Nanoparticle Assemblies for Potential Stimuli-Controlled Drug DeliveryClick to copy article linkArticle link copied!
- Sára Pytlíková*Sára Pytlíková*E-mail: [email protected]Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Sára Pytlíková
- Rafal KonefałRafal KonefałInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Rafal Konefał
- Robert PolaRobert PolaInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Robert Pola
- Alena BraunováAlena BraunováInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Alena Braunová
- Volodymyr LobazVolodymyr LobazInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Volodymyr Lobaz
- Miroslav ŠloufMiroslav ŠloufInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Miroslav Šlouf
- Hynek BenešHynek BenešInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Hynek Beneš
- Daniil StarenkoDaniil StarenkoInstitute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, Prague 4, 142 00, Czech RepublicMore by Daniil Starenko
- Kateřina BěhalováKateřina BěhalováInstitute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, Prague 4, 142 00, Czech RepublicMore by Kateřina Běhalová
- Marek KovářMarek KovářInstitute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, Prague 4, 142 00, Czech RepublicMore by Marek Kovář
- Tomáš EtrychTomáš EtrychInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Tomáš Etrych
- Richard LagaRichard LagaInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Richard Laga
- Michal PecharMichal PecharInstitute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, Prague 6, 162 00, Czech RepublicMore by Michal Pechar
Abstract
The development of stimuli-responsive drug delivery systems enables targeted delivery and environment-controlled drug release, thereby minimizing off-target effects and systemic toxicity. We prepared and studied tailor-made dual-responsive systems (thermo- and pH-) based on synthetic diblock copolymers consisting of a fully hydrophilic block of poly[N-(1,3-dihydroxypropyl)methacrylamide] (poly(DHPMA)) and a thermoresponsive block of poly[N-(2,2-dimethyl-1,3-dioxan-5-yl)methacrylamide] (poly(DHPMA-acetal)) as drug delivery and smart stimuli-responsive materials. The copolymers were designed for eventual medical application to be fully soluble in aqueous solutions at 25 °C. However, they form well-defined nanoparticles with hydrodynamic diameters of 50–800 nm when heated above the transition temperature of 27–31 °C. This temperature range is carefully tailored to align with the human body’s physiological conditions. The formation of the nanoparticles and their subsequent decomposition was studied using dynamic light scattering (DLS), transmission electron microscopy (TEM), isothermal titration calorimetry (ITC), and nuclear magnetic resonance (NMR). 1H NMR studies confirmed that after approximately 20 h of incubation at pH 5, which closely mimics tumor microenvironment, approximately 40% of the acetal groups were hydrolyzed, and the thermoresponsive behavior of the copolymers was lost. This smart polymer response led to disintegration of the supramolecular structures, possibly releasing the therapeutic cargo. By tuning the transition temperature to the values relevant for medical applications, we ensure precise and effective drug release. In addition, our systems did not exhibit any cytotoxicity against any of the three cell lines. Our findings underscore the immense potential of these nanoparticles as eventual advanced drug delivery systems, especially for cancer therapy.
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License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
This summary highlights only some of the key features and terms of the actual license. It is not a license and has no legal value. Carefully review the actual license before using these materials.
License Summary*
You are free to share(copy and redistribute) this article in any medium or format and to adapt(remix, transform, and build upon) the material for any purpose, even commercially within the parameters below:
Creative Commons (CC): This is a Creative Commons license.
Attribution (BY): Credit must be given to the creator.
*Disclaimer
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1. Introduction
2. Materials and Methods
2.1. Chemicals
2.2. Size-Exclusion Chromatography (SEC)
2.3. Synthesis of Monomers and Chain Transfer Agent (CTA)
Scheme 1
2.4. Synthesis of Poly(DHPMA-Acetal) Homopolymer (A)
Scheme 2
2.5. Synthesis of Poly(DPHMA) Homopolymer (B)
2.6. Synthesis of Diblock Copolymers (AB1-AB3)
Scheme 3
2.7. Hydrolysis of Acetal Groups
2.8. Determination of Hydrodynamic Diameter (DH) and Transition Temperature (Ttr)
2.9. NMR Spectroscopy
2.10. Isothermal Titration Calorimetry (ITC)
2.11. Transmission Electron Microscopy
2.12. Differential Scanning Calorimetry (DSC)
2.13. Cytostatic Effect and Cytotoxicity of the Diblock Copolymers InVitro
2.13.1. Cell Lines and Cell Isolation
2.13.2. Cytostatic and Cytotoxic Assays
3. Results and Discussion
3.1. Synthesis of Thermoresponsive Polymers and Copolymers
3.1.1. Thermoresponsive Block Poly(DHPMA-Acetal)
Sample | Mna | Đa | HFOB/HFILa | Conversion (%)b | Ttrc (°C) | DH20 °C (nm)c | DH30 °C (nm)c | DH37 °C (nm)c | DH46 °C (nm)c |
---|---|---|---|---|---|---|---|---|---|
A | 13,400 | 1.04 | - | 52.2 | 21–22 | 4.7 | >770 | - | - |
B | 21,100 | 1.05 | - | 71.1 | - | 7.6 | - | - | - |
AB1 | 28,300 | 1.01 | 1/0.83 | 48.0 | 27–28 | 8.3 | 600 | 120 | 55 |
AB2 | 40,300 | 1.06 | 1/1.61 | 51.6 | 27–29 | 12.0 | 700 | 115 | 90 |
AB3 | 63,400 | 1.33 | 1/3.10 | 66.0 | 26–30 | 12.9 | 700 | 75 | 60 |
Number-average molecular weight, dispersity, and ratio between the hydrophobic (poly(DHPMA-acetal) (HFOB) and hydrophilic block (poly(DHPMA)) (HFIL) were determined by SEC using RI and LS detection.
Conversion was calculated from the ratio between the measured molecular weight of the given polymer and theoretical molecular weight of the RAFT polymerization.
Transition temperature and hydrodynamic diameter values were determined using DLS measurement.
3.1.2. Amphiphilic Diblock Copolymers
3.2. Solution Behavior of the Thermoresponsive Polymers and Copolymers
3.2.1. Dynamic Light Scattering
Figure 1
Figure 1. Dependence of the hydrodynamic particle size of a) diblock copolymer (AB1) and b) homopolymer A on the temperature during heating (red) and cooling (blue).
3.2.2. 1H NMR Spectra and Fraction p of Proton Groups (Units) with Significantly Reduced Mobility
Figure 2
Figure 2. a) 1H NMR spectra of homopolymer A at 12, 30, and 57 °C. b) Temperature dependences of the fraction p as determined for signals of various proton types in D2O solution of homopolymer A during gradual heating.
Figure 3
Figure 3. a) 1H NMR spectra of copolymer AB1 at 12, 30, and 57 °C. b) Temperature dependences of the fraction p as determined for signals of various proton types in D2O solution of copolymer AB1 during gradual heating.
Figure 4
Figure 4. Temperature dependencies of the fraction p as determined for signal “c” in D2O solutions of A homopolymer and AB1, AB2, and AB3 copolymers during gradual heating.
Figure 5
Figure 5. Temperature dependencies of the fraction p of the protons with significantly reduced mobility in D2O solutions of a) homopolymer A and b) diblock copolymer AB1 during gradual heating (filled symbols) and subsequent gradual cooling (empty symbols).
3.2.3. Behavior of Water (HDO) Molecules Determined by 1H Spin–Spin Relaxation Times T2 Study
Figure 6
Figure 6. a) Temperature dependence and b) time dependence at 57 °C of 1H spin–spin relaxation times T2 of HDO in D2O solutions of the A, AB1, AB2, and AB3.
3.2.4. Conformational Changes of Block Copolymer: 2D 1H–1H NOESY NMR Spectra
Figure 7
Figure 7. a) 2D NOESY spectrum of AB2 block copolymer in D2O solution measured at 12 °C with a mixing time of 400 ms. b) 1D slice spectrum extracted from the “e” signal of the NOESY spectrum, together with chemical structure and intermolecular correlations in the AB2 block copolymer. c) Temperature dependences of integrated intensities of various signals in 1D slices extracted from the signal of protons (“e”) of poly(DHPMA-acetal) units.
3.3. Hydrolysis of the Acetal Groups in the Thermoresponsive Polymers
Figure 8
Figure 8. a) 1H NMR spectra of homopolymer A after 0.5 and 48 h of incubation at pH 5. Signals marked as ″*″ are related to solvent impurities. b) The course of hydrolysis of the ketal groups of homopolymer A at pH 5.0.
Figure 9
Figure 9. Change of the Ttr of homopolymer A and diblock copolymer AB2 at pH 5 and 7.4 over time.
3.4. Critical Aggregation Concentration of the Diblock Copolymers
Figure 10
Figure 10. Enthalpy of dilution of 5 mg mL–1 diblock copolymers in PBS to pure PBS at 37 °C.
3.5. Transmission Electron Microscopy
Figure 11
Figure 11. TEM micrographs showing the morphology of the fast-dried particles of AB1. The fast drying was performed at (a) 5 °C, (b) 37 °C, and (c) 50 °C.
3.6. Differential Scanning Calorimetry
3.7. Cytotoxicity of the Diblock Copolymers In Vitro
Figure 12
Figure 12. Cytostatic and cytotoxic effects of diblock polymers evaluated in mouse cancer cell lines and purified CD8+ T lymphocytes in vitro. Cytostatic effect of AB1, AB2, and AB3 determined in a) EL4, b) LL2 cell lines, and c) CD8+ T lymphocytes isolated from spleens of BALB/c mice using the [3H]-thymidine incorporation assay. Cytotoxic effect of AB1, AB2, and AB3 measured in d) EL4 and e) LL2 cell lines. Each experimental point represents the average value from four wells ± SD. Experiments were performed twice with similar results.
4. Conclusions
Data Availability
The data supporting this article have been included as part of the Supporting Information.
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsabm.4c01167.
SEC chromatograms of polymers, 1H NMR spectra of monomers, results from DLS, ITC and DSC analyses (PDF)
Terms & Conditions
Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Acknowledgments
This research was financially supported by the Ministry of Education, Youth and Sports of the Czech Republic (Program INTER EXCELLENCE/INTER ACTION, Project ID No. LUAUS24239), by National Institute for Cancer Research (Program EXCELES, Project ID No. LX22NPO5102) funded by the European Union, Next Generation EU, and by the Czech Science Foundation (Project No. 22-12483 S).
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- 13Wang, X.; Yang, Y.; Zhang, G.; Tang, C.-Y.; Law, W.-C.; Yu, C.; Wu, X.; Li, S.; Liao, Y. NIR-Cleavable and PH-Responsive Polymeric Yolk–Shell Nanoparticles for Controlled Drug Release. Biomacromolecules 2023, 24 (5), 2009– 2021, DOI: 10.1021/acs.biomac.2c01404Google ScholarThere is no corresponding record for this reference.
- 14Perumal, S.; Atchudan, R.; Lee, W. A Review of Polymeric Micelles and Their Applications. Polymers 2022, 14 (12), 2510, DOI: 10.3390/polym14122510Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhs1GrsbrF&md5=cce588e5bf44ff711afe82f61551ea32A Review of Polymeric Micelles and Their ApplicationsPerumal, Suguna; Atchudan, Raji; Lee, WonmokPolymers (Basel, Switzerland) (2022), 14 (12), 2510CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)A review. Self-assembly of amphiphilic polymers with hydrophilic and hydrophobic units results in micelles (polymeric nanoparticles), where polymer concns. are above crit. micelle concns. (CMCs). Recently, micelles with metal nanoparticles (MNPs) have been utilized in many bio-applications because of their excellent biocompatibility, pharmacokinetics, adhesion to biosurfaces, targetability, and longevity. The size of the micelles is in the range of 10 to 100 nm, and different shapes of micelles have been developed for applications. Micelles have been focused recently on bio-applications because of their unique properties, size, shape, and biocompatibility, which enhance drug loading and target release in a controlled manner. This review focused on how CMC has been calcd. using various techniques. Further, micelle importance is explained briefly, different types and shapes of micelles are discussed, and further extensions for the application of micelles are addressed. In the summary and outlook, points that need focus in future research on micelles are discussed. This will help researchers in the development of micelles for different applications.
- 15Du, F.-S.; Huang, X.-N.; Chen, G.-T.; Lin, S.-S.; Liang, D.; Li, Z.-C. Aqueous Solution Properties of the Acid-Labile Thermoresponsive Poly(Meth)Acrylamides with Pendent Cyclic Orthoester Groups. Macromolecules 2010, 43 (5), 2474– 2483, DOI: 10.1021/ma902227gGoogle Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVyiurY%253D&md5=35b4704ae9e563541edc83187508084cAqueous solution properties of the acid-labile thermo-responsive poly(meth)acrylamides with pendent cyclic orthoester groupsDu, Fu-Sheng; Huang, Xiao-Nan; Chen, Guang-Tao; Lin, Shrong-Shi; Liang, Dehai; Li, Zi-ChenMacromolecules (Washington, DC, United States) (2010), 43 (5), 2474-2483CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)A series of poly(meth)acrylamide derivs. with pendent six-member cyclic orthoester groups, i.e., poly(N-(2-alkyloxy-1,3-dioxan-5-yl)methacrylamide)s and poly(N-(2-alkyloxy-1,3-dioxan-5-yl)acrylamide)s, have been synthesized and characterized. The difference between these polymers lies in the type of alkyl substitutes (R3), the stereochem. structures of the pendent cyclic orthoester groups (trans vs cis), and the main chain structures (polymethacrylamide vs polyacrylamide). Aq. soln. properties and pH-dependent hydrolysis behaviors of these polymers were studied by various methods including turbidimetry, fluorescence probe, DSC, 1H NMR, microscopy, and light scattering. The results show that these polymers except PtNPM can be dissolved in water at low temp., and all of the water-sol. polymers are thermosensitive with different lower crit. soln. temps. (LCSTs) and susceptible to hydrolysis in mildly acidic conditions. Both thermosensitive properties and acid-triggered hydrolysis behaviors of the polymers are closely related to the polymer structures. In general, polymethacrylamides display higher cloud points (CPs) than polyacrylamides. In addn., the polymers with larger R3 and trans configuration have a lower CP and greater magnitude of dehydration and exhibit a liq.-solid phase transition, while those with smaller R3 and cis configuration have a smaller magnitude of dehydration and undergo a liq.-liq. phase sepn. In addn., a two-stage transition process is obsd. for the polymers with R3 being Me. 1H NMR results reveal that the acid-triggered hydrolysis rate of the pendent orthoesters increases as R3 changed from Me to iso-Pr, and the configuration changed from cis to trans.
- 16Huang, X.-N.; Du, F.-S.; Zhang, B.; Zhao, J.-Y.; Li, Z.-C. Acid-labile, Thermoresponsive (Meth)Acrylamide Polymers with Pendant Cyclic Acetal Moieties. J. Polym. Sci., Part A:Polym. Chem. 2008, 46 (13), 4332– 4343, DOI: 10.1002/pola.22751Google ScholarThere is no corresponding record for this reference.
- 17Konefał, R.; Spěváček, J.; Mužíková, G.; Laga, R. Thermoresponsive Behavior of Poly(DEGMA)-Based Copolymers. NMR and Dynamic Light Scattering Study of Aqueous Solutions. Eur. Polym. J. 2020, 124 (November 2019), 109488, DOI: 10.1016/j.eurpolymj.2020.109488Google ScholarThere is no corresponding record for this reference.
- 18Kataoka, K.; Matsumoto, T.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Fukushima, S.; Okamoto, K.; Kwon, G. S. Doxorubicin-Loaded Poly(Ethylene Glycol)–Poly(β-Benzyl-l-Aspartate) Copolymer Micelles: Their Pharmaceutical Characteristics and Biological Significance. J. Controlled Release 2000, 64 (1–3), 143– 153, DOI: 10.1016/S0168-3659(99)00133-9Google ScholarThere is no corresponding record for this reference.
- 19Hamaguchi, T.; Doi, T.; Eguchi-Nakajima, T.; Kato, K.; Yamada, Y.; Shimada, Y.; Fuse, N.; Ohtsu, A.; Matsumoto, S.; Takanashi, M.; Matsumura, Y. Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors. Clin. Cancer Res. 2010, 16 (20), 5058– 5066, DOI: 10.1158/1078-0432.CCR-10-0387Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1yqsLbE&md5=c0384f5052c3d613505e5fdc352560a6Phase I Study of NK012, a Novel SN-38-Incorporating Micellar Nanoparticle, in Adult Patients with Solid TumorsHamaguchi, Tetsuya; Doi, Toshihiko; Eguchi-Nakajima, Takako; Kato, Ken; Yamada, Yasuhide; Shimada, Yasuhiro; Fuse, Nozomu; Ohtsu, Atsushi; Matsumoto, Shin-ichi; Takanashi, Masaya; Matsumura, YasuhiroClinical Cancer Research (2010), 16 (20), 5058-5066CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: We conducted a first-in-human phase I study to det. the dose-limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38-incorporating micellar nanoparticle. Exptl. Design: Patients with solid tumors refractory to std. therapy, or for which no std. therapy is available, were enrolled. NK012 was administered as a 30-min infusion every 3 wk. The starting dose was 2 mg/m2 as SN-38 equiv, and an accelerated titrn. schedule was used. Pharmacokinetic anal. was conducted in cycles 1 and 2. RESULTS: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematol. toxicity, esp. diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m2 dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half-life of approx. 140 and 210 h, resp. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 mo, resp. CONCLUSIONS: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing.
- 20Dong, Y.; Feng, S.-S. Methoxy Poly(Ethylene Glycol)-Poly(Lactide) (MPEG-PLA) Nanoparticles for Controlled Delivery of Anticancer Drugs. Biomaterials 2004, 25 (14), 2843– 2849, DOI: 10.1016/j.biomaterials.2003.09.055Google ScholarThere is no corresponding record for this reference.
- 21Wei, X.; Gong, C.; Gou, M.; Fu, S.; Guo, Q.; Shi, S.; Luo, F.; Guo, G.; Qiu, L.; Qian, Z. Biodegradable Poly(ε-Caprolactone)–Poly(Ethylene Glycol) Copolymers as Drug Delivery System. Int. J. Pharm. 2009, 381 (1), 1– 18, DOI: 10.1016/j.ijpharm.2009.07.033Google ScholarThere is no corresponding record for this reference.
- 22Kabanov, A. V.; Batrakova, E. V.; Alakhov, V. Y. Pluronic® Block Copolymers as Novel Polymer Therapeutics for Drug and Gene Delivery. J. Controlled Release 2002, 82 (2–3), 189– 212, DOI: 10.1016/S0168-3659(02)00009-3Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlvFOktb4%253D&md5=106ee69575c4ebc3f22bf4bcd075c229Pluronic block copolymers as novel polymer therapeutics for drug and gene deliveryKabanov, Alexander V.; Batrakova, Elena V.; Alakhov, Valery Yu.Journal of Controlled Release (2002), 82 (2-3), 189-212CODEN: JCREEC; ISSN:0168-3659. (Elsevier Science Ltd.)A review. Pluronic block copolymers are found to be an efficient drug delivery system with multiple effects. The incorporation of drugs into the core of the micelles formed by Pluronic results in increased soly., metabolic stability and circulation time for the drug. The interactions of the Pluronic unimers with multidrug-resistant cancer cells result in sensitization of these cells with respect to various anticancer agents. Furthermore, the single mol. chains of copolymer, unimers, inhibit drug efflux transporters in both the blood-brain barrier and in the small intestine, which provides for the enhanced transport of select drugs to the brain and increases oral bioavailability. These and other applications of Pluronic block copolymers in various drug delivery and gene delivery systems are considered.
- 23Yin, F.; Laborie, P.; Lonetti, B.; Gineste, S.; Coppel, Y.; Lauth-de Viguerie, N.; Marty, J.-D. Dual Thermo- and PH-Responsive Block Copolymer of Poly(N -Isopropylacrylamide)- Block -Poly(N, N -Diethylamino Ethyl Acrylamide): Synthesis, Characterization, Phase Transition, and Self-Assembly Behavior in Aqueous Solution. Macromolecules 2023, 56 (10), 3703– 3720, DOI: 10.1021/acs.macromol.3c00424Google ScholarThere is no corresponding record for this reference.
- 24Su, F.; Yun, P.; Li, C.; Li, R.; Xi, L.; Wang, Y.; Chen, Y.; Li, S. Novel Self-Assembled Micelles of Amphiphilic Poly(2-Ethyl-2-Oxazoline) -Poly(L-Lactide) Diblock Copolymers for Sustained Drug Delivery. Colloids Surf., A 2019, 566, 120, DOI: 10.1016/j.colsurfa.2019.01.015Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht12gs7Y%253D&md5=a870058363af306020711f47a94463a1Novel self-assembled micelles of amphiphilic poly(2-ethyl-2-oxazoline)-poly(L-lactide) diblock copolymers for sustained drug deliverySu, Feng; Yun, Peng; Li, Chenglong; Li, Rongye; Xi, Laishun; Wang, Yuandou; Chen, Yangsheng; Li, SumingColloids and Surfaces, A: Physicochemical and Engineering Aspects (2019), 566 (), 120-127CODEN: CPEAEH; ISSN:0927-7757. (Elsevier B.V.)A series of poly(2-ethyl-2-oxazoline)-poly(L-lactide) (PEOz-PLA) diblock copolymers were synthesized by ring-opening polymn. of L-lactide using a monohydroxy terminated PEOz-OH macro-initiator in the presence of stannous octoate as catalyst. The resulting diblock copolymers were characterized by 1H NMR and gel permeation chromatog. Self-assembled micelles were prepd. using the co-solvent evapn. method in water and in phosphate buffered saline (PBS) at pH 7.4, 6.5 and 5.0. The resulting micelles exhibit different morphologies, such as spherical and worm-like micelles depending on the hydrophilic/hydrophobic balance. Spherical micelles were exclusively obsd. for PEOz-PLA copolymers with short PLA blocks, whereas co-existence of worm-like and spherical micelles was obsd. for copolymers with long PLA blocks. The micelle size increases with decreasing pH due to the electrostatic repulsion between PEOz chains resulting from ionization of the tertiary amide groups along PEOz chains. A hydrophobic anti-tumor drug, paclitaxel, was entrapped in PEOz-PLA micelles. High loading efficiency up to 86.7% was obtained for copolymers with long PLA blocks. Drug release was performed in PBS at different pH values. During the 30-day release period, faster release was obtained for copolymers with shorter PLA blocks than for copolymers with longer PLA blocks at acidic pH than at pH 7.4. It is concluded that pH-responsive PEOz-PLA copolymer micells could be promising as carrier of anti-tumor drugs.
- 25Zhang, W.-J.; Hong, C.-Y.; Pan, C.-Y. Polymerization-Induced Self-Assembly of Functionalized Block Copolymer Nanoparticles and Their Application in Drug Delivery. Macromol. Rapid Commun. 2019, 40 (2), 1800279, DOI: 10.1002/marc.201800279Google ScholarThere is no corresponding record for this reference.
- 26Louage, B.; Zhang, Q.; Vanparijs, N.; Voorhaar, L.; Vande Casteele, S.; Shi, Y.; Hennink, W. E.; Van Bocxlaer, J.; Hoogenboom, R.; De Geest, B. G. Degradable Ketal-Based Block Copolymer Nanoparticles for Anticancer Drug Delivery: A Systematic Evaluation. Biomacromolecules 2015, 16 (1), 336– 350, DOI: 10.1021/bm5015409Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVGmsLjI&md5=12abe6d343a12e23ab6f293476bad241Degradable Ketal-Based Block Copolymer Nanoparticles for Anticancer Drug Delivery: A Systematic EvaluationLouage, Benoit; Zhang, Qilu; Vanparijs, Nane; Voorhaar, Lenny; Vande Casteele, Sofie; Shi, Yang; Hennink, Wim E.; Van Bocxlaer, Jan; Hoogenboom, Richard; De Geest, Bruno G.Biomacromolecules (2015), 16 (1), 336-350CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)Low soly. of potent (anticancer) drugs is a major driving force for the development of noncytotoxic, stimuli-responsive nanocarriers, including systems based on amphiphilic block copolymers. In this regard, we investigated the potential of block copolymers based on 2-hydroxyethyl acrylate (HEA) and the acid-sensitive ketal-contg. monomer (2,2-dimethyl-1,3-dioxolane-4-yl)methyl acrylate (DMDMA) to form responsive drug nanocarriers. Block copolymers were successfully synthesized by sequential reversible addn.-fragmentation chain transfer (RAFT) polymn., in which we combined a hydrophilic poly(HEA)x block with a (responsive) hydrophobic poly(HEAm-co-DMDMAn)y copolymer block. The DMDMA content of the hydrophobic block was systematically varied to investigate the influence of polymer design on physicochem. properties and in vitro biol. performance. We found that a DMDMA content higher than 11 mol % is required for self-assembly behavior in aq. medium. All particles showed colloidal stability in PBS at 37 °C for at least 4 days, with sizes ranging from 23 to 338 nm, proportional to the block copolymer DMDMA content. Under acidic conditions, the nanoparticles decompd. into sol. unimers, of which the decompn. rate was inversely proportional to the block copolymer DMDMA content. Flow cytometry and confocal microscopy showed dose-dependent, active in vitro cellular uptake of the particles loaded with hydrophobic octadecyl rhodamine B chloride (R18). The block copolymers showed no intrinsic in vitro cytotoxicity, while loaded with paclitaxel (PTX), a significant decrease in cell viability was obsd. comparable or better than the two com. PTX nanoformulations Abraxane and Genexol-PM at equal PTX dose. This systematic approach evaluated and showed the potential of these block copolymers as nanocarriers for hydrophobic drugs.
- 27Zhang, Q.; Hou, Z.; Louage, B.; Zhou, D.; Vanparijs, N.; De Geest, B. G.; Hoogenboom, R. Acid-Labile Thermoresponsive Copolymers That Combine Fast PH-Triggered Hydrolysis and High Stability under Neutral Conditions. Angew. Chem. 2015, 127 (37), 11029– 11033, DOI: 10.1002/ange.201505145Google ScholarThere is no corresponding record for this reference.
- 28Zhang, Q.; Vanparijs, N.; Louage, B.; De Geest, B. G.; Hoogenboom, R. Dual PH- and Temperature-Responsive RAFT-Based Block Co-Polymer Micelles and Polymer–Protein Conjugates with Transient Solubility. Polym. Chem. 2014, 5 (4), 1140– 1144, DOI: 10.1039/C3PY00971HGoogle Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Ght7o%253D&md5=1dc05c8bdbd423b8ae5f6ed654204917Dual pH- and temperature-responsive RAFT-based block co-polymer micelles and polymer-protein conjugates with transient solubilityZhang, Qilu; Vanparijs, Nane; Louage, Benoit; De Geest, Bruno G.; Hoogenboom, RichardPolymer Chemistry (2014), 5 (4), 1140-1144CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Via a smart combination of temp.-responsive and acid labile acetal monomers, copolymers are obtained with a la carte lower crit. soln. temp. behavior. RAFT copolymn. of these monomers using, resp., a PEG-functionalized or amine-reactive NHS-functionalized chain transfer agent allows designing of micelles and polymer-protein conjugates with transient soly. properties within a physiol. relevant window.
- 29Kuperkar, K.; Patel, D.; Atanase, L. I.; Bahadur, P. Amphiphilic Block Copolymers: Their Structures, and Self-Assembly to Polymeric Micelles and Polymersomes as Drug Delivery Vehicles. Polymers 2022, 14 (21), 4702, DOI: 10.3390/polym14214702Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XivV2lsLjN&md5=7dc1028251f6d41dca748e2c80cdc25aAmphiphilic Block Copolymers: Their Structures, and Self-Assembly to Polymeric Micelles and Polymersomes as Drug Delivery VehiclesKuperkar, Ketan; Patel, Dhruvi; Atanase, Leonard Ionut; Bahadur, PratapPolymers (Basel, Switzerland) (2022), 14 (21), 4702CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)A review. Self-assembly of amphiphilic block copolymers display a multiplicity of nanoscale periodic patterns proposed as a dominant tool for the 'bottom-up' fabrication of nanomaterials with different levels of ordering. The present review article focuses on the recent updates to the self-assocn. of amphiphilic block copolymers in aq. media into varied core-shell morphologies. We briefly describe the block copolymers, their types, microdomain formation in bulk and micellization in selective solvents. We also discuss the characteristic features of block copolymers nanoaggregates viz., polymer micelles (PMs) and polymersomes. Amphiphilic block copolymers (with a variety of hydrophobic blocks and hydrophilic blocks; often polyethylene oxide) self-assemble in water to micelles/niosomes similar to conventional nonionic surfactants with high drug loading capacity. Double hydrophilic block copolymers (DHBCs) made of neutral block-neutral block or neutral block-charged block can transform one block to become hydrophobic under the influence of a stimulus (phys./chem./biol.), and thus induced amphiphilicity and display self-assembly are discussed. Different kinds of polymer micelles (viz. shell and core-crosslinked, core-shell-corona, schizophrenic, crew cut, Janus) are presented in detail. Updates on polymn.-induced self-assembly (PISA) and crystn.-driven self-assembly (CDSA) are also provided. Polyion complexes (PICs) and polyion complex micelles (PICMs) are discussed. Applications of these block copolymeric micelles and polymersomes as nanocarriers in drug delivery systems are described.
- 30Gupta, M.; Sharma, V.; Chauhan, D. N.; Chauhan, N. S.; Shah, K.; Goyal, R. K. Amphiphilic Block Copolymer: A Smart Option for Bioactives Delivery. In Advances and Avenues in the Development of Novel Carriers for Bioactives and Biological Agents; Elsevier, 2020, pp. 451– 479. DOI: 10.1016/B978-0-12-819666-3.00015-8 .Google ScholarThere is no corresponding record for this reference.
- 31Huang, X.; Du, F.; Ju, R.; Li, Z. Novel Acid-Labile, Thermoresponsive Poly(Methacrylamide)s with Pendent Ortho Ester Moieties. Macromol. Rapid Commun. 2007, 28 (5), 597– 603, DOI: 10.1002/marc.200600798Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjslWksLc%253D&md5=b63ce85e5fc137d778410aa1d04e91c1Novel acid-labile, thermoresponsive poly(methacrylamide)s with pendent ortho ester moietiesHuang, Xiaonan; Du, Fusheng; Ju, Rong; Li, ZichenMacromolecular Rapid Communications (2007), 28 (5), 597-603CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)Novel acid-labile, thermoresponsive methacrylamide-based (co)polymers with pendent ortho ester groups were prepd. by free radical polymn. of N-(2-methoxy-1,3-dioxan-5-yl)methacrylamide (NMM) and N-(2-ethoxy-1,3-dioxan-5-yl)methacrylamide (NEM). These polymers are both thermoresponsive and acid-sensitive in aq. soln., which was proved by transmittance measurements, fluorescence, and 1H NMR spectroscopy. The LCSTs of the (co)polymers were shifted to higher temp. by increasing the content of the more hydrophilic NMM units. All of these polymers can be hydrolyzed under acidic condition and the hydrolysis rate increased with the decrease in the pH value.
- 32Ishitake, K.; Satoh, K.; Kamigaito, M.; Okamoto, Y. Stereogradient Polymers Formed by Controlled/Living Radical Polymerization of Bulky Methacrylate Monomers. Angew. Chem. 2009, 121 (11), 2025– 2028, DOI: 10.1002/ange.200805168Google ScholarThere is no corresponding record for this reference.
- 33Pytlíková, S.; Pechar, M.; Chytil, P.; Studenovský, M.; Pola, R.; Kotrchová, L.; Konefał, R.; Čtveráčková, L.; Laga, R.; Pankrác, J. Highly Hydrophilic Methacrylamide-Based Copolymers as Precursors for Polymeric Nanomedicines Containing Anthracyclines. Eur. Polym. J. 2024, 205 (January), 112756, DOI: 10.1016/j.eurpolymj.2024.112756Google ScholarThere is no corresponding record for this reference.
- 34Kolouchová, K.; Lobaz, V.; Beneš, H.; de la Rosa, V. R.; Babuka, D.; Švec, P.; Černoch, P.; Hrubý, M.; Hoogenboom, R.; Štěpánek, P.; Groborz, O. Thermoresponsive Properties of Polyacrylamides in Physiological Solutions. Polym. Chem. 2021, 12 (35), 5077– 5084, DOI: 10.1039/D1PY00843AGoogle Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhslOntr7O&md5=9748ba876004aa2fb53dc97b1a323df1Thermoresponsive properties of polyacrylamides in physiological solutionsKolouchova, Kristyna; Lobaz, Volodymyr; Benes, Hynek; de la Rosa, Victor R.; Babuka, David; Svec, Pavel; Cernoch, Peter; Hruby, Martin; Hoogenboom, Richard; Stepanek, Petr; Groborz, OndrejPolymer Chemistry (2021), 12 (35), 5077-5084CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Polymer solns. with a lower crit. soln. temp. (LCST) undergo reversible phase sepn. when heated above their cloud point temp. (TCP or CPT). As such, they have been proposed for a wide range of biomedical applications, from injectable drug depots to switchable coatings for cell adhesion. However, in systematic studies, the TCP of these thermoresponsive polymers has been mostly measured in non-physiol. solns., thereby hindering the development of their medicinal applications. Here, we analyzed the thermoresponsive properties of four acrylamide-based polymers with LCST, namely poly[(N-2,2-difluoroethyl)acrylamide] (pDFEA), poly[(N-isopropyl)acrylamide] (pNIPAM), poly[(N,N-diethyl)acrylamide] (pDEA), and poly[(N-acryloyl)pyrrolidine] (pAP). As shown by turbidimetry, their TCP in phosphate saline buffer (PBS) and fetal bovine serum (FBS) were consistently lower than those reported in the literature, typically assessed in pure water, even when using the same setup. In addn., these physiol. solns. affected the variation of TCP as a function of polymer concn. (1.25 to 10.0 mg mL-1) and molar mass (20 to 50 kg mol-1). As shown by isothermal calorimetry, interactions between proteins in FBS and polymer aggregates were predominantly exothermic, which indicates that protein-polymer complexes are formed through enthalpically driven processes. In conclusion, the TCP of thermoresponsive polymers strongly depends on solvent compn. and therefore should be measured under physiol. conditions for future medicinal applications.
- 35Paiuk, O.; Mitina, N.; Slouf, M.; Pavlova, E.; Finiuk, N.; Kinash, N.; Karkhut, A.; Manko, N.; Gromovoy, T.; Hevus, O. Fluorine-Containing Block/Branched Polyamphiphiles Forming Bioinspired Complexes with Biopolymers. Colloids Surf., B 2019, 174 (June 2018), 393– 400, DOI: 10.1016/j.colsurfb.2018.11.047Google ScholarThere is no corresponding record for this reference.
- 36Bildziukevich, U.; Kaletová, E.; Šaman, D.; Sievänen, E.; Kolehmainen, E. T.; Šlouf, M.; Wimmer, Z. Spectral and Microscopic Study of Self-Assembly of Novel Cationic Spermine Amides of Betulinic Acid. Steroids 2017, 117, 90– 96, DOI: 10.1016/j.steroids.2016.07.007Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFymsrzK&md5=99d48db2708b369256dea5abd9d6fdfcSpectral and microscopic study of self-assembly of novel cationic spermine amides of betulinic acidBildziukevich, Uladzimir; Kaletova, Eva; Saman, David; Sievanen, Elina; Kolehmainen, Erkki T.; Slouf, Miroslav; Wimmer, ZdenekSteroids (2017), 117 (), 90-96CODEN: STEDAM; ISSN:0039-128X. (Elsevier)Supramol. characteristics of two spermine amides of betulinic acid (1 and 2) were studied by measuring and evaluating their UV-VIS-NIR spectra in aq. acetonitrile and DOSY-NMR spectra in tetradeuteromethanol, accompanied by at. force microscopy (AFM) images, SEM micrographs, and transmission electron microscopy (TEM) micrographs. Fibrous supramol. self-assembly of 1 and 2 was obsd. by AFM images, as well as by the SEM and TEM micrographs. Bathochromic shifts of the absorbance max. at 870 nm to 1015-970 nm in the UV-VIS-NIR spectra were obsd. with increasing water content in the acetonitrile/water systems, indicating formation of fibrous J-type aggregates. Variable temp. DOSY-NMR spectral measurement showed non-linear dependence that also suggests self-assembly behavior of the studied systems. Chiral supramol. structures were formed by self-assembling due to the chirality of the monomeric mols. Application of aq. media during self-assembly procedures is an important factor in the development of targeted drug delivery systems.
- 37Laga, R.; Janoušková, O.; Ulbrich, K.; Pola, R.; Blažková, J.; Filippov, S. K.; Etrych, T.; Pechar, M. Thermoresponsive Polymer Micelles as Potential Nanosized Cancerostatics. Biomacromolecules 2015, 16 (8), 2493– 2505, DOI: 10.1021/acs.biomac.5b00764Google ScholarThere is no corresponding record for this reference.
- 38Spěváček, J.; Konefał, R.; Dybal, J.; Čadová, E.; Kovářová, J. Thermoresponsive Behavior of Block Copolymers of PEO and PNIPAm with Different Architecture in Aqueous Solutions: A Study by NMR, FTIR, DSC and Quantum-Chemical Calculations. Eur. Polym. J. 2017, 94 (May), 471– 483, DOI: 10.1016/j.eurpolymj.2017.07.034Google ScholarThere is no corresponding record for this reference.
- 39Konefał, R.; Spěváček, J.; Černoch, P. Thermoresponsive Poly(2-Oxazoline) Homopolymers and Copolymers in Aqueous Solutions Studied by NMR Spectroscopy and Dynamic Light Scattering. Eur. Polym. J. 2018, 100 (January), 241– 252, DOI: 10.1016/j.eurpolymj.2018.01.019Google ScholarThere is no corresponding record for this reference.
- 40Konefał, R.; Černoch, P.; Konefał, M.; Spěváček, J. Temperature Behavior of Aqueous Solutions of Poly(2-Oxazoline) Homopolymer and Block Copolymers Investigated by NMR Spectroscopy and Dynamic Light Scattering. Polymers 2020, 12 (9), 1879, DOI: 10.3390/polym12091879Google ScholarThere is no corresponding record for this reference.
- 41Aseyev, V. O.; Tenhu, H.; Winnik, F. M. Temperature Dependence of the Colloidal Stability of Neutral Amphiphilic Polymers in Water Conformation-Dependent Design of Sequences in Copolymers IISpringer2006 1– 85Google ScholarThere is no corresponding record for this reference.
- 42Oleszko-Torbus, N.; Utrata-Wesołek, A.; Bochenek, M.; Lipowska-Kur, D.; Dworak, A.; Wałach, W. Thermal and Crystalline Properties of Poly(2-Oxazoline)S. Polym. Chem. 2020, 11 (1), 15– 33, DOI: 10.1039/C9PY01316DGoogle ScholarThere is no corresponding record for this reference.
- 43Bordat, A.; Boissenot, T.; Nicolas, J.; Tsapis, N. Thermoresponsive Polymer Nanocarriers for Biomedical Applications. Adv. Drug Delivery Rev. 2019, 138, 167– 192, DOI: 10.1016/j.addr.2018.10.005Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFKjtLbI&md5=452da5786242284467701d84fd58731aThermoresponsive polymer nanocarriers for biomedical applicationsBordat, Alexandre; Boissenot, Tanguy; Nicolas, Julien; Tsapis, NicolasAdvanced Drug Delivery Reviews (2019), 138 (), 167-192CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Polymer nanocarriers allow drug encapsulation leading to fragile mol. protection from early degrdn./metabolization, increased soly. of poorly sol. drugs and improved plasmatic half-life. However, efficiently controlling the drug release from nanocarriers is still challenging. Thermoresponsive polymers exhibiting either a lower crit. soly. temp. (LCST) or an upper crit. soly. temp. (UCST) in aq. medium may be the key to build spatially and temporally controlled drug delivery systems. In this review, we provide an overview of LCST and UCST polymers used as building blocks for thermoresponsive nanocarriers for biomedical applications. Recent nanocarriers based on thermoresponsive polymer exhibiting unprecedented features useful for biomedical applications are also discussed. While LCST nanocarriers have been studied for over two decades, UCST nanocarriers have recently emerged and already show great potential for effective thermoresponsive drug release.
- 44Säckel, C.; von Klitzing, R.; Siegel, R.; Senker, J.; Vogel, M. Water Dynamics in Solutions of Linear Poly (N-Isopropyl Acrylamide) Studied by 2H NMR Field-Cycling Relaxometry. Front. Soft Matter 2024, 4 (March), 1– 11, DOI: 10.3389/frsfm.2024.1379816Google ScholarThere is no corresponding record for this reference.
- 45Spěváček, J.; Dybal, J.; Starovoytova, L.; Zhigunov, A.; Sedláková, Z. Temperature-Induced Phase Separation and Hydration in Poly(N-Vinylcaprolactam) Aqueous Solutions: A Study by NMR and IR Spectroscopy, SAXS, and Quantum-Chemical Calculations. Soft Matter 2012, 8 (22), 6110, DOI: 10.1039/c2sm25432hGoogle ScholarThere is no corresponding record for this reference.
- 46Zhang, C.; Sanchez, R. J. P.; Fu, C.; Clayden-Zabik, R.; Peng, H.; Kempe, K.; Whittaker, A. K. Importance of Thermally Induced Aggregation on 19 F Magnetic Resonance Imaging of Perfluoropolyether-Based Comb-Shaped Poly(2-Oxazoline)S. Biomacromolecules 2019, 20 (1), 365– 374, DOI: 10.1021/acs.biomac.8b01549Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlCmsb%252FO&md5=3470b1a076ee6471eccaed54c025bae6Importance of Thermally Induced Aggregation on 19F Magnetic Resonance Imaging of Perfluoropolyether-Based Comb-Shaped Poly(2-oxazoline)sZhang, Cheng; Sanchez, Ronny Javier Pibaque; Fu, Changkui; Clayden-Zabik, Ryan; Peng, Hui; Kempe, Kristian; Whittaker, Andrew K.Biomacromolecules (2019), 20 (1), 365-374CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)An understanding of thermally induced aggregation and consequent 19F magnetic resonance imaging (MRI) performance is essential for improved design of thermoresponsive 19F MRI contrast agents. Herein we describe a series of novel thermoresponsive perfluoropolyether (PFPE)-based comb-shaped poly(2-oxazoline)s (POxs) with different side-chain structures (2-methyl- (MeOx), 2-ethyl- (EtOx), and 2-(n-propyl)-2-oxazoline (nPrOx)). The comb polymers were prepd. through reversible addn.-fragmentation chain transfer (RAFT) polymn. of the resp. oligo(2-oxazoline)acrylates using a perfluoropolyether macro-RAFT agent. The fluoropolyether chain end drives aggregation of the polymers, with small aggregates forming at 300 K for both poly(OMeOx5A)9-PFPE and poly(OEtOx4A)9-PFPE. The aggregates decrease in size and display increases in 19F MRI intensity with temp., and at 350 K the MeOx polymers are in the form of unimers in soln., similar to the oligoethylene glycol (OEG)-based PFPE polymer. Above the TCP of poly(OEtOx4A)9-PFPE, the polymer forms large aggregates, and the 19F MR imaging performance is degraded. Likewise, poly(OnPrOx4A)-PFPE is above the LCST at all temps. studied (300-350 K), and so weak imaging intensity is obtained. This report of novel thermoresponsive POx-based PFPE polymers highlights the importance of understanding self-assocn. of polymers in soln. and provides important insights for the development of "smart" thermoresponsive 19F MRI contrast agents.
- 47Lobaz, V.; Liščáková, V.; Sedlák, F.; Musil, D.; Petrova, S. L.; Šeděnková, I.; Pánek, J.; Kučka, J.; Konefał, R.; Tihlaříková, E.; Neděla, V.; Pankrác, J.; Šefc, L.; Hrubý, M.; Šácha, P.; Štěpánek, P. Tuning Polymer–Blood and Polymer–Cytoplasm Membrane Interactions by Manipulating the Architecture of Poly(2-Oxazoline) Triblock Copolymers. Colloids Surf., B 2023, 231 (July), 113564, DOI: 10.1016/j.colsurfb.2023.113564Google ScholarThere is no corresponding record for this reference.
- 48Smith, O. E. P.; Waters, L. J.; Small, W.; Mellor, S. CMC Determination Using Isothermal Titration Calorimetry for Five Industrially Significant Non-Ionic Surfactants. Colloids Surf., B 2022, 211 (November 2021), 112320, DOI: 10.1016/j.colsurfb.2022.112320Google ScholarThere is no corresponding record for this reference.
- 49Yamamoto, Y.; Yasugi, K.; Harada, A.; Nagasaki, Y.; Kataoka, K. Temperature-Related Change in the Properties Relevant to Drug Delivery of Poly(Ethylene Glycol)-Poly(D,L-Lactide) Block Copolymer Micelles in Aqueous Milieu. J. Controlled Release 2002, 82 (2–3), 359– 371, DOI: 10.1016/S0168-3659(02)00147-5Google ScholarThere is no corresponding record for this reference.
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Abstract
Scheme 1
Scheme 1. Synthesis of DHPMA-Acetal MonomerScheme 2
Scheme 2. Synthesis of Poly(DHPMA-Acetal) (Homopolymer A)Scheme 3
Scheme 3. Synthesis of Diblock Copolymers Poly(DHPMA)-b-Poly(DHPMA-Acetal) (AB1– AB3)Figure 1
Figure 1. Dependence of the hydrodynamic particle size of a) diblock copolymer (AB1) and b) homopolymer A on the temperature during heating (red) and cooling (blue).
Figure 2
Figure 2. a) 1H NMR spectra of homopolymer A at 12, 30, and 57 °C. b) Temperature dependences of the fraction p as determined for signals of various proton types in D2O solution of homopolymer A during gradual heating.
Figure 3
Figure 3. a) 1H NMR spectra of copolymer AB1 at 12, 30, and 57 °C. b) Temperature dependences of the fraction p as determined for signals of various proton types in D2O solution of copolymer AB1 during gradual heating.
Figure 4
Figure 4. Temperature dependencies of the fraction p as determined for signal “c” in D2O solutions of A homopolymer and AB1, AB2, and AB3 copolymers during gradual heating.
Figure 5
Figure 5. Temperature dependencies of the fraction p of the protons with significantly reduced mobility in D2O solutions of a) homopolymer A and b) diblock copolymer AB1 during gradual heating (filled symbols) and subsequent gradual cooling (empty symbols).
Figure 6
Figure 6. a) Temperature dependence and b) time dependence at 57 °C of 1H spin–spin relaxation times T2 of HDO in D2O solutions of the A, AB1, AB2, and AB3.
Figure 7
Figure 7. a) 2D NOESY spectrum of AB2 block copolymer in D2O solution measured at 12 °C with a mixing time of 400 ms. b) 1D slice spectrum extracted from the “e” signal of the NOESY spectrum, together with chemical structure and intermolecular correlations in the AB2 block copolymer. c) Temperature dependences of integrated intensities of various signals in 1D slices extracted from the signal of protons (“e”) of poly(DHPMA-acetal) units.
Figure 8
Figure 8. a) 1H NMR spectra of homopolymer A after 0.5 and 48 h of incubation at pH 5. Signals marked as ″*″ are related to solvent impurities. b) The course of hydrolysis of the ketal groups of homopolymer A at pH 5.0.
Figure 9
Figure 9. Change of the Ttr of homopolymer A and diblock copolymer AB2 at pH 5 and 7.4 over time.
Figure 10
Figure 10. Enthalpy of dilution of 5 mg mL–1 diblock copolymers in PBS to pure PBS at 37 °C.
Figure 11
Figure 11. TEM micrographs showing the morphology of the fast-dried particles of AB1. The fast drying was performed at (a) 5 °C, (b) 37 °C, and (c) 50 °C.
Figure 12
Figure 12. Cytostatic and cytotoxic effects of diblock polymers evaluated in mouse cancer cell lines and purified CD8+ T lymphocytes in vitro. Cytostatic effect of AB1, AB2, and AB3 determined in a) EL4, b) LL2 cell lines, and c) CD8+ T lymphocytes isolated from spleens of BALB/c mice using the [3H]-thymidine incorporation assay. Cytotoxic effect of AB1, AB2, and AB3 measured in d) EL4 and e) LL2 cell lines. Each experimental point represents the average value from four wells ± SD. Experiments were performed twice with similar results.
References
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- 4Maeda, H. Macromolecular Therapeutics in Cancer Treatment: The EPR Effect and Beyond. J. Controlled Release 2012, 164 (2), 138– 144, DOI: 10.1016/j.jconrel.2012.04.0384https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnsFOquro%253D&md5=68a4406cf23da32c0893d17354ec52bbMacromolecular therapeutics in cancer treatment: The EPR effect and beyondMaeda, HiroshiJournal of Controlled Release (2012), 164 (2), 138-144CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)In this review, the author has discussed various issues of the cancer drug targeting primarily related to the EPR (enhanced permeability and retention) effect, which utilized nanomedicine or macromol. drugs. The content goes back to the development of the first polymer-protein conjugate anticancer agent SMANCS and development of the arterial infusion in Lipiodol formulation into the tumor feeding artery (hepatic artery for hepatoma). The brief account on the EPR effect and its definition, factors involved, heterogeneity, and various methods of augmentation of the EPR effect, which showed remarkably improved clin. outcomes are also discussed. Various obstacles involved in drug developments and commercialization are also discussed through the author's personal experience and recollections.
- 5Wu, J. The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application. J. Pers. Med. 2021, 11 (8), 771, DOI: 10.3390/jpm11080771There is no corresponding record for this reference.
- 6Audureau, N.; Coumes, F.; Guigner, J.-M.; Nguyen, T. P. T.; Ménager, C.; Stoffelbach, F.; Rieger, J. Thermoresponsive Properties of Poly(Acrylamide- Co -Acrylonitrile)-Based Diblock Copolymers Synthesized (by PISA) in Water. Polym. Chem. 2020, 11 (37), 5998– 6008, DOI: 10.1039/D0PY00895HThere is no corresponding record for this reference.
- 7Pola, R.; Pechar, M.; Ulbrich, K.; Fabra Fres, A. Polymer Doxorubicin Conjugate with a Synthetic Peptide Ligand Targeted on Prostate Tumor. J. Bioact. Compat. Polym. 2007, 22 (6), 602– 620, DOI: 10.1177/0883911507084423There is no corresponding record for this reference.
- 8Gillies, E. R.; Fréchet, J. M. J. Development of Acid-Sensitive Copolymer Micelles for Drug Delivery. Pure Appl. Chem. 2004, 76 (7–8), 1295– 1307, DOI: 10.1351/pac2004760712958https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotV2msb0%253D&md5=52a04a8897ef04a2768ac2b157a82c5eDevelopment of acid-sensitive copolymer micelles for drug deliveryGillies, Elizabeth R.; Frechet, Jean M. J.Pure and Applied Chemistry (2004), 76 (7-8), 1295-1307CODEN: PACHAS; ISSN:0033-4545. (International Union of Pure and Applied Chemistry)In recent years, supramol. micellar assemblies formed from amphiphilic block copolymers have been receiving attention as potential drug carriers. The size of the carriers is ideal for avoiding rapid renal exclusion and reticuloendothelial uptake, and enables them to be targeted to certain tissues such as tumors. One important issue detg. the effectiveness of a micellar drug carrier is the ability to control the time over which drug release takes place, or to possibly trigger drug release at a specific location or time. The mildly acidic pH encountered in tumor and inflammatory tissues as well as in the endosomal and lysosomal compartments of cells has inspired the development of micellar carriers capable of releasing their drug load in response to small changes in pH. One approach to the development of these systems has been to incorporate "titratable" groups such as amines and carboxylic acids into the copolymer backbone, thus altering the soly. of the polymer upon protonation and disrupting micelle formation. Another approach has been to incorporate acid degradable linkages into the copolymer, either for direct attachment of the drug, or to cause a structural change of such magnitude that micellar integrity is lost and the drug is released.
- 9Gillies, E. R.; Fréchet, J. M. J. PH-Responsive Copolymer Assemblies for Controlled Release of Doxorubicin. Bioconjugate Chem. 2005, 16 (2), 361– 368, DOI: 10.1021/bc049851c9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtF2jsL8%253D&md5=fd200f7d1acbf478e52e2ad5179e1673pH-responsive copolymer assemblies for controlled release of doxorubicinGillies, Elizabeth R.; Frechet, Jean M. J.Bioconjugate Chemistry (2005), 16 (2), 361-368CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)PH-Responsive drug carriers have the potential to provide selective drug release at therapeutic targets including tumors and in acidic intracellular vesicles such as endosomes and lysosomes. We have developed a new approach to the design of acid-sensitive micelles by incorporating hydrophobic acetal groups on the core block of a micelle-forming block copolymer. Hydrolysis of the acetals at mildly acidic pH is designed to reveal polar groups on the core-forming block, thus changing its soly. and disrupting the micelle, triggering drug release. The anticancer drug doxorubicin (DOX) was encapsulated in these pH-sensitive micelles, and the acetal hydrolysis rates and DOX release rates were detd. in the pH range of 4.0 to 7.4 and were compared to those of control systems. The micelle disruption was investigated by dynamic light scattering. The in vitro toxicities of the empty and DOX-loaded micelles were detd., and the intracellular fate of the encapsulated DOX was compared to free DOX using fluorescence confocal microscopy.
- 10Huang, X.; Du, F.; Cheng, J.; Dong, Y.; Liang, D.; Ji, S.; Lin, S. S.; Li, Z. Acid-Sensitive Polymeric Micelles Based on Thermoresponsive Block Copolymers with Pendent Cyclic Orthoester Groups. Macromolecules 2009, 42 (3), 783– 790, DOI: 10.1021/ma802138r10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmvVWqtg%253D%253D&md5=4118fa5ac836e082a772eeaa5866bee2Acid-Sensitive Polymeric Micelles Based on Thermoresponsive Block Copolymers with Pendent Cyclic Orthoester GroupsHuang, Xiaonan; Du, Fusheng; Cheng, Jing; Dong, Yongquan; Liang, Dehai; Ji, Shouping; Lin, Shrong-Shi; Li, ZichenMacromolecules (Washington, DC, United States) (2009), 42 (3), 783-790CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)An orthoester-contg. monomer, trans-N-(2-ethoxy-1,3-dioxan-5-yl)acrylamide (tNEA), was synthesized. Atom transfer radical polymn. of tNEA using a poly(ethylene glycol) (PEG) macroinitiator afforded three acid-labile thermoresponsive block copolymers: PEG-b-PtNEA27, PEG-b-PtNEA56, and PEG-b-PtNEA73. These block copolymers are water-sol. at low temps. (<13°). Thermally induced phase transition behaviors, including the crit. aggregation temps. (CATs), of these polymers were investigated by light scattering and 1H NMR. The results indicated that the longer the PtNEA chain length, the lower the CAT. Upon heating above the CATs, all the three polymers underwent a phase transition and formed polymeric micelles or micelle-like nanoparticles with PEG as the shell and PtNEA block as the core. Both the sizes and morphologies of the micelles were found to be affected by the heating rate and the salt concn. in the buffers. The micelles, formed through a fast heating procedure in the buffer with a relatively high salt concn., have a smaller size and a more compacted structure. PH-dependent destabilization of the polymeric micelles prepd. from PEG-b-PtNEA73 was studied by using light scattering and Nile Red fluorescence. The results demonstrated that hydrophobic Nile Red could be loaded in the micelles that were stable at pH 7.4, but destabilized in mildly acidic media. The dissocn. of the micelles and the subsequent release of Nile Red were induced by the acid-triggered hydrolysis of the orthoester groups, which was proved by the 1H NMR spectra.
- 11Xu, Q.; He, C.; Xiao, C.; Chen, X. Reactive Oxygen Species (ROS) Responsive Polymers for Biomedical Applications. Macromol. Biosci. 2016, 16 (5), 635– 646, DOI: 10.1002/mabi.20150044011https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XislSqu7g%253D&md5=7245d9a7ed4eb239700126908e22945eReactive Oxygen Species (ROS) Responsive Polymers for Biomedical ApplicationsXu, Qinghua; He, Chaoliang; Xiao, Chunsheng; Chen, XuesiMacromolecular Bioscience (2016), 16 (5), 635-646CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)Reactive oxygen species (ROS) play important roles in cell signaling pathways, while increased prodn. of ROS may disrupt cellular homeostasis, giving rise to oxidative stress and a series of diseases. Utilizing these cell-generated species as triggers for selective tuning polymer structures and properties represents a promising methodol. for disease diagnosis and treatment. Recently, significant progress has been made in fabricating biomaterials including nanoparticles and macroscopic networks to interact with this dynamic physiol. condition. These ROS-responsive platforms have shown potential in a range of biomedical applications, such as cancer targeted drug delivery systems, cell therapy platforms for inflammation related disease, and so on.
- 12Wang, X.; Chen, Z.; Yang, Y.; Guo, H.; Yang, Y.; Tang, C.-Y.; Li, X.; Law, W.-C. Near-Infrared and PH Responsive Molecular Machine for Controlled Encapsulation and Release of Drugs. Polym. Test. 2022, 112 (February), 107631, DOI: 10.1016/j.polymertesting.2022.107631There is no corresponding record for this reference.
- 13Wang, X.; Yang, Y.; Zhang, G.; Tang, C.-Y.; Law, W.-C.; Yu, C.; Wu, X.; Li, S.; Liao, Y. NIR-Cleavable and PH-Responsive Polymeric Yolk–Shell Nanoparticles for Controlled Drug Release. Biomacromolecules 2023, 24 (5), 2009– 2021, DOI: 10.1021/acs.biomac.2c01404There is no corresponding record for this reference.
- 14Perumal, S.; Atchudan, R.; Lee, W. A Review of Polymeric Micelles and Their Applications. Polymers 2022, 14 (12), 2510, DOI: 10.3390/polym1412251014https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhs1GrsbrF&md5=cce588e5bf44ff711afe82f61551ea32A Review of Polymeric Micelles and Their ApplicationsPerumal, Suguna; Atchudan, Raji; Lee, WonmokPolymers (Basel, Switzerland) (2022), 14 (12), 2510CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)A review. Self-assembly of amphiphilic polymers with hydrophilic and hydrophobic units results in micelles (polymeric nanoparticles), where polymer concns. are above crit. micelle concns. (CMCs). Recently, micelles with metal nanoparticles (MNPs) have been utilized in many bio-applications because of their excellent biocompatibility, pharmacokinetics, adhesion to biosurfaces, targetability, and longevity. The size of the micelles is in the range of 10 to 100 nm, and different shapes of micelles have been developed for applications. Micelles have been focused recently on bio-applications because of their unique properties, size, shape, and biocompatibility, which enhance drug loading and target release in a controlled manner. This review focused on how CMC has been calcd. using various techniques. Further, micelle importance is explained briefly, different types and shapes of micelles are discussed, and further extensions for the application of micelles are addressed. In the summary and outlook, points that need focus in future research on micelles are discussed. This will help researchers in the development of micelles for different applications.
- 15Du, F.-S.; Huang, X.-N.; Chen, G.-T.; Lin, S.-S.; Liang, D.; Li, Z.-C. Aqueous Solution Properties of the Acid-Labile Thermoresponsive Poly(Meth)Acrylamides with Pendent Cyclic Orthoester Groups. Macromolecules 2010, 43 (5), 2474– 2483, DOI: 10.1021/ma902227g15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVyiurY%253D&md5=35b4704ae9e563541edc83187508084cAqueous solution properties of the acid-labile thermo-responsive poly(meth)acrylamides with pendent cyclic orthoester groupsDu, Fu-Sheng; Huang, Xiao-Nan; Chen, Guang-Tao; Lin, Shrong-Shi; Liang, Dehai; Li, Zi-ChenMacromolecules (Washington, DC, United States) (2010), 43 (5), 2474-2483CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)A series of poly(meth)acrylamide derivs. with pendent six-member cyclic orthoester groups, i.e., poly(N-(2-alkyloxy-1,3-dioxan-5-yl)methacrylamide)s and poly(N-(2-alkyloxy-1,3-dioxan-5-yl)acrylamide)s, have been synthesized and characterized. The difference between these polymers lies in the type of alkyl substitutes (R3), the stereochem. structures of the pendent cyclic orthoester groups (trans vs cis), and the main chain structures (polymethacrylamide vs polyacrylamide). Aq. soln. properties and pH-dependent hydrolysis behaviors of these polymers were studied by various methods including turbidimetry, fluorescence probe, DSC, 1H NMR, microscopy, and light scattering. The results show that these polymers except PtNPM can be dissolved in water at low temp., and all of the water-sol. polymers are thermosensitive with different lower crit. soln. temps. (LCSTs) and susceptible to hydrolysis in mildly acidic conditions. Both thermosensitive properties and acid-triggered hydrolysis behaviors of the polymers are closely related to the polymer structures. In general, polymethacrylamides display higher cloud points (CPs) than polyacrylamides. In addn., the polymers with larger R3 and trans configuration have a lower CP and greater magnitude of dehydration and exhibit a liq.-solid phase transition, while those with smaller R3 and cis configuration have a smaller magnitude of dehydration and undergo a liq.-liq. phase sepn. In addn., a two-stage transition process is obsd. for the polymers with R3 being Me. 1H NMR results reveal that the acid-triggered hydrolysis rate of the pendent orthoesters increases as R3 changed from Me to iso-Pr, and the configuration changed from cis to trans.
- 16Huang, X.-N.; Du, F.-S.; Zhang, B.; Zhao, J.-Y.; Li, Z.-C. Acid-labile, Thermoresponsive (Meth)Acrylamide Polymers with Pendant Cyclic Acetal Moieties. J. Polym. Sci., Part A:Polym. Chem. 2008, 46 (13), 4332– 4343, DOI: 10.1002/pola.22751There is no corresponding record for this reference.
- 17Konefał, R.; Spěváček, J.; Mužíková, G.; Laga, R. Thermoresponsive Behavior of Poly(DEGMA)-Based Copolymers. NMR and Dynamic Light Scattering Study of Aqueous Solutions. Eur. Polym. J. 2020, 124 (November 2019), 109488, DOI: 10.1016/j.eurpolymj.2020.109488There is no corresponding record for this reference.
- 18Kataoka, K.; Matsumoto, T.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Fukushima, S.; Okamoto, K.; Kwon, G. S. Doxorubicin-Loaded Poly(Ethylene Glycol)–Poly(β-Benzyl-l-Aspartate) Copolymer Micelles: Their Pharmaceutical Characteristics and Biological Significance. J. Controlled Release 2000, 64 (1–3), 143– 153, DOI: 10.1016/S0168-3659(99)00133-9There is no corresponding record for this reference.
- 19Hamaguchi, T.; Doi, T.; Eguchi-Nakajima, T.; Kato, K.; Yamada, Y.; Shimada, Y.; Fuse, N.; Ohtsu, A.; Matsumoto, S.; Takanashi, M.; Matsumura, Y. Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors. Clin. Cancer Res. 2010, 16 (20), 5058– 5066, DOI: 10.1158/1078-0432.CCR-10-038719https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1yqsLbE&md5=c0384f5052c3d613505e5fdc352560a6Phase I Study of NK012, a Novel SN-38-Incorporating Micellar Nanoparticle, in Adult Patients with Solid TumorsHamaguchi, Tetsuya; Doi, Toshihiko; Eguchi-Nakajima, Takako; Kato, Ken; Yamada, Yasuhide; Shimada, Yasuhiro; Fuse, Nozomu; Ohtsu, Atsushi; Matsumoto, Shin-ichi; Takanashi, Masaya; Matsumura, YasuhiroClinical Cancer Research (2010), 16 (20), 5058-5066CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: We conducted a first-in-human phase I study to det. the dose-limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38-incorporating micellar nanoparticle. Exptl. Design: Patients with solid tumors refractory to std. therapy, or for which no std. therapy is available, were enrolled. NK012 was administered as a 30-min infusion every 3 wk. The starting dose was 2 mg/m2 as SN-38 equiv, and an accelerated titrn. schedule was used. Pharmacokinetic anal. was conducted in cycles 1 and 2. RESULTS: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematol. toxicity, esp. diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m2 dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half-life of approx. 140 and 210 h, resp. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 mo, resp. CONCLUSIONS: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing.
- 20Dong, Y.; Feng, S.-S. Methoxy Poly(Ethylene Glycol)-Poly(Lactide) (MPEG-PLA) Nanoparticles for Controlled Delivery of Anticancer Drugs. Biomaterials 2004, 25 (14), 2843– 2849, DOI: 10.1016/j.biomaterials.2003.09.055There is no corresponding record for this reference.
- 21Wei, X.; Gong, C.; Gou, M.; Fu, S.; Guo, Q.; Shi, S.; Luo, F.; Guo, G.; Qiu, L.; Qian, Z. Biodegradable Poly(ε-Caprolactone)–Poly(Ethylene Glycol) Copolymers as Drug Delivery System. Int. J. Pharm. 2009, 381 (1), 1– 18, DOI: 10.1016/j.ijpharm.2009.07.033There is no corresponding record for this reference.
- 22Kabanov, A. V.; Batrakova, E. V.; Alakhov, V. Y. Pluronic® Block Copolymers as Novel Polymer Therapeutics for Drug and Gene Delivery. J. Controlled Release 2002, 82 (2–3), 189– 212, DOI: 10.1016/S0168-3659(02)00009-322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlvFOktb4%253D&md5=106ee69575c4ebc3f22bf4bcd075c229Pluronic block copolymers as novel polymer therapeutics for drug and gene deliveryKabanov, Alexander V.; Batrakova, Elena V.; Alakhov, Valery Yu.Journal of Controlled Release (2002), 82 (2-3), 189-212CODEN: JCREEC; ISSN:0168-3659. (Elsevier Science Ltd.)A review. Pluronic block copolymers are found to be an efficient drug delivery system with multiple effects. The incorporation of drugs into the core of the micelles formed by Pluronic results in increased soly., metabolic stability and circulation time for the drug. The interactions of the Pluronic unimers with multidrug-resistant cancer cells result in sensitization of these cells with respect to various anticancer agents. Furthermore, the single mol. chains of copolymer, unimers, inhibit drug efflux transporters in both the blood-brain barrier and in the small intestine, which provides for the enhanced transport of select drugs to the brain and increases oral bioavailability. These and other applications of Pluronic block copolymers in various drug delivery and gene delivery systems are considered.
- 23Yin, F.; Laborie, P.; Lonetti, B.; Gineste, S.; Coppel, Y.; Lauth-de Viguerie, N.; Marty, J.-D. Dual Thermo- and PH-Responsive Block Copolymer of Poly(N -Isopropylacrylamide)- Block -Poly(N, N -Diethylamino Ethyl Acrylamide): Synthesis, Characterization, Phase Transition, and Self-Assembly Behavior in Aqueous Solution. Macromolecules 2023, 56 (10), 3703– 3720, DOI: 10.1021/acs.macromol.3c00424There is no corresponding record for this reference.
- 24Su, F.; Yun, P.; Li, C.; Li, R.; Xi, L.; Wang, Y.; Chen, Y.; Li, S. Novel Self-Assembled Micelles of Amphiphilic Poly(2-Ethyl-2-Oxazoline) -Poly(L-Lactide) Diblock Copolymers for Sustained Drug Delivery. Colloids Surf., A 2019, 566, 120, DOI: 10.1016/j.colsurfa.2019.01.01524https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht12gs7Y%253D&md5=a870058363af306020711f47a94463a1Novel self-assembled micelles of amphiphilic poly(2-ethyl-2-oxazoline)-poly(L-lactide) diblock copolymers for sustained drug deliverySu, Feng; Yun, Peng; Li, Chenglong; Li, Rongye; Xi, Laishun; Wang, Yuandou; Chen, Yangsheng; Li, SumingColloids and Surfaces, A: Physicochemical and Engineering Aspects (2019), 566 (), 120-127CODEN: CPEAEH; ISSN:0927-7757. (Elsevier B.V.)A series of poly(2-ethyl-2-oxazoline)-poly(L-lactide) (PEOz-PLA) diblock copolymers were synthesized by ring-opening polymn. of L-lactide using a monohydroxy terminated PEOz-OH macro-initiator in the presence of stannous octoate as catalyst. The resulting diblock copolymers were characterized by 1H NMR and gel permeation chromatog. Self-assembled micelles were prepd. using the co-solvent evapn. method in water and in phosphate buffered saline (PBS) at pH 7.4, 6.5 and 5.0. The resulting micelles exhibit different morphologies, such as spherical and worm-like micelles depending on the hydrophilic/hydrophobic balance. Spherical micelles were exclusively obsd. for PEOz-PLA copolymers with short PLA blocks, whereas co-existence of worm-like and spherical micelles was obsd. for copolymers with long PLA blocks. The micelle size increases with decreasing pH due to the electrostatic repulsion between PEOz chains resulting from ionization of the tertiary amide groups along PEOz chains. A hydrophobic anti-tumor drug, paclitaxel, was entrapped in PEOz-PLA micelles. High loading efficiency up to 86.7% was obtained for copolymers with long PLA blocks. Drug release was performed in PBS at different pH values. During the 30-day release period, faster release was obtained for copolymers with shorter PLA blocks than for copolymers with longer PLA blocks at acidic pH than at pH 7.4. It is concluded that pH-responsive PEOz-PLA copolymer micells could be promising as carrier of anti-tumor drugs.
- 25Zhang, W.-J.; Hong, C.-Y.; Pan, C.-Y. Polymerization-Induced Self-Assembly of Functionalized Block Copolymer Nanoparticles and Their Application in Drug Delivery. Macromol. Rapid Commun. 2019, 40 (2), 1800279, DOI: 10.1002/marc.201800279There is no corresponding record for this reference.
- 26Louage, B.; Zhang, Q.; Vanparijs, N.; Voorhaar, L.; Vande Casteele, S.; Shi, Y.; Hennink, W. E.; Van Bocxlaer, J.; Hoogenboom, R.; De Geest, B. G. Degradable Ketal-Based Block Copolymer Nanoparticles for Anticancer Drug Delivery: A Systematic Evaluation. Biomacromolecules 2015, 16 (1), 336– 350, DOI: 10.1021/bm501540926https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVGmsLjI&md5=12abe6d343a12e23ab6f293476bad241Degradable Ketal-Based Block Copolymer Nanoparticles for Anticancer Drug Delivery: A Systematic EvaluationLouage, Benoit; Zhang, Qilu; Vanparijs, Nane; Voorhaar, Lenny; Vande Casteele, Sofie; Shi, Yang; Hennink, Wim E.; Van Bocxlaer, Jan; Hoogenboom, Richard; De Geest, Bruno G.Biomacromolecules (2015), 16 (1), 336-350CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)Low soly. of potent (anticancer) drugs is a major driving force for the development of noncytotoxic, stimuli-responsive nanocarriers, including systems based on amphiphilic block copolymers. In this regard, we investigated the potential of block copolymers based on 2-hydroxyethyl acrylate (HEA) and the acid-sensitive ketal-contg. monomer (2,2-dimethyl-1,3-dioxolane-4-yl)methyl acrylate (DMDMA) to form responsive drug nanocarriers. Block copolymers were successfully synthesized by sequential reversible addn.-fragmentation chain transfer (RAFT) polymn., in which we combined a hydrophilic poly(HEA)x block with a (responsive) hydrophobic poly(HEAm-co-DMDMAn)y copolymer block. The DMDMA content of the hydrophobic block was systematically varied to investigate the influence of polymer design on physicochem. properties and in vitro biol. performance. We found that a DMDMA content higher than 11 mol % is required for self-assembly behavior in aq. medium. All particles showed colloidal stability in PBS at 37 °C for at least 4 days, with sizes ranging from 23 to 338 nm, proportional to the block copolymer DMDMA content. Under acidic conditions, the nanoparticles decompd. into sol. unimers, of which the decompn. rate was inversely proportional to the block copolymer DMDMA content. Flow cytometry and confocal microscopy showed dose-dependent, active in vitro cellular uptake of the particles loaded with hydrophobic octadecyl rhodamine B chloride (R18). The block copolymers showed no intrinsic in vitro cytotoxicity, while loaded with paclitaxel (PTX), a significant decrease in cell viability was obsd. comparable or better than the two com. PTX nanoformulations Abraxane and Genexol-PM at equal PTX dose. This systematic approach evaluated and showed the potential of these block copolymers as nanocarriers for hydrophobic drugs.
- 27Zhang, Q.; Hou, Z.; Louage, B.; Zhou, D.; Vanparijs, N.; De Geest, B. G.; Hoogenboom, R. Acid-Labile Thermoresponsive Copolymers That Combine Fast PH-Triggered Hydrolysis and High Stability under Neutral Conditions. Angew. Chem. 2015, 127 (37), 11029– 11033, DOI: 10.1002/ange.201505145There is no corresponding record for this reference.
- 28Zhang, Q.; Vanparijs, N.; Louage, B.; De Geest, B. G.; Hoogenboom, R. Dual PH- and Temperature-Responsive RAFT-Based Block Co-Polymer Micelles and Polymer–Protein Conjugates with Transient Solubility. Polym. Chem. 2014, 5 (4), 1140– 1144, DOI: 10.1039/C3PY00971H28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Ght7o%253D&md5=1dc05c8bdbd423b8ae5f6ed654204917Dual pH- and temperature-responsive RAFT-based block co-polymer micelles and polymer-protein conjugates with transient solubilityZhang, Qilu; Vanparijs, Nane; Louage, Benoit; De Geest, Bruno G.; Hoogenboom, RichardPolymer Chemistry (2014), 5 (4), 1140-1144CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Via a smart combination of temp.-responsive and acid labile acetal monomers, copolymers are obtained with a la carte lower crit. soln. temp. behavior. RAFT copolymn. of these monomers using, resp., a PEG-functionalized or amine-reactive NHS-functionalized chain transfer agent allows designing of micelles and polymer-protein conjugates with transient soly. properties within a physiol. relevant window.
- 29Kuperkar, K.; Patel, D.; Atanase, L. I.; Bahadur, P. Amphiphilic Block Copolymers: Their Structures, and Self-Assembly to Polymeric Micelles and Polymersomes as Drug Delivery Vehicles. Polymers 2022, 14 (21), 4702, DOI: 10.3390/polym1421470229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XivV2lsLjN&md5=7dc1028251f6d41dca748e2c80cdc25aAmphiphilic Block Copolymers: Their Structures, and Self-Assembly to Polymeric Micelles and Polymersomes as Drug Delivery VehiclesKuperkar, Ketan; Patel, Dhruvi; Atanase, Leonard Ionut; Bahadur, PratapPolymers (Basel, Switzerland) (2022), 14 (21), 4702CODEN: POLYCK; ISSN:2073-4360. (MDPI AG)A review. Self-assembly of amphiphilic block copolymers display a multiplicity of nanoscale periodic patterns proposed as a dominant tool for the 'bottom-up' fabrication of nanomaterials with different levels of ordering. The present review article focuses on the recent updates to the self-assocn. of amphiphilic block copolymers in aq. media into varied core-shell morphologies. We briefly describe the block copolymers, their types, microdomain formation in bulk and micellization in selective solvents. We also discuss the characteristic features of block copolymers nanoaggregates viz., polymer micelles (PMs) and polymersomes. Amphiphilic block copolymers (with a variety of hydrophobic blocks and hydrophilic blocks; often polyethylene oxide) self-assemble in water to micelles/niosomes similar to conventional nonionic surfactants with high drug loading capacity. Double hydrophilic block copolymers (DHBCs) made of neutral block-neutral block or neutral block-charged block can transform one block to become hydrophobic under the influence of a stimulus (phys./chem./biol.), and thus induced amphiphilicity and display self-assembly are discussed. Different kinds of polymer micelles (viz. shell and core-crosslinked, core-shell-corona, schizophrenic, crew cut, Janus) are presented in detail. Updates on polymn.-induced self-assembly (PISA) and crystn.-driven self-assembly (CDSA) are also provided. Polyion complexes (PICs) and polyion complex micelles (PICMs) are discussed. Applications of these block copolymeric micelles and polymersomes as nanocarriers in drug delivery systems are described.
- 30Gupta, M.; Sharma, V.; Chauhan, D. N.; Chauhan, N. S.; Shah, K.; Goyal, R. K. Amphiphilic Block Copolymer: A Smart Option for Bioactives Delivery. In Advances and Avenues in the Development of Novel Carriers for Bioactives and Biological Agents; Elsevier, 2020, pp. 451– 479. DOI: 10.1016/B978-0-12-819666-3.00015-8 .There is no corresponding record for this reference.
- 31Huang, X.; Du, F.; Ju, R.; Li, Z. Novel Acid-Labile, Thermoresponsive Poly(Methacrylamide)s with Pendent Ortho Ester Moieties. Macromol. Rapid Commun. 2007, 28 (5), 597– 603, DOI: 10.1002/marc.20060079831https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjslWksLc%253D&md5=b63ce85e5fc137d778410aa1d04e91c1Novel acid-labile, thermoresponsive poly(methacrylamide)s with pendent ortho ester moietiesHuang, Xiaonan; Du, Fusheng; Ju, Rong; Li, ZichenMacromolecular Rapid Communications (2007), 28 (5), 597-603CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)Novel acid-labile, thermoresponsive methacrylamide-based (co)polymers with pendent ortho ester groups were prepd. by free radical polymn. of N-(2-methoxy-1,3-dioxan-5-yl)methacrylamide (NMM) and N-(2-ethoxy-1,3-dioxan-5-yl)methacrylamide (NEM). These polymers are both thermoresponsive and acid-sensitive in aq. soln., which was proved by transmittance measurements, fluorescence, and 1H NMR spectroscopy. The LCSTs of the (co)polymers were shifted to higher temp. by increasing the content of the more hydrophilic NMM units. All of these polymers can be hydrolyzed under acidic condition and the hydrolysis rate increased with the decrease in the pH value.
- 32Ishitake, K.; Satoh, K.; Kamigaito, M.; Okamoto, Y. Stereogradient Polymers Formed by Controlled/Living Radical Polymerization of Bulky Methacrylate Monomers. Angew. Chem. 2009, 121 (11), 2025– 2028, DOI: 10.1002/ange.200805168There is no corresponding record for this reference.
- 33Pytlíková, S.; Pechar, M.; Chytil, P.; Studenovský, M.; Pola, R.; Kotrchová, L.; Konefał, R.; Čtveráčková, L.; Laga, R.; Pankrác, J. Highly Hydrophilic Methacrylamide-Based Copolymers as Precursors for Polymeric Nanomedicines Containing Anthracyclines. Eur. Polym. J. 2024, 205 (January), 112756, DOI: 10.1016/j.eurpolymj.2024.112756There is no corresponding record for this reference.
- 34Kolouchová, K.; Lobaz, V.; Beneš, H.; de la Rosa, V. R.; Babuka, D.; Švec, P.; Černoch, P.; Hrubý, M.; Hoogenboom, R.; Štěpánek, P.; Groborz, O. Thermoresponsive Properties of Polyacrylamides in Physiological Solutions. Polym. Chem. 2021, 12 (35), 5077– 5084, DOI: 10.1039/D1PY00843A34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhslOntr7O&md5=9748ba876004aa2fb53dc97b1a323df1Thermoresponsive properties of polyacrylamides in physiological solutionsKolouchova, Kristyna; Lobaz, Volodymyr; Benes, Hynek; de la Rosa, Victor R.; Babuka, David; Svec, Pavel; Cernoch, Peter; Hruby, Martin; Hoogenboom, Richard; Stepanek, Petr; Groborz, OndrejPolymer Chemistry (2021), 12 (35), 5077-5084CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)Polymer solns. with a lower crit. soln. temp. (LCST) undergo reversible phase sepn. when heated above their cloud point temp. (TCP or CPT). As such, they have been proposed for a wide range of biomedical applications, from injectable drug depots to switchable coatings for cell adhesion. However, in systematic studies, the TCP of these thermoresponsive polymers has been mostly measured in non-physiol. solns., thereby hindering the development of their medicinal applications. Here, we analyzed the thermoresponsive properties of four acrylamide-based polymers with LCST, namely poly[(N-2,2-difluoroethyl)acrylamide] (pDFEA), poly[(N-isopropyl)acrylamide] (pNIPAM), poly[(N,N-diethyl)acrylamide] (pDEA), and poly[(N-acryloyl)pyrrolidine] (pAP). As shown by turbidimetry, their TCP in phosphate saline buffer (PBS) and fetal bovine serum (FBS) were consistently lower than those reported in the literature, typically assessed in pure water, even when using the same setup. In addn., these physiol. solns. affected the variation of TCP as a function of polymer concn. (1.25 to 10.0 mg mL-1) and molar mass (20 to 50 kg mol-1). As shown by isothermal calorimetry, interactions between proteins in FBS and polymer aggregates were predominantly exothermic, which indicates that protein-polymer complexes are formed through enthalpically driven processes. In conclusion, the TCP of thermoresponsive polymers strongly depends on solvent compn. and therefore should be measured under physiol. conditions for future medicinal applications.
- 35Paiuk, O.; Mitina, N.; Slouf, M.; Pavlova, E.; Finiuk, N.; Kinash, N.; Karkhut, A.; Manko, N.; Gromovoy, T.; Hevus, O. Fluorine-Containing Block/Branched Polyamphiphiles Forming Bioinspired Complexes with Biopolymers. Colloids Surf., B 2019, 174 (June 2018), 393– 400, DOI: 10.1016/j.colsurfb.2018.11.047There is no corresponding record for this reference.
- 36Bildziukevich, U.; Kaletová, E.; Šaman, D.; Sievänen, E.; Kolehmainen, E. T.; Šlouf, M.; Wimmer, Z. Spectral and Microscopic Study of Self-Assembly of Novel Cationic Spermine Amides of Betulinic Acid. Steroids 2017, 117, 90– 96, DOI: 10.1016/j.steroids.2016.07.00736https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFymsrzK&md5=99d48db2708b369256dea5abd9d6fdfcSpectral and microscopic study of self-assembly of novel cationic spermine amides of betulinic acidBildziukevich, Uladzimir; Kaletova, Eva; Saman, David; Sievanen, Elina; Kolehmainen, Erkki T.; Slouf, Miroslav; Wimmer, ZdenekSteroids (2017), 117 (), 90-96CODEN: STEDAM; ISSN:0039-128X. (Elsevier)Supramol. characteristics of two spermine amides of betulinic acid (1 and 2) were studied by measuring and evaluating their UV-VIS-NIR spectra in aq. acetonitrile and DOSY-NMR spectra in tetradeuteromethanol, accompanied by at. force microscopy (AFM) images, SEM micrographs, and transmission electron microscopy (TEM) micrographs. Fibrous supramol. self-assembly of 1 and 2 was obsd. by AFM images, as well as by the SEM and TEM micrographs. Bathochromic shifts of the absorbance max. at 870 nm to 1015-970 nm in the UV-VIS-NIR spectra were obsd. with increasing water content in the acetonitrile/water systems, indicating formation of fibrous J-type aggregates. Variable temp. DOSY-NMR spectral measurement showed non-linear dependence that also suggests self-assembly behavior of the studied systems. Chiral supramol. structures were formed by self-assembling due to the chirality of the monomeric mols. Application of aq. media during self-assembly procedures is an important factor in the development of targeted drug delivery systems.
- 37Laga, R.; Janoušková, O.; Ulbrich, K.; Pola, R.; Blažková, J.; Filippov, S. K.; Etrych, T.; Pechar, M. Thermoresponsive Polymer Micelles as Potential Nanosized Cancerostatics. Biomacromolecules 2015, 16 (8), 2493– 2505, DOI: 10.1021/acs.biomac.5b00764There is no corresponding record for this reference.
- 38Spěváček, J.; Konefał, R.; Dybal, J.; Čadová, E.; Kovářová, J. Thermoresponsive Behavior of Block Copolymers of PEO and PNIPAm with Different Architecture in Aqueous Solutions: A Study by NMR, FTIR, DSC and Quantum-Chemical Calculations. Eur. Polym. J. 2017, 94 (May), 471– 483, DOI: 10.1016/j.eurpolymj.2017.07.034There is no corresponding record for this reference.
- 39Konefał, R.; Spěváček, J.; Černoch, P. Thermoresponsive Poly(2-Oxazoline) Homopolymers and Copolymers in Aqueous Solutions Studied by NMR Spectroscopy and Dynamic Light Scattering. Eur. Polym. J. 2018, 100 (January), 241– 252, DOI: 10.1016/j.eurpolymj.2018.01.019There is no corresponding record for this reference.
- 40Konefał, R.; Černoch, P.; Konefał, M.; Spěváček, J. Temperature Behavior of Aqueous Solutions of Poly(2-Oxazoline) Homopolymer and Block Copolymers Investigated by NMR Spectroscopy and Dynamic Light Scattering. Polymers 2020, 12 (9), 1879, DOI: 10.3390/polym12091879There is no corresponding record for this reference.
- 41Aseyev, V. O.; Tenhu, H.; Winnik, F. M. Temperature Dependence of the Colloidal Stability of Neutral Amphiphilic Polymers in Water Conformation-Dependent Design of Sequences in Copolymers IISpringer2006 1– 85There is no corresponding record for this reference.
- 42Oleszko-Torbus, N.; Utrata-Wesołek, A.; Bochenek, M.; Lipowska-Kur, D.; Dworak, A.; Wałach, W. Thermal and Crystalline Properties of Poly(2-Oxazoline)S. Polym. Chem. 2020, 11 (1), 15– 33, DOI: 10.1039/C9PY01316DThere is no corresponding record for this reference.
- 43Bordat, A.; Boissenot, T.; Nicolas, J.; Tsapis, N. Thermoresponsive Polymer Nanocarriers for Biomedical Applications. Adv. Drug Delivery Rev. 2019, 138, 167– 192, DOI: 10.1016/j.addr.2018.10.00543https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFKjtLbI&md5=452da5786242284467701d84fd58731aThermoresponsive polymer nanocarriers for biomedical applicationsBordat, Alexandre; Boissenot, Tanguy; Nicolas, Julien; Tsapis, NicolasAdvanced Drug Delivery Reviews (2019), 138 (), 167-192CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)Polymer nanocarriers allow drug encapsulation leading to fragile mol. protection from early degrdn./metabolization, increased soly. of poorly sol. drugs and improved plasmatic half-life. However, efficiently controlling the drug release from nanocarriers is still challenging. Thermoresponsive polymers exhibiting either a lower crit. soly. temp. (LCST) or an upper crit. soly. temp. (UCST) in aq. medium may be the key to build spatially and temporally controlled drug delivery systems. In this review, we provide an overview of LCST and UCST polymers used as building blocks for thermoresponsive nanocarriers for biomedical applications. Recent nanocarriers based on thermoresponsive polymer exhibiting unprecedented features useful for biomedical applications are also discussed. While LCST nanocarriers have been studied for over two decades, UCST nanocarriers have recently emerged and already show great potential for effective thermoresponsive drug release.
- 44Säckel, C.; von Klitzing, R.; Siegel, R.; Senker, J.; Vogel, M. Water Dynamics in Solutions of Linear Poly (N-Isopropyl Acrylamide) Studied by 2H NMR Field-Cycling Relaxometry. Front. Soft Matter 2024, 4 (March), 1– 11, DOI: 10.3389/frsfm.2024.1379816There is no corresponding record for this reference.
- 45Spěváček, J.; Dybal, J.; Starovoytova, L.; Zhigunov, A.; Sedláková, Z. Temperature-Induced Phase Separation and Hydration in Poly(N-Vinylcaprolactam) Aqueous Solutions: A Study by NMR and IR Spectroscopy, SAXS, and Quantum-Chemical Calculations. Soft Matter 2012, 8 (22), 6110, DOI: 10.1039/c2sm25432hThere is no corresponding record for this reference.
- 46Zhang, C.; Sanchez, R. J. P.; Fu, C.; Clayden-Zabik, R.; Peng, H.; Kempe, K.; Whittaker, A. K. Importance of Thermally Induced Aggregation on 19 F Magnetic Resonance Imaging of Perfluoropolyether-Based Comb-Shaped Poly(2-Oxazoline)S. Biomacromolecules 2019, 20 (1), 365– 374, DOI: 10.1021/acs.biomac.8b0154946https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlCmsb%252FO&md5=3470b1a076ee6471eccaed54c025bae6Importance of Thermally Induced Aggregation on 19F Magnetic Resonance Imaging of Perfluoropolyether-Based Comb-Shaped Poly(2-oxazoline)sZhang, Cheng; Sanchez, Ronny Javier Pibaque; Fu, Changkui; Clayden-Zabik, Ryan; Peng, Hui; Kempe, Kristian; Whittaker, Andrew K.Biomacromolecules (2019), 20 (1), 365-374CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)An understanding of thermally induced aggregation and consequent 19F magnetic resonance imaging (MRI) performance is essential for improved design of thermoresponsive 19F MRI contrast agents. Herein we describe a series of novel thermoresponsive perfluoropolyether (PFPE)-based comb-shaped poly(2-oxazoline)s (POxs) with different side-chain structures (2-methyl- (MeOx), 2-ethyl- (EtOx), and 2-(n-propyl)-2-oxazoline (nPrOx)). The comb polymers were prepd. through reversible addn.-fragmentation chain transfer (RAFT) polymn. of the resp. oligo(2-oxazoline)acrylates using a perfluoropolyether macro-RAFT agent. The fluoropolyether chain end drives aggregation of the polymers, with small aggregates forming at 300 K for both poly(OMeOx5A)9-PFPE and poly(OEtOx4A)9-PFPE. The aggregates decrease in size and display increases in 19F MRI intensity with temp., and at 350 K the MeOx polymers are in the form of unimers in soln., similar to the oligoethylene glycol (OEG)-based PFPE polymer. Above the TCP of poly(OEtOx4A)9-PFPE, the polymer forms large aggregates, and the 19F MR imaging performance is degraded. Likewise, poly(OnPrOx4A)-PFPE is above the LCST at all temps. studied (300-350 K), and so weak imaging intensity is obtained. This report of novel thermoresponsive POx-based PFPE polymers highlights the importance of understanding self-assocn. of polymers in soln. and provides important insights for the development of "smart" thermoresponsive 19F MRI contrast agents.
- 47Lobaz, V.; Liščáková, V.; Sedlák, F.; Musil, D.; Petrova, S. L.; Šeděnková, I.; Pánek, J.; Kučka, J.; Konefał, R.; Tihlaříková, E.; Neděla, V.; Pankrác, J.; Šefc, L.; Hrubý, M.; Šácha, P.; Štěpánek, P. Tuning Polymer–Blood and Polymer–Cytoplasm Membrane Interactions by Manipulating the Architecture of Poly(2-Oxazoline) Triblock Copolymers. Colloids Surf., B 2023, 231 (July), 113564, DOI: 10.1016/j.colsurfb.2023.113564There is no corresponding record for this reference.
- 48Smith, O. E. P.; Waters, L. J.; Small, W.; Mellor, S. CMC Determination Using Isothermal Titration Calorimetry for Five Industrially Significant Non-Ionic Surfactants. Colloids Surf., B 2022, 211 (November 2021), 112320, DOI: 10.1016/j.colsurfb.2022.112320There is no corresponding record for this reference.
- 49Yamamoto, Y.; Yasugi, K.; Harada, A.; Nagasaki, Y.; Kataoka, K. Temperature-Related Change in the Properties Relevant to Drug Delivery of Poly(Ethylene Glycol)-Poly(D,L-Lactide) Block Copolymer Micelles in Aqueous Milieu. J. Controlled Release 2002, 82 (2–3), 359– 371, DOI: 10.1016/S0168-3659(02)00147-5There is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsabm.4c01167.
SEC chromatograms of polymers, 1H NMR spectra of monomers, results from DLS, ITC and DSC analyses (PDF)
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