Glycopolymer and Poly(β-amino ester)-Based Amphiphilic Block Copolymer as a Drug Carrier

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   Advanced drug delivery 2020 and beyond: Perspectives on the future

   Bae, You Han; Park, Kinam

   Advanced Drug Delivery Reviews (2020), 158 (), 4-16CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)

   A review. Drug delivery systems are developed to maximize drug efficacy and minimize side effects. As drug delivery technologies improve, the drug becomes safer and more comfortable for patients to use. During the last seven decades, extraordinary progress has been made in drug delivery technologies, such as systems for long-term delivery for months and years, localized delivery, and targeted delivery. The advances, however, will face a next phase considering the future technologies we need to overcome many physicochem. barriers for new formulation development and biol. unknowns for treating various diseases. For immediate and long-term progress into the future, the drug delivery field should use time and resources for more translatable research ideas. The drug delivery discipline has to continue working on basic, applied, translational, and clin. research in a concerted manner to produce drug delivery systems that work for patients. It is a time to focus our attention on things that matter. It is also a time to develop realistic research goals and outcomes, diversify drug delivery technologies, and take the collective responsibility for our actions.
2. 2

   Mitchell, M. J.; Billingsley, M. M.; Haley, R. M.; Wechsler, M. E.; Peppas, N. A.; Langer, R. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discovery 2021, 20, 101– 124,  DOI: 10.1038/s41573-020-0090-8

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   Engineering precision nanoparticles for drug delivery

   Mitchell, Michael J.; Billingsley, Margaret M.; Haley, Rebecca M.; Wechsler, Marissa E.; Peppas, Nicholas A.; Langer, Robert

   Nature Reviews Drug Discovery (2021), 20 (2), 101-124CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)

   In recent years, the development of nanoparticles has expanded into a broad range of clin. applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biol. barriers systemic, microenvironmental and cellular that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one size fits all soln. As lipid based, polymeric and inorg. nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.
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   Principles of nanoparticle design for overcoming biological barriers to drug delivery

   Blanco, Elvin; Shen, Haifa; Ferrari, Mauro

   Nature Biotechnology (2015), 33 (9), 941-951CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)

   Biol. barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biol. barriers that a particle encounters upon i.v. administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
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   Kamaly, N.; Xiao, Z.; Valencia, P. M.; Radovic-Moreno, A. F.; Farokhzad, O. C. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem. Soc. Rev. 2012, 41, 2971– 3010,  DOI: 10.1039/c2cs15344k

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   Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

   Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M.; Radovic-Moreno, Aleksandar F.; Farokhzad, Omid C.

   Chemical Society Reviews (2012), 41 (7), 2971-3010CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

   A review. Polymeric materials have been used in a range of pharmaceutical and biotechnol. products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concn. and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacol. as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chem. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their compn., and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug mols. themselves may also be facilitated following their incorporation into NPs, as drug properties (soly., metab., plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chem. compn., but also become in-part the function of the physicochem. properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clin. outcomes that may not be achievable with the administration of drugs in their conventional form. In this crit. review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges assocd. with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochem. properties. Addnl., we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 refs.).
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   Roy, D.; Cambre, J. N.; Sumerlin, B. S. Future perspectives and recent advances in stimuli-responsive materials. Prog. Polym. Sci. 2010, 35, 278– 301,  DOI: 10.1016/j.progpolymsci.2009.10.008

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   Future perspectives and recent advances in stimuli-responsive materials

   Roy, Debashish; Cambre, Jennifer N.; Sumerlin, Brent S.

   Progress in Polymer Science (2010), 35 (1-2), 278-301CODEN: PRPSB8; ISSN:0079-6700. (Elsevier Ltd.)

   A review. Interest in stimuli-responsive polymers has persisted over many decades, and a great deal of work has been dedicated to developing environmentally sensitive macromols. that can be crafted into new smart materials. However, the overwhelming majority of reports in the literature describe stimuli-responsive polymers that are sensitive to only a few common triggers, including changes in pH, temp., and electrolyte concn. Herein, we aim to highlight recent results and future trends that exploit stimuli that have not yet been as heavily considered, despite their unique potential. Many of the topics represent clear opportunities for making advances in biomedical fields due to their specificity and the ability to respond to stimuli that are inherently present in living systems. Recent results in the area of polymers that respond to specific antigen-antibody interactions, enzymes, and glucose are specifically discussed. Also considered are polymeric systems that respond to light, elec., magnetic, and sonic fields, all of which have potential in the area of controlled release as a result of their ability to be applied in a non-invasive and easily controlled manner. Thiol-responsive and redox-responsive polymers are also highlighted, with particular attention being devoted to their reversible dynamic covalent chem. It is our goal to emphasize these underutilized adaptive behaviors so that novel applications and new generations of smart materials can be realized.
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   Stuart, M. A. C.; Huck, W. T. S.; Genzer, J.; Müller, M.; Ober, C.; Stamm, M.; Sukhorukov, G. B.; Szleifer, I.; Tsukruk, V. V.; Urban, M.; Winnik, F.; Zauscher, S.; Luzinov, I.; Minko, S. Emerging applications of stimuli-responsive polymer materials. Nat. Mater. 2010, 9, 101– 113,  DOI: 10.1038/nmat2614

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   Emerging applications of stimuli-responsive polymer materials

   Stuart Martien A Cohen; Huck Wilhelm T S; Genzer Jan; Muller Marcus; Ober Christopher; Stamm Manfred; Sukhorukov Gleb B; Szleifer Igal; Tsukruk Vladimir V; Urban Marek; Winnik Francoise; Zauscher Stefan; Luzinov Igor; Minko Sergiy

   Nature materials (2010), 9 (2), 101-13 ISSN:.

   Responsive polymer materials can adapt to surrounding environments, regulate transport of ions and molecules, change wettability and adhesion of different species on external stimuli, or convert chemical and biochemical signals into optical, electrical, thermal and mechanical signals, and vice versa. These materials are playing an increasingly important part in a diverse range of applications, such as drug delivery, diagnostics, tissue engineering and 'smart' optical systems, as well as biosensors, microelectromechanical systems, coatings and textiles. We review recent advances and challenges in the developments towards applications of stimuli-responsive polymeric materials that are self-assembled from nanostructured building blocks. We also provide a critical outline of emerging developments.
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   Blakney, A. K.; Zhu, Y.; McKay, P. F.; Bouton, C. R.; Yeow, J.; Tang, J.; Hu, K.; Samnuan, K.; Grigsby, C. L.; Shattock, R. J.; Stevens, M. M. Big Is Beautiful: Enhanced saRNA Delivery and Immunogenicity by a Higher Molecular Weight, Bioreducible, Cationic Polymer. ACS Nano 2020, 14, 5711– 5727,  DOI: 10.1021/acsnano.0c00326

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   Big Is Beautiful: Enhanced saRNA Delivery and Immunogenicity by a Higher Molecular Weight, Bioreducible, Cationic Polymer

   Blakney, Anna K.; Zhu, Yunqing; McKay, Paul F.; Bouton, Clement R.; Yeow, Jonathan; Tang, Jiaqing; Hu, Kai; Samnuan, Karnyart; Grigsby, Christopher L.; Shattock, Robin J.; Stevens, Molly M.

   ACS Nano (2020), 14 (5), 5711-5727CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

   Self-amplifying RNA (saRNA) vaccines are highly advantageous, as they result in enhanced protein expression compared to mRNA, thus minimizing the required dose. However, previous delivery strategies were optimized for siRNA or mRNA and do not necessarily deliver saRNA efficiently due to structural differences of these RNAs, thus motivating the development of saRNA delivery platforms. Here, we engineer a bioreducible, linear, cationic polymer called "pABOL" for saRNA delivery and show that increasing its mol. wt. enhances delivery both in vitro and in vivo. We demonstrate that pABOL enhances protein expression and cellular uptake via both i.m. and intradermal injection compared to com. available polymers in vivo and that i.m. injection confers complete protection against influenza challenge. Due to the scalability of polymer synthesis and ease of formulation prepn., we anticipate that this polymer is highly clin. translatable as a delivery vehicle for saRNA for both vaccines and therapeutics.
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   Corbet, C.; Feron, O. Tumour acidosis: from the passenger to the driver’s seat. Nat. Rev. Cancer 2017, 17, 577– 593,  DOI: 10.1038/nrc.2017.77

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   Tumour acidosis: from the passenger to the driver's seat

   Corbet, Cyril; Feron, Olivier

   Nature Reviews Cancer (2017), 17 (10), 577-593CODEN: NRCAC4; ISSN:1474-175X. (Nature Research)

   The high metabolic demand of cancer cells leads to an accumulation of H+ ions in the tumor microenvironment. The disorganized tumor vasculature prevents an efficient wash-out of H+ ions released into the extracellular medium but also favors the development of tumor hypoxic regions assocd. with a shift towards glycolytic metab. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the prodn. of lactate and a stoichiometric amt. of H+ ions. Another major source of H+ ions results from hydration of CO2 produced in the more oxidative tumor areas. All of these events occur at high rates in tumors to fulfil bioenergetic and biosynthetic needs. This Review summarizes the current understanding of how H+-generating metabolic processes segregate within tumors according to the distance from blood vessels and inversely how ambient acidosis influences tumor metab., reducing glycolysis while promoting mitochondrial activity. The Review also presents novel insights supporting the participation of acidosis in cancer progression via stimulation of autophagy and immunosuppression. Finally, recent advances in the different therapeutic modalities aiming to either block pH-regulatory systems or exploit acidosis will be discussed.
9. 9

   Estrella, V.; Chen, T.; Lloyd, M.; Wojtkowiak, J.; Cornnell, H. H.; Ibrahim-Hashim, A.; Bailey, K.; Balagurunathan, Y.; Rothberg, J. M.; Sloane, B. F.; Johnson, J.; Gatenby, R. A.; Gillies, R. J. Acidity Generated by the Tumor Microenvironment Drives Local Invasion. Cancer Res. 2013, 73, 1524– 1535,  DOI: 10.1158/0008-5472.CAN-12-2796

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   Acidity Generated by the Tumor Microenvironment Drives Local Invasion

   Estrella, Veronica; Chen, Tingan; Lloyd, Mark; Wojtkowiak, Jonathan; Cornnell, Heather H.; Ibrahim-Hashim, Arig; Bailey, Kate; Balagurunathan, Yoganand; Rothberg, Jennifer M.; Sloane, Bonnie F.; Johnson, Joseph; Gatenby, Robert A.; Gillies, Robert J.

   Cancer Research (2013), 73 (5), 1524-1535CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)

   The pH of solid tumors is acidic due to increased fermentative metab. and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H+ diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal extracellular pH. Immunohistochem. analyses revealed that cells in the invasive edges expressed the glucose transporter-1 and the sodium-hydrogen exchanger-1, both of which were assocd. with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclin. model, supporting the acid-mediated invasion hypothesis.
10. 10

    van Sluis, R.; Bhujwalla, Z. M.; Raghunand, N.; Ballesteros, P.; Alvarez, J.; Cerdán, S.; Galons, J.-P.; Gillies, R. J. In vivo imaging of extracellular pH using 1H MRSI. Magn. Reson. Med. 1999, 41, 743– 750,  DOI: 10.1002/(SICI)1522-2594(199904)41:4<743::AID-MRM13>3.0.CO;2-Z

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    In vivo imaging of extracellular pH using 1H MRSI

    van Sluis R; Bhujwalla Z M; Raghunand N; Ballesteros P; Alvarez J; Cerdan S; Galons J P; Gillies R J

    Magnetic resonance in medicine (1999), 41 (4), 743-50 ISSN:0740-3194.

    Tumor pH is physiologically important since it influences a number of processes relevant to tumorigenesis and therapy. Hence, knowledge of localized pH within tumors would contribute to understanding these processes. The destructiveness, poor spatial resolution, and poor signal-to-noise ratio (SNR) of current technologies (e.g., microelectrodes, 31P magnetic resonance spectroscopy) have limited such studies. An extrinsic chemical extracellular pH (pHe) probe is described that is used in combination with 1H magnetic resonance spectroscopic imaging to yield pHe maps with a spatial resolution of 1 x 1 x 4 mm3. The principle of the technique is demonstrated on a phantom. Further data are shown to demonstrate its application in vivo, and results agree with previously reported pH values. The accuracy of the reported pH measurements is <0.1 pH units, as derived from a detailed analysis of the errors associated with the technique, the description of which is included.
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    Liu, J.; Huang, Y.; Kumar, A.; Tan, A.; Jin, S.; Mozhi, A.; Liang, X.-J. pH-Sensitive nano-systems for drug delivery in cancer therapy. Biotechnol. Adv. 2014, 32, 693– 710,  DOI: 10.1016/j.biotechadv.2013.11.009

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    pH-Sensitive nano-systems for drug delivery in cancer therapy

    Liu, Juan; Huang, Yuran; Kumar, Anil; Tan, Aaron; Jin, Shubin; Mozhi, Anbu; Liang, Xing-Jie

    Biotechnology Advances (2014), 32 (4), 693-710CODEN: BIADDD; ISSN:0734-9750. (Elsevier)

    A review. Nanotechnol. has been widely used in the development of new strategies for drug delivery and cancer therapy. Compared to traditional drug delivery systems, nano-based drug delivery system have greater potential in a variety of areas, such as multiple targeting functionalization, in vivo imaging, combined drug delivery, extended circulation time, and systemic control release. Nano-systems incorporating stimulus-responsive materials have remarkable properties which allow them to bypass biol. barriers and achieve targeted intracellular drug delivery. As a result of the active metab. of tumor cells, the tumor microenvironment (TME) is highly acidic compared to normal tissues. PH-Sensitive nano-systems have now been developed in which drug release is specifically triggered by the acidic tumor environment. Studies have demonstrated that novel pH-sensitive drug delivery systems are capable of improving the efficiency of cancer treatment. A no. of these have been translated from bench to clin. application and have been approved by the Food and Drug Administration (FDA) for treatment of various cancerous diseases. Herein, this review mainly focuses on pH-sensitive nano-systems, including advances in drug delivery, mechanisms of drug release, and possible improvements in drug absorption, with the emphasis on recent research in this field. With deeper understanding of the difference between normal and tumor tissues, it might be possible to design ever more promising pH-responsive nano-systems for drug delivery and cancer therapy in the near future.
12. 12

    Lee, E. S.; Oh, K. T.; Kim, D.; Youn, Y. S.; Bae, Y. H. Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine). J. Controlled Release 2007, 123, 19– 26,  DOI: 10.1016/j.jconrel.2007.08.006

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    Tumor pH-responsive flower-like micelles of poly(L-lactic acid)-b-poly(ethylene glycol)-b-poly(L-histidine)

    Lee, Eun Seong; Oh, Kyung Taek; Kim, Dongin; Youn, Yu Seok; Bae, You Han

    Journal of Controlled Release (2007), 123 (1), 19-26CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

    Polymeric micelles were constructed from poly(-lactic acid) (PLA; Mn 3K)-b-poly(ethylene glycol) (PEG; Mn 2K)-b-poly(-histidine) (polyHis; Mn 5K) as a tumor pH-specific anticancer drug carrier. Micelles (particle diam.: ∼ 80 nm; crit. micelle concn. (CMC): 2 μg/mL) formed by dialysis of the polymer soln. in dimethylsulfoxide (DMSO) against pH 8.0 aq. soln., are assumed to have a flower-like assembly of PLA and polyHis blocks in the core and PEG block as the shell. The pH-sensitivity of the micelles originates from the deformation of the micellar core due to the ionization of polyHis at a slightly acidic pH. However, the co-presence of pH-insensitive lipophilic PLA block in the core prevented disintegration of the micelles and caused swelling/aggregation. A fluorescence probe study showed that the polarity of pyrene retained in the micelles increased as pH was decreased from 7.4 to 6.6, indicating a change to a more hydrophilic environment in the micelles. Considering that the size increased up to 580 nm at pH 6.6 from 80 nm at pH 7.4 and that the transmittance of micellar soln. increased with decreasing pH, the micelles were not dissocd. but rather swollen/aggregated. Interestingly, the subsequent decline of pyrene polarity below pH 6.6 suggested re-self-assembly of the block copolymers, most likely forming a PLA block core while polyHis block relocation to the surface. Consequently, these pH-dependent phys. changes of the PLA-b-PEG-b-polyHis micelles provide a mechanism for triggered drug release from the micelles triggered by the small change in pH (pH 7.2-6.5).
13. 13

    Lee, E. S.; Gao, Z. G.; Bae, Y. H. Recent progress in tumor pH targeting nanotechnology. J. Controlled Release 2008, 132, 164– 170,  DOI: 10.1016/j.jconrel.2008.05.003

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    Recent progress in tumor pH targeting nanotechnology

    Lee, Eun Seong; Gao, Zhonggao; Bae, You Han

    Journal of Controlled Release (2008), 132 (3), 164-170CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

    A review. PH-sensitive polymeric micelles and nanogels have recently been developed to target slightly acidic extracellular pH environment of solid tumors. The pH targeting approach is regarded as a more general strategy than conventional specific tumor cell surface targeting approaches, because the acidic tumor microclimate is most common in solid tumors. When nanosystems are combined with triggered release mechanisms by endosomal or lysosomal acidity plus endosomolytic capability, the nanocarriers demonstrated to overcome multidrug resistance of various tumors. This review highlights recent progress of the pH-sensitive nanotechnol. developed in Bae research group.
14. 14

    Li, J. H.; Zhang, X. Q.; Zhao, M. Y.; Wu, L. H.; Luo, K.; Pu, Y. J.; He, B. Tumor-pH-Sensitive PLLA-Based Microsphere with Acid Cleavable Acetal Bonds on the Backbone for Efficient Localized Chemotherapy. Biomacromolecules 2018, 19, 3140– 3148,  DOI: 10.1021/acs.biomac.8b00734

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    Tumor-pH-Sensitive PLLA-Based Microsphere with Acid Cleavable Acetal Bonds on the Backbone for Efficient Localized Chemotherapy

    Li, Junhua; Zhang, Xuequan; Zhao, Mingying; Wu, Lihuang; Luo, Kui; Pu, Yuji; He, Bin

    Biomacromolecules (2018), 19 (7), 3140-3148CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    Nanoparticle- and microsphere-based drug delivery systems (DDSs) have attracted wide attention in cancer therapy; those DDSs that are responsive to tumor environment can selectively identify tumor and normal tissues and therefore have shown enhanced anticancer efficacy and alleviated systemic toxicity. Here, tumor-pH-sensitive polymeric microspheres, which are prepd. by multiblock poly(L-lactide) with pH-sensitive acetal bonds in the backbone, are employed to efficiently load water-sol. anticancer drug doxorubicin hydrochloride (DOX·HCl, drug loading content: ∼10%). The pH-sensitive DOX-loaded hollow microspheres were in the size range 2-10 μm and exhibited acid-accelerated degrdn. of polymer matrix and drug release, and thereby efficient in vitro cancer cell inhibition. The microspheres were further intratumorally injected into breast-tumor-bearing mice, and the in vivo anticancer expt. showed that pH-sensitive DOX-loaded microsphere showed better antitumor efficiency and prolonged life-span than its counterpart that does not have pH-responsive property. Moreover, negligible organ toxicity, esp. cardiotoxicity that generally exists in DOX-involved chemotherapy where DOX is administrated by i.v. injection, was obsd. for DOX-loaded microspheres. Hence, tumor-pH-sensitive polymeric microspheres have appeared to be a simple and efficient platform for delivering hydrophilic anticancer drug with excellent anticancer efficacy and low systemic toxicity.
15. 15

    Wei, P.; Gangapurwala, G.; Pretzel, D.; Leiske, M. N.; Wang, L. M.; Hoeppener, S.; Schubert, S.; Brendel, J. C.; Schubert, U. S. Smart pH-Sensitive Nanogels for Controlled Release in an Acidic Environment. Biomacromolecules 2019, 20, 130– 140,  DOI: 10.1021/acs.biomac.8b01228

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    Smart pH-Sensitive Nanogels for Controlled Release in an Acidic Environment

    Wei, Peng; Gangapurwala, Gauri; Pretzel, David; Leiske, Meike N.; Wang, Limin; Hoeppener, Stephanie; Schubert, Stephanie; Brendel, Johannes C.; Schubert, Ulrich S.

    Biomacromolecules (2019), 20 (1), 130-140CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    The encapsulation of therapeutic compds. into nanosized delivery vectors has become an important strategy to improve efficiency and reduce side effects in drug delivery applications. Here, we report the synthesis of pH-sensitive nanogels, which are based on the monomer N-[(2,2-dimethyl-1,3-dioxolane)methyl]acrylamide (DMDOMA) bearing an acid cleavable acetal group. Degrdn. studies revealed that these nanogels hydrolyze under acidic conditions and degrade completely, depending on the cross-linker, but are stable in physiol. environment. The best performing system was further studied regarding its release kinetics using the anticancer drug doxorubicin. In vitro studies revealed a good compatibility of the unloaded nanogel and the capability of the doxorubicin loaded nanogel to mediate cytotoxic effects in a concn. and time-dependent manner with an even higher efficiency than the free drug. Based on the investigated features, the presented nanogels represent a promising and conveniently prepd. alternative to existing carrier systems for drug delivery.
16. 16

    Ulbrich, K.; Subr, V. Polymeric anticancer drugs with pH-controlled activation. Adv. Drug Delivery Rev. 2004, 56, 1023– 1050,  DOI: 10.1016/j.addr.2003.10.040

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    Polymeric anticancer drugs with pH-controlled activation

    Ulbrich, Karel; Subr, Vladimir

    Advanced Drug Delivery Reviews (2004), 56 (7), 1023-1050CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science B.V.)

    A review. Use of macromol. water-sol. carriers of anti-cancer drugs represents a promising approach to cancer therapy. Release of drugs from the carrier system is a prerequisite for therapeutic activity of most macromol. anti-cancer conjugates. Incorporation of acid-sensitive spacers between the drug and carrier enables release of an active drug from the carrier in a tumor tissue, either in slightly acidic extracellular fluids or, after endocytosis, in endosomes or lysosomes of cancer cells. This paper reviews advances in development and study of properties of various acid-sensitive macromol. drug delivery systems, starting from simple polymer-drug conjugates to ending with site-specific antibody-targeted polymer-drug conjugates.
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    Prabaharan, M.; Grailer, J. J.; Pilla, S.; Steeber, D. A.; Gong, S. Q. Amphiphilic multi-arm-block copolymer conjugated with doxorubicin via pH-sensitive hydrazone bond for tumor-targeted drug delivery. Biomaterials 2009, 30, 5757– 5766,  DOI: 10.1016/j.biomaterials.2009.07.020

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    Amphiphilic multi-arm-block copolymer conjugated with doxorubicin via pH-sensitive hydrazone bond for tumor-targeted drug delivery

    Prabaharan, Mani; Grailer, Jamison J.; Pilla, Srikanth; Steeber, Douglas A.; Gong, Shaoqin

    Biomaterials (2009), 30 (29), 5757-5766CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

    Folate-conjugated unimol. micelles based on amphiphilic hyperbranched block copolymer, Boltorn H40-poly(-aspartate-doxorubicin)-b-poly(ethylene glycol)/FA-conjugated poly(ethylene glycol) (H40-P(LA-DOX)-b-PEG-OH/FA), were synthesized as a carrier for tumor-targeted drug delivery. The anticancer drug DOX was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms by pH-sensitive hydrazone linkage. The size of the unimol. micelles was detd. as ∼17-36 and 10-20 nm by dynamic light scattering (DLS) and transmission electron microscopy (TEM), resp. The release profiles of the DOX from the H40-P(LA-DOX)-b-PEG-OH/FA micelles showed a strong dependence on the environmental pH values. The DOX release rate increased in the acidic medium due to the acid-cleavable hydrazone linkage between the DOX and micelles. Cellular uptake of the H40-P(LA-DOX)-b-PEG-OH/FA micelles was found to be higher than that of the H40-P(LA-DOX)-b-PEG-OH micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. Degrdn. studies showed that the H40-P(LA-DOX)-b-PEG-OH/FA copolymer hydrolytically degraded into polymer fragments within six weeks. These results suggest that H40-P(LA-DOX)-b-PEG-OH/FA micelles could be a promising nanocarrier with excellent in vivo stability for targeting the drugs to cancer cells and releasing the drug mols. inside the cells by sensing the acidic environment of the endosomal compartments.
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    Du, J. Z.; Du, X. J.; Mao, C. Q.; Wang, J. Tailor-Made Dual pH-Sensitive Polymer-Doxorubicin Nanoparticles for Efficient Anticancer Drug Delivery. J. Am. Chem. Soc. 2011, 133, 17560– 17563,  DOI: 10.1021/ja207150n

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    Tailor-Made Dual pH-Sensitive Polymer-Doxorubicin Nanoparticles for Efficient Anticancer Drug Delivery

    Du, Jin-Zhi; Du, Xiao-Jiao; Mao, Cheng-Qiong; Wang, Jun

    Journal of the American Chemical Society (2011), 133 (44), 17560-17563CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Efficient delivery of therapeutics into tumor cells to increase the intracellular drug concn. is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. Herein, a tailor-made dual pH-sensitive polymer-drug conjugate nanoparticulate system is designed to overcome the challenges. The nanoparticle is capable of reversing its surface charge from neg. to pos. at tumor extracellular pH (∼6.8) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments such as the endosome (∼5.0) further promotes doxorubicin release from the endocytosed drug carriers. This dual pH-sensitive nanoparticle shows enhanced cytotoxicity in drug-resistant cancer stem cells, indicating its great potential for cancer therapy.
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    Shenoy, D.; Little, S.; Langer, R.; Amiji, M. Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs. 1. In vitro evaluations. Mol. Pharmaceutics 2005, 2, 357– 366,  DOI: 10.1021/mp0500420

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    19

    Poly(ethylene oxide)-Modified Poly(β-amino ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs. 1. In Vitro Evaluations

    Shenoy, Dinesh; Little, Steven; Langer, Robert; Amiji, Mansoor

    Molecular Pharmaceutics (2005), 2 (5), 357-366CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)

    A representative poly(β-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate a nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissoln. when the pH of the medium is less than 6.5 and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepd. by solvent displacement method and characterized for particle size, charge, and surface morphol. Pluronic F-108, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), was blended with PbAE to induce surface modification of the nanoparticles. In vitro cellular uptake of tritiated [3H]-paclitaxel in soln. form and as a nanoparticulate formulation was studied in MDA-MB-231 human breast adenocarcinoma cells grown in 12-well plates. We also examd. the intracellular degrdn. pattern of the formulations within the cells by estg. the drug release profile. Cytotoxicity assay was performed on the formulations at different doses and time intervals. Nanoparticles prepd. from poly(ε-caprolactone) (PCL) that do not display pH-sensitive release behavior were used as control. Spherical nanoparticles having pos. ζ potential (∼40 mV) were obtained in the size range of 150-200 nm with PbAE. The PEO chains of the Pluronic were well-anchored within the nanomatrix as detd. by electron spectroscopy for chem. anal. (ESCA). The intracellular accumulation of paclitaxel within tumor cells was significantly higher when administered in the nanoparticle formulations as compared to aq. soln. Qual. fluorescent microscopy confirmed the rapid release of the payload into the cytosol in the case of PbAE nanoparticles, while the integrity of the PCL nanoparticles remained intact. The cytotoxicity assay results showed significantly higher tumoricidal activity of paclitaxel when administered in the nanoparticle formulations. The cell-kill effect was maximal for paclitaxel-loaded PbAE nanoparticles when normalized with respect to intracellular drug concns. Thus, PEO-modified PbAE nanoparticles show tremendous potential as novel carriers of cytotoxic agents for achieving improved drug disposition and enhanced efficacy.
20. 20

    Song, W. T.; Tang, Z. H.; Li, M. Q.; Lv, S. X.; Yu, H. Y.; Ma, L. L.; Zhuang, X. L.; Huang, Y. B.; Chen, X. S. Tunable pH-Sensitive Poly(beta-amino ester)s Synthesized from Primary Amines and Diacrylates for Intracellular Drug Delivery. Macromol. Biosci. 2012, 12, 1375– 1383,  DOI: 10.1002/mabi.201200122

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    Tunable pH-sensitive Poly(β-amino ester)s synthesized from primary amines and diacrylates for intracellular drug delivery

    Song, Wantong; Tang, Zhaohui; Li, Mingqiang; Lv, Shixian; Yu, Haiyang; Ma, Lili; Zhuang, Xiuli; Huang, Yubin; Chen, Xuesi

    Macromolecular Bioscience (2012), 12 (10), 1375-1383CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)

    The pH sensitivity of a series of PbAEs synthesized from primary amines and diacrylates is studied. By changing alkyl groups of the amine monomers, the pKb can be tuned across a broad range (from 3.5 to 7.2). Micelles formed from a PEG-PbAE block copolymer retain the pH sensitivity of PbAE and can stably load hydrophobic mols. under neutral pH, while quickly dissoc. and release their cargoes at pH ≈ 6.0. When the chemotherapy drug DOX is loaded, the micelles show efficient cell proliferation inhibition to HeLa cells and fast intracellular release. Thus, the primary-amine-based PbAEs are shown to be promising in the construction of intracellular targeting drug delivery systems.
21. 21

    Jon, S.; Anderson, D. G.; Langer, R. Degradable Poly(amino alcohol esters) As Potential DNA Vectors with Low Cytotoxicity. Biomacromolecules 2003, 4, 1759– 1762,  DOI: 10.1021/bm034176f

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    Degradable poly(amino alc. esters) as potential DNA vectors with low cytotoxicity

    Jon, Sangyong; Anderson, Daniel G.; Langer, Robert

    Biomacromolecules (2003), 4 (6), 1759-1762CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    The synthesis of a new degradable polymer system, poly(amino alc. esters) and the resulting polymers' potential for use in gene transfection vectors are reported. The polymn. proceeded in a one step reaction from com. available bis(secondary amines) monomers (N,N'-dimethyl-1,3-propanediamine and N,N'-dimethyl-1,6-hexanediamine, resp.) through nucleophilic addn. to the diglycidyl ester of dicarboxylic acid (diglycidyl adipate). Poly(amino alc. ester) 1 and 2 were synthesized with a yield of 89% and 91% with Mn = 24 800 and Mn = 36 400, resp. Poly(amino alc. ester) 1 degraded hydrolytically in phosphate buffer at pH 7.4 with a half-life of approx. 5 days. Both polymers readily self-assembled with plasmid DNA into nanometer-sized DNA/polymer complexes less than 180 nm diam. and are significantly less cytotoxic than the commonly used DNA delivery polymer, poly(ethylene imine) (PEI).
22. 22

    Akinc, A.; Anderson, D. G.; Lynn, D. M.; Langer, R. Synthesis of Poly(β-amino ester)s Optimized for Highly Effective Gene Delivery. Bioconjugate Chem. 2003, 14, 979– 988,  DOI: 10.1021/bc034067y

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    22

    Synthesis of poly(β-amino ester)s optimized for highly effective gene delivery

    Akinc, Akin; Anderson, Daniel G.; Lynn, David M.; Langer, Robert

    Bioconjugate Chemistry (2003), 14 (5), 979-988CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    Several families of synthetic polymers, including degradable poly(β-amino ester)s, have been previously shown to effectively mediate gene transfer. However, the combined impact of potentially significant factors-such as polymer mol. wt., polymer chain end-group, and polymer/DNA ratio-on different gene transfer properties has yet to be systematically investigated. The elucidation of these relationships may aid in the design of nonviral vectors with greatly enhanced transfection properties. To examine these factors, two distinct poly(β-amino ester) structures, Poly-1 and Poly-2, were generated by adding 1,4-butanediol diacrylate and 1,6-hexanediol diacrylate, resp., to 1-aminobutanol. Twelve unique versions of each structure were synthesized by varying amine/diacrylate stoichiometric ratios, resulting in polymers with either amine or acrylate end-groups and with mol. wts. ranging from 3350 to 18 000. Using high throughput methods, all polymers were tested in quadruplicate at nine different polymer/DNA ratios ranging from 10:1 wt./wt. to 150:1 wt./wt. Through the optimization of mol. wt., polymer chain end-group, and polymer/DNA ratio, these polymers successfully mediated gene transfer at levels that surpassed both PEI and Lipofectamine 2000 in vitro.
23. 23

    Lynn, D. M.; Langer, R. Degradable Poly(β-amino esters): Synthesis, Characterization, and Self-Assembly with Plasmid DNA. J. Am. Chem. Soc. 2000, 122, 10761– 10768,  DOI: 10.1021/ja0015388

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    23

    Degradable Poly(β-amino esters): Synthesis, Characterization, and Self-Assembly with Plasmid DNA

    Lynn, David M.; Langer, Robert

    Journal of the American Chemical Society (2000), 122 (44), 10761-10768CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Poly(β-amino esters) 1-3 were synthesized via the addn. of N,N'-dimethylethylenediamine, piperazine, and 4,4'-trimethylenedipiperidine to 1,4-butanediol diacrylate. Polymn. proceeded exclusively via the conjugate addn. of the secondary amines to the bis(acrylate ester). Polymers were isolated in up to 86% yields with mol. wts. ranging up to 31 200 relative to polystyrene stds. The polymers degraded hydrolytically in acidic and alk. media to yield 1,4-butanediol and β-amino acids 4a-6a and the degrdn. kinetics were investigated at pH 5.1 and 7.4. In general, the polymers degraded more rapidly at pH 7.4 than at pH 5.1. In initial screening assays, both the polymers and their degrdn. products were detd. to be noncytotoxic relative to poly(ethylene imine), a polymer conventionally employed as a synthetic transfection vector. Polymers 1-3 interacted electrostatically with polyanionic plasmid DNA in water and buffer at physiol. pH, as detd. by agarose gel electrophoresis, quasi-elastic dynamic light scattering (QELS), and ζ-potential measurements. All three polymers condensed DNA into sol. DNA/polymer particles on the order of 50-200 nm. Particles formed from polymers 1 and 2 aggregated extensively, while particles formed from polymer 3 exhibited pos. ζ-potentials (e.g., +10 to +15 mV) and did not aggregate for up to 18 h. The nanometer-sized dimensions and reduced cytotoxicities of these DNA/polymer complexes suggest that these types of polymers may be useful as degradable polymeric gene transfer vectors.
24. 24

    Min, K. H.; Kim, J.-H.; Bae, S. M.; Shin, H.; Kim, M. S.; Park, S.; Lee, H.; Park, R.-W.; Kim, I.-S.; Kim, K.; Kwon, I. C.; Jeong, S. Y.; Lee, D. S. Tumoral acidic pH-responsive MPEG-poly(β-amino ester) polymeric micelles for cancer targeting therapy. J. Controlled Release 2010, 144, 259– 266,  DOI: 10.1016/j.jconrel.2010.02.024

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    24

    Tumoral acidic pH-responsive MPEG-poly(β-amino ester) polymeric micelles for cancer targeting therapy

    Min, Kyung-Hyun; Kim, Jong-Ho; Bae, Sang-Mun; Shin, Hye-Ri; Kim, Min-Sang; Park, Sang-Jin; Lee, Hye-Jung; Park, Rang-Woon; Kim, In-San; Kim, Kwang-Meyung; Kwon, Ick-Chan; Jeong, Seo-Young; Lee, Doo-Sung

    Journal of Controlled Release (2010), 144 (2), 259-266CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

    Herein, we evaluated the tumoral low pH targeting characteristics of pH-responsive polymer micelles in cancer targeting therapy. To design the pH-responsive polymeric micelles, hydrophilic Me ether poly(ethylene glycol) (MPEG) and pH-responsive/biodegradable poly(β-amino ester) (PAE) were copolymd. using a Michael-type step polymn., resulting in an MEPG-PAE block copolymer. The amphiphilic MPEG-PAE block copolymer formed polymeric micelles with nano-sized diam. by self-assembly, which showed a sharp pH-dependant micellization/demicellization transition at the tumoral acidic pH value (pH 6.4). For the cancer image and therapy, fluorescence dye, tetramethylrhodamine isothiocyanate (TRITC), or anticancer drug, camptothecin (CPT), was efficiently encapsulated into the pH-responsive polymeric micelles (pH-PMs) by a simple solvent casting method. The TRITC or CPT encapsulated pH-PMs (TRITC-pH-PMs or CPT-pH-PMs) showed rapid release of TRITC or CPT in weakly acidic aq. (pH 6.4) because they still presented a sharp tumoral acid pH-responsive micellization/demicellization transition. The pH-PMs with 10 wt.% of TRITC could deliver substantially more fluorescence dyes to the target tumor tissue in MDA-MB231 human breast tumor-bearing mice, compared to the control polymeric micelles of PEG-poly(l-lactic acid) (PEG-PLLA). Importantly, CPT-pH-PMs exhibited significantly increased therapeutic efficacy with min. side effects by other tissues in breast tumor-bearing mice, compared to free CPT and CPT encapsulated PEG-PLLA micelles. The tumoral acidic pH-responsive polymeric micelles are highly useful for cancer targeting therapy.
25. 25

    Ko, J.; Park, K.; Kim, Y.-S.; Kim, M. S.; Han, J. K.; Kim, K.; Park, R.-W.; Kim, I.-S.; Song, H. K.; Lee, D. S.; Kwon, I. C. Tumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapy. J. Controlled Release 2007, 123, 109– 115,  DOI: 10.1016/j.jconrel.2007.07.012

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    25

    Tumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapy

    Ko, Jinyoung; Park, Kyeongsoon; Kim, Yoo-Shin; Kim, Min Sang; Han, Jong Kwon; Kim, Kwangmeyung; Park, Rang-Woon; Kim, In-San; Song, Hyun Kyu; Lee, Doo Sung; Kwon, Ick Chan

    Journal of Controlled Release (2007), 123 (2), 109-115CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

    The main objective of this study was to develop and characterize a pH-responsive and biodegradable polymeric micelle as a tumor-targeting drug delivery system. The pH-responsive block copolymer was synthesized by a Michael-type step polymn. of hydrophilic Me ether poly(ethylene glycol) (MPEG) and pH-responsive and biodegradable poly(β-amino ester), resulting in an amphiphilic MPEG-poly(β-amino ester) block copolymer. This copolymer, which formed nano-sized self-assembled micelles under aq. conditions, could be efficiently (74.5%) loaded with doxorubicin (DOX) using a solvent evapn. method. In an in vitro drug release study, these DOX-loaded polymeric micelles showed noticeable pH-dependent micellization-demicellization behavior, with rapid release of DOX from the micelles in weakly acidic environments (pH 6.4) but very slow release under physiol. conditions (pH 7.4). Moreover, due to demicellization, the tumor cell uptake of DOX released from polymeric micelles was much higher at pH 6.4 than at pH 7.4. When in vivo antitumor activity of pH-responsive polymeric micelles was evaluated by injecting the DOX-loaded polymeric micelles into B16F10 tumor-bearing mice, these micelles notably suppressed tumor growth and also prolonged survival of the tumor-bearing mice, compared with mice treated with free DOX.
26. 26

    Zhang, C. Y.; Yang, Y. Q.; Huang, T. X.; Zhao, B.; Guo, X. D.; Wang, J. F.; Zhang, L. J. Self-assembled pH-responsive MPEG-b-(PLA-co-PAE) block copolymer micelles for anticancer drug delivery. Biomaterials 2012, 33, 6273– 6283,  DOI: 10.1016/j.biomaterials.2012.05.025

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    26

    Self-assembled pH-responsive MPEG-b-(PLA-co-PAE) block copolymer micelles for anticancer drug delivery

    Zhang, Can Yang; Yang, You Qiang; Huang, Tu Xiong; Zhao, Bin; Guo, Xin Dong; Wang, Ju Fang; Zhang, Li Juan

    Biomaterials (2012), 33 (26), 6273-6283CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

    A series of amphiphilic pH-responsive poly (ethylene glycol) Me ether-b-(poly lactic acid-co-poly (β-amino esters)) (MPEG-b-(PLA-co-PAE)) block copolymers with different PLA/PAE ratios were designed and synthesized via a Michael-type step polymn. The mol. structures of the copolymers were confirmed with 1H NMR and gel permeation chromatog. (GPC). These amphiphilic copolymers were shown to self-assemble into core/shell micelles in aq. soln. at low concns., and their crit. micelle concns. (CMC) in water were 1.2-9.5 mg/L. The pH-responsive PAE segment was insol. at pH 7.4, but it became pos. charged and sol. via protonation of amino groups at pH lower than 6.5. The av. particle size and zeta potential of micelles increased from 180 nm and 15 mV to 220 nm and 40 mV, resp., when the pH decreased from 7.4 to 5.0. Doxorubicin (DOX) was loaded into the core of these micelles with a high drug loading of 18%. The in vitro DOX release from the micelles was significantly accelerated when soln. pH decreased from 7.4 to 5.0. DOX release in the first 10 h appeared to follow Fickian diffusion mechanism. Toxicity test showed that the copolymers had low toxicity whereas the DOX-loaded micelles remained high cytotoxicity for HepG2 cells. The results indicate the pH-sensitive MPEG-b-(PLA-co-PAE) micelle may be a potential hydrophobic drug delivery carrier for cancer targeting therapy with sustained release.
27. 27

    Potineni, A.; Lynn, D. M.; Langer, R.; Amiji, M. M. Poly(ethylene oxide)-modified poly(β-amino ester) nanoparticles as a pH-sensitive biodegradable system for paclitaxel delivery. J. Controlled Release 2003, 86, 223– 234,  DOI: 10.1016/S0168-3659(02)00374-7

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    27

    Poly(ethylene oxide)-modified poly(β-amino ester) nanoparticles as a pH-sensitive biodegradable system for paclitaxel delivery

    Potineni, Anupama; Lynn, David M.; Langer, Robert; Amiji, Mansoor M.

    Journal of Controlled Release (2003), 86 (2-3), 223-234CODEN: JCREEC; ISSN:0168-3659. (Elsevier Science Ltd.)

    The main objective of this study was to develop and characterize a pH-sensitive biodegradable polymeric nanoparticulate system for tumor-selective paclitaxel delivery. A representative hydrophobic poly(β-amino ester) (poly-1) was synthesized by conjugate addn. of 4,4'-trimethyldipiperidine with 1,4-butanediol diacrylate. Poly-1 (Mn 10,000 daltons) nanoparticles were prepd. by the controlled solvent displacement method in an ethanol-water system in the presence of Pluronic F-108, a poly(ethylene oxide) (PEO)-contg. non-ionic surfactant. Control and PEO-modified nanoparticles were characterized by Coulter counter, SEM, zeta potential measurements, and electron spectroscopy for chem. anal. (ESCA). Polymer degrdn. studies were performed in phosphate-buffered saline (PBS, pH 7.4) at 37°. Paclitaxel loading capacities and efficiencies were detd. and release studies were performed in Tween-80 (0.1%, w/v)-contg. PBS at 37°. Control and PEO-modified nanoparticles, labeled with rhodamine-123, were incubated with BT-20 cells to examine the uptake and cellular distribution as a function of time. PEO-modified nanoparticles with an av. size of 100-150 nm and a pos. surface charge of 37.0 mV were prepd. SEM anal. showed distinct smooth, spherical particles. The ether (-C-O-) peak of the C1s envelope in ESCA confirmed the surface presence of PEO chains. Polymer biodegrdn. studies showed that almost 85% of the starting material degraded after 6 days. The max. paclitaxel loading efficiency attained was 97% at 1.0% (wt./wt.) of the drug. Paclitaxel release studies showed that approx. 10% was released in the first 24 h, 80% after 3 days, and the entire content was released in approx. 5 days. After 1 h of incubation, a large fraction of the administered control and PEO-modified poly-1 nanoparticles was internalized in BT-20 cells. These results demonstrated that PEO-modified poly-1 nanoparticles could provide increased therapeutic effect by delivering the encapsulated drug to tumor cells.
28. 28

    Huynh, D. P.; Nguyen, M. K.; Pi, B. S.; Kim, M. S.; Chae, S. Y.; Lee, K. C.; Kim, B. S.; Kim, S. W.; Lee, D. S. Functionalized injectable hydrogels for controlled insulin delivery. Biomaterials 2008, 29, 2527– 2534,  DOI: 10.1016/j.biomaterials.2008.02.016

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    28

    Functionalized injectable hydrogels for controlled insulin delivery

    Huynh, Dai P.; Nguyen, Minh K.; Pi, Bong S.; Kim, Min S.; Chae, Su Y.; Lee, Kang C.; Kim, Bong S.; Kim, Sung W.; Lee, Doo S.

    Biomaterials (2008), 29 (16), 2527-2534CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

    The concept of this research is using poly(β-amino ester) (PAE) as a duo-functional group for synthesis of the novel sensitive injectable hydrogel for controlled drug/protein delivery. Firstly, PAE made of 1,4-butanediol diacrylate and 4,4'-trimethylene dipiperidine is used as a pH-sensitive moiety to conjugate to the temp.-sensitive biodegradable triblock copolymer of poly(ethylene glycol)-poly(.vepsiln.-caprolactone) (PCL-PEG-PCL) to manuf. pH/temp.-sensitive injectable hydrogel of pentablock copolymer PAE-PCL-PEG-PCL-PAE. Furthermore, the cationic nature of PAE is used as the second function to make the ionic complexes with anionic biomol. loaded into the hydrogel such as insulin. As a result, the release of drug/protein from this hydrogel device can be controlled by the degrdn. of copolymer. Sol-gel phase transition behavior of PAE-PCL-PEG-PCL-PAE block copolymer was studied; the aq. media of the pentablock copolymer changed from a sol to a gel phase with increasing temp. and pH. The effect of anionic biomol. such as insulin on sol-gel phase transition, degrdn. of the complex gel of the material with insulin was studied in vitro. Then the schematic of the ionic complexes between pos. charges in PAE and the neg. charges in protein was simulated. In addn., the mechanism of controlled release behavior of insulin from the complex gel was supposed, which includes the chem.-controlled and diffusion-controlled stages. To prove the simulations, the cumulative release of the protein from the complex gel was studied in vitro with different methods. Furthermore, the pharmacokinetic release of insulin from the complex gel in vivo on male Sprague-Dawley (SD) rats was compared with that from triblock copolymer hydrogel of PCL-PEG-PCL.
29. 29

    Bingol, B.; Altuncu, S.; Duman, F. D.; Ak, A.; Gulyuz, U.; Acar, H. Y.; Okay, O.; Avci, D. One-Step Injectable and Bioreducible Poly(β-Amino Ester) Hydrogels as Controlled Drug Delivery Platforms. ACS Appl. Polym. Mater. 2019, 1, 1724– 1734,  DOI: 10.1021/acsapm.9b00287

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    29

    One-Step Injectable and Bioreducible Poly(β-Amino Ester) Hydrogels as Controlled Drug Delivery Platforms

    Bingol, Betul; Altuncu, Seckin; Duman, Fatma Demir; Ak, Ayse; Gulyuz, Umit; Acar, Havva Yagci; Okay, Oguz; Avci, Duygu

    ACS Applied Polymer Materials (2019), 1 (7), 1724-1734CODEN: AAPMCD; ISSN:2637-6105. (American Chemical Society)

    A one-step synthesis strategy based on aza-Michael reaction of poly(ethylene glycol) diacrylate (PEGDA) or PEGDA/1,6-hexanediol diacrylate (HDDA) mixt. and cystamine was employed to fabricate injectable, biocompatible, and degradable novel poly(β-amino ester) (PBAE) hydrogels. The gelation was monitored by real-time dynamic rheol. measurements to follow the formation of PBAE hydrogel networks. The obtained hydrogels were responsive to both pH and redox state, which enabled the control of swelling, degrdn., and release properties by external triggers. Degrdn. products of the hydrogels were shown to have no significant cytotoxicity on A549 adenocarcinomic human alveolar basal epithelial cells and MCF-7 human breast cancer cells. The hydrogels were loaded with a photosensitizer, methylene blue (MB), as a model compd. by simple addn. of the MB mols. into the precursor mixt. The activity of released MB was assessed by in vitro photodynamic therapy (PDT) studies conducted with A549 cells.
30. 30

    Lu, X.-J.; Yang, X.-Y.; Meng, Y.; Li, S.-Z. Temperature and pH dually-responsive poly(β-amino ester) nanoparticles for drug delivery. Chin. J. Polym. Sci. 2017, 35, 534– 546,  DOI: 10.1007/s10118-017-1916-7

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    30

    Temperature and pH dually-responsive poly(β-amino ester) nanoparticles for drug delivery

    Lu, Xiao-ju; Yang, Xiang-yu; Meng, Yuan; Li, Shao-zhen

    Chinese Journal of Polymer Science (2017), 35 (4), 534-546CODEN: CJPSEG; ISSN:0256-7679. (Springer)

    Stimuli-responsive polymers have undoubtedly been of great interest in the past decades due to a variety of their potential applications in biomedical territory. However, their non-degradability limits their in vivo applications. Herein, we report a novel pH and temp. dual-stimuli responsive-poly(β-amino ester). The pH/temp. sensitivities are interrelated and can be easily tuned by changing PEG-diacrylate chain length and the percentage of biamines in the feed ratio. These dual-responsive polymers are very useful in drug delivery. Reaction of Me ether poly(ethylene glycol) (MPEG) and poly(β-amino ester) resulted in an amphiphilic MPEG-PBAE block copolymer which could form nanoparticles by self-assembly. A hydrophobic drug (DOX) was loaded in the self-assembled nanoparticles at low temp. without using org. solvents. The loaded drug was released very slowly and steadily at 37 °C under physiol. conditions (pH 7.4), but rapidly released from the micelles in weakly acidic environments (pH 6.4 and 5.0) for intracellular drug release. Thus, these poly(β-amino ester) polymers constitute ideal drug carriers since their thermal sensitivity allows the drug loadings without using org. solvent and their pH sensitivity permits fast intracellular drug release.
31. 31

    Zhou, M.; Zhang, X.; Xie, J.; Qi, R.; Lu, H.; Leporatti, S.; Chen, J.; Hu, Y. pH-Sensitive Poly(β-amino ester)s Nanocarriers Facilitate the Inhibition of Drug Resistance in Breast Cancer Cells. Nanomaterials 2018, 8, 952,  DOI: 10.3390/nano8110952

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    pH-sensitive poly(β-amino ester)s nanocarriers facilitate the inhibition of drug resistance in breast cancer cells

    Zhou, Mengxue; Zhang, Xingcai; Xie, Jin; Qi, Rongxiang; Lu, Huiru; Leporatti, Stefano; Chen, Jun; Hu, Yi

    Nanomaterials (2018), 8 (11), 952/1-952/16CODEN: NANOKO; ISSN:2079-4991. (MDPI AG)

    Multidrug resistance (MDR) remains an unmet challenge in chemotherapy. Stimuli-responsive nanocarriers emerge as a promising tool to overcome MDR. Herein, pH-sensitive poly(β-amino ester)s polymers (PHP)-based micellar nanoparticles were synthesized for enhanced doxorubicin (DOX) delivery in drug resistant breast cancer MCF-7/ADR cells. DOX-loaded PHP micelles showed rapid cell-internalization and lysosomal escape in MCF-7/ADR cells. The cytotoxicity assays showed relatively higher cell inhibition of DOX-loaded PHP micelles than that of free DOX against MCF-7/ADR cells. Further mechanistic studies showed that PHP micelles were able to inhibit P-glycoprotein (P-gp) activity by lowering mitochondrial membrane potentials and ATP levels. These results suggested that the enhanced antitumor effect might be attributed to PHP-mediated lysosomal escape and drug efflux inhibition. Therefore, PHP would be a promising pH-responsive nanocarrier for enhanced intracellular drug delivery and overcoming MDR in cancer cells.
32. 32

    Zhang, R.; Wang, S.-B.; Wu, W.-G.; Kankala, R. K.; Chen, A.-Z.; Liu, Y.-G.; Fan, J.-Q. Co-delivery of doxorubicin and AS1411 aptamer by poly(ethylene glycol)-poly(β-amino esters) polymeric micelles for targeted cancer therapy. J. Nanopart. Res. 2017, 19, 224,  DOI: 10.1007/s11051-017-3913-8

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    Chen, J.; Qiu, X.; Ouyang, J.; Kong, J.; Zhong, W.; Xing, M. M. Q. pH and Reduction Dual-Sensitive Copolymeric Micelles for Intracellular Doxorubicin Delivery. Biomacromolecules 2011, 12, 3601– 3611,  DOI: 10.1021/bm200804j

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    pH and Reduction Dual-Sensitive Copolymeric Micelles for Intracellular Doxorubicin Delivery

    Chen, Jun; Qiu, Xiaozhong; Ouyang, Jun; Kong, Jiming; Zhong, Wen; Xing, Malcolm M. Q.

    Biomacromolecules (2011), 12 (10), 3601-3611CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    This study develops novel pH and redn. dual-sensitive micelles for the anticancer drug doxorubicin (DOX) delivery owing to the fact that the tumor tissues show low pH and high redn. environment. These sub-100 nm micelles present a core-shell structure under physiol. conditions, but quickly release the loaded drugs responding to acidic and reductive stimuli. With disulfide bonds in each repeat unit of poly(β-amino ester)s, the novel copolymer was synthesized via Michael addn. polymn. from 2,2'-dithiodiethanol diacrylate, 4,4'-trimethylene dipiperidine, and methoxy-PEG-NH2. DOX released faster from micelles in a weakly acidic environment (pH 6.5) than at pH 7.4 or in the presence of a higher concn. (5 mM) of reducing agent (DTT). The release is even more effective in a scenario of both stimuli (pH 6.5 and 5 mM DTT). MTT assay showed that the DOX-loaded micelles had a higher cytotoxicity for HepG2 tumor cells than DOX at higher concns., and that blank micelles had a very low cytotoxicity to the tumor cells. Confocal microscopy observation showed that the micelles can be quickly internalized, effectively deliver the drugs into nuclei, and inhibit cell growth. These results present the copolymer as a novel and effective pH and redn. dual-responsive nanocarrier to enhance drug efficacy for cancer cells.
34. 34

    Shenoy, D.; Little, S.; Langer, R.; Amiji, M. Poly(Ethylene Oxide)-Modified Poly(β-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part 2. In Vivo Distribution and Tumor Localization Studies. Pharm. Res. 2005, 22, 2107– 2114,  DOI: 10.1007/s11095-005-8343-0

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    Poly(Ethylene Oxide)-Modified Poly(β-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part 2. In Vivo Distribution and Tumor Localization Studies

    Shenoy, Dinesh; Little, Steven; Langer, Robert; Amiji, Mansoor

    Pharmaceutical Research (2005), 22 (12), 2107-2114CODEN: PHREEB; ISSN:0724-8741. (Springer)

    This study was carried out to det. the biodistribution profiles and tumor localization potential of poly(ethylene oxide) (PEO)-modified poly(β-amino ester) (PbAE) as a novel, pH-sensitive biodegradable polymeric nanoparticulate system for tumor-targeted drug delivery. The biodistribution studies of PEO-modified PbAE and PEO-modified poly(ε-caprolactone) (PCL), a non-pH-sensitive polymer, nanoparticle systems were carried out in normal mice using 111indium-oxine [111In] as a lipophilic radiolabel encapsulated within the polymeric matrix, and the distribution of the nanoparticles was studied in plasma and all the vital organs following i.v. administration. Solid tumors were developed on nude mice using human ovarian carcinoma xenograft (SKOV-3) and the change in concns. of tritium [3H]-labeled paclitaxel encapsulated in polymeric nanoparticles was examd. in blood, tumor mass, and liver. Study in normal mice with a gamma-emitting isotope [111In] provided a thorough biodistribution anal. of the PEO-modified nanoparticulate carrier systems, whereas 3H-paclitaxel was useful to understand the change in concn. and tumor localization of anticancer compd. directly in major sites of distribution. Both PEO-PbAE and PEO-PCL nanoparticles showed long systemic circulating properties by virtue of surface modification with PEO-contg. triblock block copolymer (Pluronic) stabilizer. Although the PCL nanoparticles showed higher uptake by the reticuloendothelial system, the PbAE nanoparticles effectively delivered the encapsulated payload into the tumor mass. PEO-modified PbAE nanoparticles showed considerable passive tumor targeting potential in early stages of biodistribution via the enhanced permeation and retention (EPR) mechanism. This prompts a detailed biodistribution profiling of the nanocarrier for prolonged periods to provide conclusive evidence for superiority of the delivery system.
35. 35

    Shenoy, D.; Little, S.; Langer, R.; Amiji, M. Poly(ethylene oxide)-Modified Poly(β-amino ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs. 1. In Vitro Evaluations. Mol. Pharmaceutics 2005, 2, 357– 366,  DOI: 10.1021/mp0500420

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    Poly(ethylene oxide)-Modified Poly(β-amino ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs. 1. In Vitro Evaluations

    Shenoy, Dinesh; Little, Steven; Langer, Robert; Amiji, Mansoor

    Molecular Pharmaceutics (2005), 2 (5), 357-366CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)

    A representative poly(β-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate a nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissoln. when the pH of the medium is less than 6.5 and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepd. by solvent displacement method and characterized for particle size, charge, and surface morphol. Pluronic F-108, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), was blended with PbAE to induce surface modification of the nanoparticles. In vitro cellular uptake of tritiated [3H]-paclitaxel in soln. form and as a nanoparticulate formulation was studied in MDA-MB-231 human breast adenocarcinoma cells grown in 12-well plates. We also examd. the intracellular degrdn. pattern of the formulations within the cells by estg. the drug release profile. Cytotoxicity assay was performed on the formulations at different doses and time intervals. Nanoparticles prepd. from poly(ε-caprolactone) (PCL) that do not display pH-sensitive release behavior were used as control. Spherical nanoparticles having pos. ζ potential (∼40 mV) were obtained in the size range of 150-200 nm with PbAE. The PEO chains of the Pluronic were well-anchored within the nanomatrix as detd. by electron spectroscopy for chem. anal. (ESCA). The intracellular accumulation of paclitaxel within tumor cells was significantly higher when administered in the nanoparticle formulations as compared to aq. soln. Qual. fluorescent microscopy confirmed the rapid release of the payload into the cytosol in the case of PbAE nanoparticles, while the integrity of the PCL nanoparticles remained intact. The cytotoxicity assay results showed significantly higher tumoricidal activity of paclitaxel when administered in the nanoparticle formulations. The cell-kill effect was maximal for paclitaxel-loaded PbAE nanoparticles when normalized with respect to intracellular drug concns. Thus, PEO-modified PbAE nanoparticles show tremendous potential as novel carriers of cytotoxic agents for achieving improved drug disposition and enhanced efficacy.
36. 36

    Tang, S.; Yin, Q.; Zhang, Z.; Gu, W.; Chen, L.; Yu, H.; Huang, Y.; Chen, X.; Xu, M.; Li, Y. Co-delivery of doxorubicin and RNA using pH-sensitive poly (β-amino ester) nanoparticles for reversal of multidrug resistance of breast cancer. Biomaterials 2014, 35, 6047– 6059,  DOI: 10.1016/j.biomaterials.2014.04.025

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    Co-delivery of doxorubicin and RNA using pH-sensitive poly (β-amino ester) nanoparticles for reversal of multidrug resistance of breast cancer

    Tang, Shan; Yin, Qi; Zhang, Zhiwen; Gu, Wangwen; Chen, Lingli; Yu, Haijun; Huang, Yongzhuo; Chen, Xianzhi; Xu, Minghua; Li, Yaping

    Biomaterials (2014), 35 (23), 6047-6059CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)

    An appropriate co-delivery system for chemotherapeutic agents and nucleic acid drugs will provide a more efficacious approach for the treatment of breast cancer by reversing multidrug resistance (MDR). In this work, a new amphiphilic poly (β-amino ester), poly[(1,4-butanediol)-diacrylate-β-5-polyethylenimine]-block-poly[(1,4-butanediol)-diacrylate-β-5-hydroxy amylamine] (PDP-PDHA) was synthesized, and the doxorubicin (DOX) and survivin-targeting shRNA (shSur) co-loading nanoparticle (PDNs) were prepd. The pH-sensitive poly[(1,4-butanediol) diacrylate-β-5-hydroxy amylamine] (PDHA) endowed PDNs both pH-triggered drug release characteristics and enhanced endo/lysosomal escape ability, thus improving the cytotoxicity of DOX and the transfection efficiency. PDNs also increased the DOX accumulation, down-regulated 57.7% survivin expression, induced 80.8% cell apoptosis and changed the cell cycle in MCF-7/ADR cells. In the MCF-7/ADR tumor-bearing mice models, after administered i.v., PDNs raised the accumulation of DOX and shSur in the tumor tissue by 10.4 and 20.2 folds, resp., resulting in obvious inhibition of the tumor growth with tumor inhibiting rate of 95.9%. The combination of DOX and RNA interference showed synergistic effect on overcoming MDR. Therefore, PDNs could be a promising co-delivery vector for effective therapy of drug resistant breast cancer.
37. 37

    Zhao, S.; Tan, S.; Guo, Y.; Huang, J.; Chu, M.; Liu, H.; Zhang, Z. pH-Sensitive Docetaxel-Loaded d-α-Tocopheryl Polyethylene Glycol Succinate–Poly(β-amino ester) Copolymer Nanoparticles for Overcoming Multidrug Resistance. Biomacromolecules 2013, 14, 2636– 2646,  DOI: 10.1021/bm4005113

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    pH-Sensitive Docetaxel-Loaded d-α-Tocopheryl Polyethylene Glycol Succinate-Poly(β-amino ester) Copolymer Nanoparticles for Overcoming Multidrug Resistance

    Zhao, Shuang; Tan, Songwei; Guo, Yuanyuan; Huang, Jing; Chu, Min; Liu, Hudan; Zhang, Zhiping

    Biomacromolecules (2013), 14 (8), 2636-2646CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    Multidrug resistance (MDR) is one of the major obstacles to successful chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is an important factor responsible for MDR. Herein, a novel copolymer, d-α-tocopheryl polyethylene glycol 1000-block-poly(β-amino ester) (TPGS-b-PBAE, TP), was synthesized for overcoming multidrug resistance by the synergistic effect of the pH-sensitive behavior of PBAE and P-gp inhibiting activity of TPGS. Docetaxel (DTX) was chosen as the model drug. The resulting DTX-loaded nanoparticles were stable at pH 7.4, while they dissocd. in a weakly acidic environment (pH 5.5) and released the incorporated DTX quickly. The DTX-loaded TP nanoparticles increased the cell cytotoxicity against both drug-sensitive human ovarian A2780 and drug-resistant A2780/T cells. The IC50 of DTX-loaded TP against A2780/T cells was 100-fold lower than that of com. DTX. This was assocd. with enhanced DTX-induced apoptosis and cell arrest in the G2/M phase. Furthermore, P-gp inhibition assays, including enhancement of the fluorescence intensity of rhodamine 123 and redn. of the intracellular ATP levels, confirmed the P-gp inhibition nature of the TP copolymer. The use of the TP copolymer is a new approach to improve the therapeutic effect of anticancer drugs in MDR tumors.
38. 38

    Li, H.; Qian, Z. M. Transferrin/transferrin receptor-mediated drug delivery. Med. Res. Rev. 2002, 22, 225– 250,  DOI: 10.1002/med.10008

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    Transferrin/transferrin receptor-mediated drug delivery

    Li, Hongyan; Qian, Zhong Ming

    Medicinal Research Reviews (2002), 22 (3), 225-250CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)

    A review. Since transferrin was discovered more than half a century ago, a considerable effort has been made towards understanding transferrin-mediated iron uptake. However, it was not until recently with the identification and characterization of several new genes related to iron homeostasis, such as the hemochromatosis protein HFE and the iron transporter DMT1, that our knowledge has been advanced dramatically. A major pathway for cellular iron uptake is through internalization of the complex of iron-bound transferrin and the transferrin receptor, which is neg. modulated by HFE, a protein related to hereditary hemochromatosis. Iron is released from transferrin as the result of the acidic pH in endosome and then is transported to the cytosol by DMT1. The iron is then utilized as a cofactor by heme and ribonucleotide reductase or stored in ferritin. Apart from iron, many other metal ions of therapeutic and diagnostic interests can also bind to transferrin at the iron sites and their transferrin complexes can be recognized by many cells. Therefore, transferrin has been thought as a "delivery system" for many beneficial and harmful metal ions into the cells. Transferrin has also be widely applied as a targeting ligand in the active targeting of anticancer agents, proteins, and genes to primary proliferating malignant cells that overexpress transferrin receptors. This is achieved by conjugation of transferrin with drugs, proteins, hybrid systems with macromols. and as liposomal-coated systems. Conjugates of anticancer drugs with transferrin can significantly improve the selectivity and toxicity and overcome drug resistance, thereby leading to a better treatment. The coupling of DNA to transferrin via a polycation such as polylysine or via cationic liposomes can target and transfer of the exogenous DNA particularly into proliferating cells through receptor-mediated endocytosis. These kinds of non-viral vectors are potential alternatives to viral vectors for gene therapy, if the transfection efficiency can be improved. Moreover, transferrin receptors have shown potentials in delivery of therapeutic drugs or genes into the brain across blood-brain barrier.
39. 39

    Sudimack, J.; Lee, R. J. Targeted drug delivery via the folate receptor. Adv. Drug Delivery Rev. 2000, 41, 147– 162,  DOI: 10.1016/S0169-409X(99)00062-9

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    Targeted drug delivery via the folate receptor

    Sudimack, J.; Lee, R. J.

    Advanced Drug Delivery Reviews (2000), 41 (2), 147-162CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)

    A review with 92 refs. The folate receptor is a highly selective tumor marker overexpressed in >90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-pos. tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including their fragments and derivs., have been evaluated for tumor imaging and immunotherapy clin. and have shown significant targeting efficacy in ovarian cancer patients. Folic acid, a high affinity ligand of the folate receptor, retains its receptor binding properties when derivatized via its γ-carboxyl. Folate conjugation, therefore, presents an alternative method of targeting the folate receptor. This second strategy has been successfully applied in vitro for the receptor-specific delivery of protein toxins, anti-T-cell receptor antibodies, interleukin-2, chemotherapy agents, γ-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. Low mol. wt. radiopharmaceuticals based on folate conjugates showed much more favorable pharmacokinetic properties than radiolabeled antibodies and greater tumor selectivity in folate receptor-pos. animal tumor models. The small size, convenient availability, simple conjugation chem., and presumed lack of immunogenicity of folic acid make it an ideal ligand for targeted delivery to tumors.
40. 40

    Stenzel, M. H. Glycopolymers for Drug Delivery: Opportunities and Challenges. Macromolecules 2022, 55, 4867– 4890,  DOI: 10.1021/acs.macromol.2c00557

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    Glycopolymers for Drug Delivery: Opportunities and Challenges

    Stenzel, Martina H.

    Macromolecules (Washington, DC, United States) (2022), 55 (12), 4867-4890CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)

    A review. Glycopolymers are synthetic polymers with pendant sugars, which hold promise for a range of biomedical applications ranging from tissue engineering to sensing. The known specific interaction of glycopolymers with lectins has inspired researchers to use these polymers to deliver drugs to cells that overexpress lectin receptors. As a result, many glycopolymers-based on mannose, galactose, fructose, or other saccharides-have been used for the targeted delivery of drugs, ranging from traditional anticancer drugs to nucleic acid-derived therapeutics. For drug delivery purposes, glycopolymers are typically processed into nanoparticles that form a matrix to entrap the drug safely, such as micelles, polyplexes, polyion complex micelles, or other nanosized carriers. In vitro and in vivo studies have shown that drugs can indeed be delivered selectively to specific cells by leveraging the selective recognition of surface bound lectins. The key to the interaction between glycopolymers and lectins is the presence of strong intermol. forces such as hydrogen bonding. The formation of strong hydrogen bonds can, however, also be one of the drawbacks of these materials. Glycopolymers tend to self-aggregate, they interact with drugs in unexpected ways, or they bind proteins in a nonspecific manner. Despite these challenges, nanoparticles based on glycopolymers might offer possibilities that cannot be replicated by other water-sol. polymers. They have already shown that they can effectively deliver drugs in vivo, though more preclin. studies are necessary to enable their broader clin. uptake. Further focus could be directed at an improved understanding of the interface between glycopolymers and the biol. surrounding as a key to improve the targeting ability of these nanoparticles in vivo. In this Perspective, I will discuss the aspects to consider when prepg. drug delivery carrier using glycopolymers. This will include the interaction of the glyconanoparticles with the drug and the resulting property changes, the types of glycopolymers suitable for drug delivery, the effect of the nanoparticle structure on the affinity to cell surface bound lectins or GLUT transporters and the promising in vivo results that show selective delivery.
41. 41

    Granchi, C.; Fortunato, S.; Minutolo, F. Anticancer agents interacting with membrane glucose transporters. MedChemComm 2016, 7, 1716– 1729,  DOI: 10.1039/C6MD00287K

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    Anticancer agents interacting with membrane glucose transporters

    Granchi, C.; Fortunato, S.; Minutolo, F.

    MedChemComm (2016), 7 (9), 1716-1729CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)

    The altered metab. obsd. in cancer cells generally consists of increased glucose uptake and glycolytic activity. This is assocd. with an overexpression of glucose transporter proteins (GLUTs), which facilitate glucose uptake across the plasma membrane and play a crucial role in the survival of cancer cells. Therefore, GLUTs are considered as suitable targets for treatment of cancer. Herein we review some of the most relevant GLUT inhibitors that have been recently developed as prospective anticancer agents.
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    Lin, J.; Ma, L.; Zhang, D.; Gao, J.; Jin, Y.; Han, Z.; Lin, D. Tumour biomarkers─Tracing the molecular function and clinical implication. Cell Proliferation 2019, 52, e12589  DOI: 10.1111/cpr.12589

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    Large, D. E.; Soucy, J. R.; Hebert, J.; Auguste, D. T. Advances in Receptor-Mediated, Tumor-Targeted Drug Delivery. Adv. Ther. 2019, 2, 1800091  DOI: 10.1002/adtp.201800091

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    Macheda, M. L.; Rogers, S.; Best, J. D. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell. Physiol. 2005, 202, 654– 662,  DOI: 10.1002/jcp.20166

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    Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

    Macheda Maria L; Rogers Suzanne; Best James D

    Journal of cellular physiology (2005), 202 (3), 654-62 ISSN:0021-9541.

    Malignant cells are known to have accelerated metabolism, high glucose requirements, and increased glucose uptake. Transport of glucose across the plasma membrane of mammalian cells is the first rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter (GLUT) proteins. Increased glucose transport in malignant cells has been associated with increased and deregulated expression of glucose transporter proteins, with overexpression of GLUT1 and/or GLUT3 a characteristic feature. Oncogenic transformation of cultured mammalian cells causes a rapid increase of glucose transport and GLUT1 expression via interaction with GLUT1 promoter enhancer elements. In human studies, high levels of GLUT1 expression in tumors have been associated with poor survival. Studies indicate that glucose transport in breast cancer is not fully explained by GLUT1 or GLUT3 expression, suggesting involvement of another glucose transporter. Recently, a novel glucose transporter protein, GLUT12, has been found in breast and prostate cancers. In human breast and prostate tumors and cultured cells, GLUT12 is located intracellularly and at the cell surface. Trafficking of GLUT12 to the plasma membrane could therefore contribute to glucose uptake. Several factors have been implicated in the regulation of glucose transporter expression in breast cancer. Hypoxia can increase GLUT1 levels and glucose uptake. Estradiol and epidermal growth factor, both of which can play a role in breast cancer cell growth, increase glucose consumption. Estradiol and epidermal growth factor also increase GLUT12 protein levels in cultured breast cancer cells. Targeting GLUT12 could provide novel methods for detection and treatment of breast and prostate cancer.
45. 45

    Jeannot, V.; Mazzaferro, S.; Lavaud, J.; Vanwonterghem, L.; Henry, M.; Arboléas, M.; Vollaire, J.; Josserand, V.; Coll, J.-L.; Lecommandoux, S.; Schatz, C.; Hurbin, A. Targeting CD44 receptor-positive lung tumors using polysaccharide-based nanocarriers: Influence of nanoparticle size and administration route. Nanomed.: Nanotechnol., Biol. Med. 2016, 12, 921– 932,  DOI: 10.1016/j.nano.2015.11.018

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    Zhang, Y.; Chan, J. W.; Moretti, A.; Uhrich, K. E. Designing polymers with sugar-based advantages for bioactive delivery applications. J. Controlled Release 2015, 219, 355– 368,  DOI: 10.1016/j.jconrel.2015.09.053

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    Designing polymers with sugar-based advantages for bioactive delivery applications

    Zhang, Yingyue; Chan, Jennifer W.; Moretti, Alysha; Uhrich, Kathryn E.

    Journal of Controlled Release (2015), 219 (), 355-368CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

    Sugar-based polymers have been extensively explored as a means to increase drug delivery systems' biocompatibility and biodegrdn. Here, we review the use of sugar-based polymers for drug delivery applications, with a particular focus on the utility of the sugar component(s) to provide benefits for drug targeting and stimuli-responsive systems. Specifically, numerous synthetic methods have been developed to reliably modify naturally-occurring polysaccharides, conjugate sugar moieties to synthetic polymer scaffolds to generate glycopolymers, and utilize sugars as a multifunctional building block to develop sugar-linked polymers. The design of sugar-based polymer systems has tremendous implications on both the physiol. and biol. properties imparted by the saccharide units and are unique from synthetic polymers. These features include the ability of glycopolymers to preferentially target various cell types and tissues through receptor interactions, exhibit bioadhesion for prolonged residence time, and be rapidly recognized and internalized by cancer cells. Also discussed are the distinct stimuli-sensitive properties of saccharide-modified polymers to mediate drug release under desired conditions. Saccharide-based systems with inherent pH- and temp.-sensitive properties, as well as enzyme-cleavable polysaccharides for targeted bioactive delivery, are covered. Overall, this work emphasizes inherent benefits of sugar-contg. polymer systems for bioactive delivery.
47. 47

    Lin, Y.-S.; Tungpradit, R.; Sinchaikul, S.; An, F.-M.; Liu, D.-Z.; Phutrakul, S.; Chen, S.-T. Targeting the Delivery of Glycan-Based Paclitaxel Prodrugs to Cancer Cells via Glucose Transporters. J. Med. Chem. 2008, 51, 7428– 7441,  DOI: 10.1021/jm8006257

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    Targeting the Delivery of Glycan-Based Paclitaxel Prodrugs to Cancer Cells via Glucose Transporters

    Lin, Yih-Shyan; Tungpradit, Rudeewan; Sinchaikul, Supachok; An, Feng-Ming; Liu, Der-Zen; Phutrakul, Suree; Chen, Shui-Tein

    Journal of Medicinal Chemistry (2008), 51 (23), 7428-7441CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    This report describes the synthesis of four novel paclitaxel based prodrugs with glycan conjugation. Glycans were conjugated using an ester or ether bond as the linker between 2'-paclitaxel and the 2'-glucose or glucuronic acid moiety. These prodrugs showed good water soly. and selective cytotoxicity against cancer cell lines, but showed reduced toxicity toward normal cell lines and cancer cell lines with low expression levels of GLUTs. The ester conjugated prodrug showed the most cytotoxicity among the prodrugs examd. and could be transported into cells via GLUTs. Fluorescent and confocal microscopy demonstrated that targeted cells exhibited morphol. changes in tubulin and chromosomal alterations that were similar to those obsd. with paclitaxel treatment. Therefore, these glycan-based prodrugs may be good drug candidates for cancer therapy, and the glycan conjugation approach is an alternative method to enhance the targeted delivery of other drugs to cancer cells that overexpress GLUTs.
48. 48

    Vázquez-Dorbatt, V.; Tolstyka, Z. P.; Chang, C.-W.; Maynard, H. D. Synthesis of a Pyridyl Disulfide End-Functionalized Glycopolymer for Conjugation to Biomolecules and Patterning on Gold Surfaces. Biomacromolecules 2009, 10, 2207– 2212,  DOI: 10.1021/bm900395h

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    Synthesis of a Pyridyl Disulfide End-Functionalized Glycopolymer for Conjugation to Biomolecules and Patterning on Gold Surfaces

    Vazquez-Dorbatt, Vimary; Tolstyka, Zachary P.; Chang, Chien-Wen; Maynard, Heather D.

    Biomacromolecules (2009), 10 (8), 2207-2212CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    A pyridyl disulfide end-functionalized polymer with N-acetyl-D-glucosamine pendant side-chains was synthesized by atom transfer radical polymn. (ATRP). The glycopolymer was prepd. from a pyridyl disulfide initiator catalyzed by a Cu(I)/Cu(II)/2,2'-bipyridine system in a mixt. of methanol and water at 30°. The final polymer had a no.-av. mol. wt. (Mn) of 13.0 kDa detd. by 1H NMR spectroscopy and a narrow polydispersity index (1.12) detd. by gel permeation chromatog. (GPC). The pyridyl disulfide end-group was then utilized to conjugate the glycopolymer to a double-stranded short interfering RNA (siRNA). Characterization of the glycopolymer-siRNA by PAGE showed 97% conjugation. The activated disulfide polymer was also patterned on gold via microcontact printing. The pyridyl disulfide allowed for ready immobilization of the glycopolymer into 200 μm sized features on the surface.
49. 49

    Vázquez-Dorbatt, V.; Lee, J.; Lin, E.-W.; Maynard, H. D. Synthesis of Glycopolymers by Controlled Radical Polymerization Techniques and Their Applications. ChemBioChem 2012, 13, 2478– 2487,  DOI: 10.1002/cbic.201200480

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    Synthesis of Glycopolymers by Controlled Radical Polymerization Techniques and Their Applications

    Vazquez-Dorbatt, Vimary; Lee, Juneyoung; Lin, En-Wei; Maynard, Heather D.

    ChemBioChem (2012), 13 (17), 2478-2487CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A review. Natural saccharides are involved in numerous biol. processes. It has been shown that these carbohydrates play a role in cell adhesion and proliferation, as well as protein stabilization, organization, and recognition. Certain carbohydrates also serve as receptors for viruses and bacteria. They are over expressed in diseases such as cancer. Hence, a lot of effort has been focused on mimicking these sugars. Polymers with pendent saccharide groups, also known as glycopolymers, are studied as oligo- and polysaccharide mimics. Controlled radical polymn. (CRP) techniques such as atom transfer radical polymn. (ATRP), reversible addn.-fragmentation chain transfer (RAFT) polymn., and nitroxide-mediated polymn. (NMP), as well as cyanoxyl-mediated free radical polymn. have allowed chemists to synthesize well-defined glycopolymers that, in some cases, have particular end-group functionalities. This review focuses on the synthesis of glycopolymers by these methods and the applications of glycopolymers as natural saccharide mimics.
50. 50

    Jafari, F.; Yilmaz, G.; Becer, C. R. Stimuli-responsive glycopolymers and their biological applications. Eur. Polym. J. 2021, 142, 110147  DOI: 10.1016/j.eurpolymj.2020.110147

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    Stimuli-responsive glycopolymers and their biological applications

    Jafari, Farnaz; Yilmaz, Gokhan; Becer, C. Remzi

    European Polymer Journal (2021), 142 (), 110147CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)

    A review. Glycopolymers are synthetic polymers, contg. sugar groups on their pendant chains. They have been widely investigated for various biol. and biomedical applications due to excellent hydrophilicity, biodegradability, and biocompatibility. Glycopolymers can mimic the biol. functions of glycan in recognition processes through multivalent lectin interactions. Stimuli-responsive polymers such as thermo-responsive, pH-responsive, and light-responsive materials have also attracted much attention in biomedical applications. By incorporation of responsive chains in glycopolymers, they can be responsive to the changes in their surrounding medium. Moreover, this combination provides materials with selective binding to specific cells and the ability to enhance and control the lectin-polymer interactions effectively and selectively with changes in the surrounded environment. These smart glycopolymers have potential applications in the biomedical field and targeted drug delivery systems. Various investigations and research have been done to design novel polymeric systems with enhanced properties. This review mainly highlights the progress done in recent years on stimuli-responsive glycopolymers primarily focusing on mostly used (thermo, pH, and light) stimuli-responsive glycopolymers and their applications.
51. 51

    Dag, A.; Cakilkaya, E.; Omurtag Ozgen, P. S.; Atasoy, S.; Yigit Erdem, G.; Cetin, B.; Çavuş Kokuroǧlu, A.; Gürek, A. G. Phthalocyanine-Conjugated Glyconanoparticles for Chemo-photodynamic Combination Therapy. Biomacromolecules 2021, 22, 1555– 1567,  DOI: 10.1021/acs.biomac.0c01811

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    Phthalocyanine-Conjugated Glyconanoparticles for Chemo-photodynamic Combination Therapy

    Dag, Aydan; Cakilkaya, Eda; Omurtag Ozgen, Pinar Sinem; Atasoy, Sezen; Yigit Erdem, Gulsah; Cetin, Busra; Cavus Kokuroglu, Aytac; Gurek, Ayse Gul

    Biomacromolecules (2021), 22 (4), 1555-1567CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    Combination cancer therapy based on multifunctional nanomaterials has attracted great attention. The present work focuses on the prepn. of the glycopolymeric nanoparticle, which contains a photosensitizer (zinc(II)phthalocyanine, ZnPc) and an anticancer drug (Doxorubicin, Dox). First, a novel mono azide-functional ZnPc-N3 with seven hydrophilic ethylene oxide chains was synthesized. Next, ZnPc alone or together with Dox bearing glycopolymers was synthesized via the RAFT polymn. method and then self-assembled into glyconanoparticles (GNPs) with narrow particle size distribution. Then the evaluation of the biol. activity of GNPs (GNPs-ZnPc and GNPs-ZnPc/Dox) for dual photodynamic therapy (PDT) and chemotherapy against human breast cancer cells was investigated. The constructed GNPs were identified via general characterization methods, including dynamic light scattering (DLS) and transmission electron microscopy (TEM). The prepd. GNPs-ZnPc/Dox demonstrated remarkable photophys. and photochem. properties, involving good colloidal stability in biol. conditions, pH-responsive drug release, and the capacity to generate singlet oxygen under light irradn. The outer layer of nanoparticles covered by fructose sugar moieties achieves a targeted cancer therapy owing to GLUT5 (a well-known fructose transporter) overexpression toward breast cancer cells. In vitro expts. were then performed to evaluate the chemo/phototoxicity, cellular uptake, and anticancer efficacy of GNPs-ZnPc/Dox. In comparison with free Dox, human breast cancer cells treated with GNPs-ZnPc/Dox exhibited a higher cellular internalization via GLUT5 targeting. In particular, the GNPs-ZnPc/Dox nanoplatform revealed an excellent synergistic anticancer activity in comparison with free ZnPc-N3 and free Dox, representing a novel and promising chemo-photodynamic combination therapeutic methodol. to improve therapeutic efficacy.
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    Babiuch, K.; Dag, A.; Zhao, J.; Lu, H.; Stenzel, M. H. Carbohydrate-Specific Uptake of Fucosylated Polymeric Micelles by Different Cancer Cell Lines. Biomacromolecules 2015, 16, 1948– 1957,  DOI: 10.1021/acs.biomac.5b00299

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    Carbohydrate-Specific Uptake of Fucosylated Polymeric Micelles by Different Cancer Cell Lines

    Babiuch, Krzysztof; Dag, Aydan; Zhao, Jiacheng; Lu, Hongxu; Stenzel, Martina H.

    Biomacromolecules (2015), 16 (7), 1948-1957CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    Inspired by upregulated levels of fucosylated proteins on the surfaces of multiple types of cancer cells, micelles carrying β-L-fucose and β-D-glucose were prepd. A range of block copolymers were synthesized by reacting a mixt. of 2-azidoethyl β-L-fucopyranoside (FucEtN3) and 2-azideoethyl β-D-glucopyranoside (GlcEtN3) with poly(propargyl methacrylate)-block-poly(Bu acrylate) (PPMA-b-PBA) using copper-catalyzed azide-alkyne cycloaddn. (CuAAC). Five block copolymers were obtained ranging from 100 mol % fucose to 100% glucose functionalization. The resulting micelles had hydrodynamic diams. of around 30 nm. In this work, we show that fucosylated micelles reveal an increased uptake by pancreatic, lung, and ovarian carcinoma cell lines, whereas the uptake by the healthy cell lines (CHO) is negligible. This finding suggests that these micelles can be used for targeted drug delivery toward cancer cells.
53. 53

    Zashikhina, N.; Levit, M.; Dobrodumov, A.; Gladnev, S.; Lavrentieva, A.; Tennikova, T.; Korzhikova-Vlakh, E. Biocompatible Nanoparticles Based on Amphiphilic Random Polypeptides and Glycopolymers as Drug Delivery Systems. Polymer 2022, 14, 1677,  DOI: 10.3390/polym14091677

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54. 54

    Smith, A. E.; Sizovs, A.; Grandinetti, G.; Xue, L.; Reineke, T. M. Diblock Glycopolymers Promote Colloidal Stability of Polyplexes and Effective pDNA and siRNA Delivery under Physiological Salt and Serum Conditions. Biomacromolecules 2011, 12, 3015– 3022,  DOI: 10.1021/bm200643c

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    54

    Diblock Glycopolymers Promote Colloidal Stability of Polyplexes and Effective pDNA and siRNA Delivery under Physiological Salt and Serum Conditions

    Smith, Adam E.; Sizovs, Antons; Grandinetti, Giovanna; Xue, Lian; Reineke, Theresa M.

    Biomacromolecules (2011), 12 (8), 3015-3022CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    A series of glycopolymers composed of 2-deoxy-2-methacrylamido glucopyranose (MAG) and the primary amine-contg. N-(2-aminoethyl) methacrylamide (AEMA) were synthesized via aq. reversible addn.-fragmentation chain transfer (RAFT) polymn. The colloidal stability of the polyplexes formed with three diblock glycopolymers and pDNA was assessed using dynamic light scattering, and the polyplexes were found to be stable against aggregation in the presence of salt and serum over the 4 h time period studied. Delivery expts. were performed in vitro to examine the cellular uptake, transfection efficiency, and cytotoxicity of the glycopolymer/pDNA polyplexes in cultured HeLa cells and the diblock copolymer with the shortest AEMA block was found to be the most effective. Addnl., the ability of the diblock glycopolymers to deliver siRNA to U-87 (glioblastoma) cells was screened, and the diblock copolymer with the longest AEMA block was found to have gene knockdown efficacy similar to Lipofectamine 2000.
55. 55

    Wu, Y.; Wang, M.; Sprouse, D.; Smith, A. E.; Reineke, T. M. Glucose-Containing Diblock Polycations Exhibit Molecular Weight, Charge, and Cell-Type Dependence for pDNA Delivery. Biomacromolecules 2014, 15, 1716– 1726,  DOI: 10.1021/bm5001229

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    Glucose-Containing Diblock Polycations Exhibit Molecular Weight, Charge, and Cell-Type Dependence for pDNA Delivery

    Wu, Yaoying; Wang, Miao; Sprouse, Dustin; Smith, Adam E.; Reineke, Theresa M.

    Biomacromolecules (2014), 15 (5), 1716-1726CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    A series of diblock glycopolycations were created by polymg. 2-deoxy-2-methacrylamido glucopyranose (MAG) with either a tertiary amine-contg. monomer, N-[3-(N,N-dimethylamino) propyl] methacrylamide (DMAPMA), or a primary amine-contg. unit, N-(2-aminoethyl) methacrylamide (AEMA). Seven structures were synthesized via aq. reversible addn.-fragmentation chain transfer (RAFT) polymn. that varied in the block lengths of MAG, DMAPMA, and AEMA along with two homopolymer controls of DMAPMA and AEMA that lacked a MAG block. The polymers were all able to complex plasmid DNA into polyplex structures and to prevent colloidal aggregation of polyplexes in physiol. salt conditions. In vitro transfection expts. were performed in both HeLa (human cervix adenocarcinoma) cells and HepG2 (human liver hepatocellular carcinoma) cells to examine the role of charge type, block length, and cell type on transfection efficiency and toxicity. The glycopolycation vehicles with primary amine blocks and PAEMA homopolymers revealed much higher transfection efficiency and lower toxicity when compared to analogs created with DMAPMA. Block length was also shown to influence cellular delivery and toxicity; as the block length of DMAPMA increased in the glycopolycation-based polyplexes, toxicity increased while transfection decreased. While the charge block played a major role in delivery, the MAG block length did not affect these cellular parameters. Lastly, cell type played a major role in efficiency. These glycopolymers revealed higher cellular uptake and transfection efficiency in HepG2 cells than in HeLa cells, while homopolycations (PAEMA and PDMAPMA) lacking the MAG blocks exhibited the opposite trend, signifying that the MAG block could aid in hepatocyte transfection.
56. 56

    Levit, M.; Vdovchenko, A.; Dzhuzha, A.; Zashikhina, N.; Katernyuk, E.; Gostev, A.; Sivtsov, E.; Lavrentieva, A.; Tennikova, T.; Korzhikova-Vlakh, E. Self-Assembled Nanoparticles Based on Block-Copolymers of Poly(2-Deoxy-2-methacrylamido-d-glucose)/Poly(N-Vinyl Succinamic Acid) with Poly(O-Cholesteryl Methacrylate) for Delivery of Hydrophobic Drugs. Int. J. Mol. Sci. 2021, 22, 11457,  DOI: 10.3390/ijms222111457

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    56

    Self-Assembled Nanoparticles Based on Block-Copolymers of Poly(2-Deoxy-2-methacrylamido-d-glucose)/Poly(N-Vinyl Succinamic Acid) with Poly(O-Cholesteryl Methacrylate) for Delivery of Hydrophobic Drugs

    Levit, Mariia; Vdovchenko, Alena; Dzhuzha, Apollinariia; Zashikhina, Natalia; Katernyuk, Elena; Gostev, Alexey; Sivtsov, Eugene; Lavrentieva, Antonina; Tennikova, Tatiana; Korzhikova-Vlakh, Evgenia

    International Journal of Molecular Sciences (2021), 22 (21), 11457CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    The self-assembly of amphiphilic block-copolymers is a convenient way to obtain soft nanomaterials of different morphol. and scale. In turn, the use of a biomimetic approach makes it possible to synthesize polymers with fragments similar to natural macromols. but more resistant to biodegrdn. In this study, we synthesized the novel bio-inspired amphiphilic block-copolymers consisting of poly(N-methacrylamido-d-glucose) or poly(N-vinyl succinamic acid) as a hydrophilic fragment and poly(O-cholesteryl methacrylate) as a hydrophobic fragment. Block-copolymers were synthesized by radical addn.-fragmentation chain-transfer (RAFT) polymn. using dithiobenzoate or trithiocarbonate chain-transfer agent depending on the first monomer, further forming the hydrophilic block. Both homopolymers and copolymers were characterized by 1H NMR and Fourier transform IR spectroscopy, as well as thermogravimetric anal. The obtained copolymers had low dispersity (1.05-1.37) and mol. wts. in the range of ∼13,000-32,000. The amphiphilic copolymers demonstrated enhanced thermal stability in comparison with hydrophilic precursors. According to dynamic light scattering and nanoparticle tracking anal., the obtained amphiphilic copolymers were able to self-assemble in aq. media into nanoparticles with a hydrodynamic diam. of approx. 200 nm. An investigation of nanoparticles by transmission electron microscopy revealed their spherical shape. The obtained nanoparticles did not demonstrate cytotoxicity against human embryonic kidney (HEK293) and bronchial epithelial (BEAS-2B) cells, and they were characterized by a low uptake by macrophages in vitro. Paclitaxel loaded into the developed polymer nanoparticles retained biol. activity against lung adenocarcinoma epithelial cells (A549).
57. 57

    Iyer, A. K.; Khaled, G.; Fang, J.; Maeda, H. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discovery Today 2006, 11, 812– 818,  DOI: 10.1016/j.drudis.2006.07.005

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    Exploiting the enhanced permeability and retention effect for tumor targeting

    Iyer, Arun K.; Khaled, Greish; Fang, Jun; Maeda, Hiroshi

    Drug Discovery Today (2006), 11 (17 & 18), 812-818CODEN: DDTOFS; ISSN:1359-6446. (Elsevier B.V.)

    A review. Of the tumor targeting strategies, the enhanced permeability and retention (EPR) effect of macromols. is a key mechanism for solid tumor targeting, and considered a gold std. for novel drug design. In this review, we discuss various endogenous factors that can pos. impact the EPR effect in tumor tissues. Further, we discuss ways to augment the EPR effect by use of exogenous agents, as well as practical methods available in the clin. setting. Some innovative examples developed by researchers to combat cancer by the EPR mechanism are also discussed.
58. 58

    Bakirdogen, G.; Sahkulubey Kahveci, E. L.; Kahveci, M. U. Fast and efficient preparation of three-arm star block copolymers via tetrazine ligation. Eur. Polym. J. 2020, 140, 110027  DOI: 10.1016/j.eurpolymj.2020.110027

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    Fast and efficient preparation of three-arm star block copolymers via tetrazine ligation

    Bakirdogen, Gulsah; Sahkulubey Kahveci, Elif L.; Kahveci, Muhammet U.

    European Polymer Journal (2020), 140 (), 110027CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)

    The inverse Electron Demand Diels-Alder (IEDDA) reaction between tetrazine and trans-cyclooctenol (TCO) is a fast and effective method employed to connect two or more mols. In this study, an efficient and fast methodol. based on tetrazine/trans-cyclooctene IEDDA reaction was developed for prepn. of star-shaped block copolymers. Three-arm star polylactide-b-poly(ethylene glycol) (PLA-b-PEG) was chosen as a model system to show efficiency of the approach. First, three-arm PLAs with two different mol. masses were synthesized in a typical ring opening polymn. and functionalized with tetrazine end functionalities. while TCO end functionalized PEGs in two different mol. masses were prepd. Exact stoichiometric IEDDA click reaction between tetrazine moieties on three ends of the star polymer (s-3PLA-Tz) in the core and trans-cyclooctene (TCO) moieties of the periphery polymer (PEG-TCO) was performed in high click efficiency (up to 95.8%) in a short period (after 50-75 min). Ligation of PEG was confirmed by UV-vis, NMR and FT-IR spectroscopies, and size exclusion chromatog. (SEC) and differential scanning calorimetry (DSC) analyses. In this way, various copolymers of desired architectures can be prepd. in a short time and in high efficiency.
59. 59

    Lu, W.; Ma, W.; Lu, J.; Li, X.; Zhao, Y.; Chen, G. Microwave-Assisted Synthesis of Glycopolymer-Functionalized Silver Nanoclusters: Combining the Bioactivity of Sugar with the Fluorescence and Cytotoxicity of Silver. Macromol. Rapid Commun. 2014, 35, 827– 833,  DOI: 10.1002/marc.201300905

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    59

    Microwave-Assisted Synthesis of Glycopolymer-Functionalized Silver Nanoclusters: Combining the Bioactivity of Sugar with the Fluorescence and Cytotoxicity of Silver

    Lu, Wei; Ma, Wenjuan; Lu, Jiawei; Li, Xiao; Zhao, Yun; Chen, Gaojian

    Macromolecular Rapid Communications (2014), 35 (8), 827-833CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Copolymers of 2-(methacrylamido)glucopyranose (MAG) and methacrylic acid (MAA) are synthesized by RAFT polymn. and then used as templates to prep. glycopolymer-functionalized Ag nanoclusters (Gly-Ag NCs) through microwave irradn. Polymers and the resulting nanoclusters are characterized by NMR, GPC, UV-Vis, SEM, TEM, AAS and fluorescence spectroscopy. The bio-activity of the fluorescent Gly-Ag NCs are further examd. using GLUT-1 over-expressing cancer cells K562. Gly-Ag NCs show efficient binding ability toward K562 cells and inhibit the cell viability in a dose dependent manner (IC50 = 0.65 μg mL-1), indicating their potential biol. applications for both cancer imaging and targeted cancer therapy.
60. 60

    Ting, S. R. S.; Min, E. H.; Zetterlund, P. B.; Stenzel, M. H. Controlled/Living ab Initio Emulsion Polymerization via a Glucose RAFTstab: Degradable Cross-Linked Glyco-Particles for Concanavalin A/FimH Conjugations to Cluster E. coli Bacteria. Macromolecules 2010, 43, 5211– 5221,  DOI: 10.1021/ma1004937

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    60

    Controlled/Living ab Initio Emulsion Polymerization via a Glucose RAFTstab: Degradable Cross-Linked Glyco-Particles for Concanavalin A/FimH Conjugations to Cluster E. coli Bacteria

    Ting, S. R. Simon; Min, Eun Hee; Zetterlund, Per B.; Stenzel, Martina H.

    Macromolecules (Washington, DC, United States) (2010), 43 (12), 5211-5221CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)

    Glyco-particles bearing glucose units have been prepd. via a one-step controlled/living ab initio crosslinking emulsion polymn. of styrene based on self-assembly via a glucose RAFTstab (reversible addn.-fragmentation chain transfer colloidal stabilizer). The RAFTstab was synthesized from the monomer 2-(methacrylamido)glucopyranose (MAG) and the hydrophobic trithiocarbonate RAFT agent S-methoxycarbonylphenylmethyl dodecyltrithiocarbonate (MCPDT). In order to obtain glyco-particles stable for biomedical applications, a degradable bis(2-acryloyloxyethyl) disulfide crosslinker (disulfide diacrylate, DSDA) was employed in the emulsion polymn. The crosslinked glyco-particles were stable in N,N-dimethylacetamide (DMAc), in contrast to the corresponding non-crosslinked glyco-particles which disintegrate to form linear glycopolymers in soln. The crosslinked particles underwent reductive degrdn. into the constituent linear (primary) chains upon treatment with 1,4-dithiothreitol (DDT). The bioactivity of the glucose moieties on the surface of the particles was examd. using two classes of lectins, namely plant lectin (Con A, Canavalia ensiformis) and bacteria lectin (fimH, from Escherichia coli). Successful binding was demonstrated, thus illustrating that these particles have potential as "smart" materials in biol. systems.
61. 61

    Levit, M.; Zashikhina, N.; Dobrodumov, A.; Kashina, A.; Tarasenko, I.; Panarin, E.; Fiorucci, S.; Korzhikova-Vlakh, E.; Tennikova, T. Synthesis and characterization of well-defined poly(2-deoxy-2-methacrylamido-d-glucose) and its biopotential block copolymers via RAFT and ROP polymerization. Eur. Polym. J. 2018, 105, 26– 37,  DOI: 10.1016/j.eurpolymj.2018.05.018

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    61

    Synthesis and characterization of well-defined poly(2-deoxy-2-methacrylamido-D-glucose) and its biopotential block copolymers via RAFT and ROP polymerization

    Levit, Mariia; Zashikhina, Natalia; Dobrodumov, Anatoliy; Kashina, Anna; Tarasenko, Irina; Panarin, Evgeniy; Fiorucci, Stefano; Korzhikova-Vlakh, Evgenia; Tennikova, Tatiana

    European Polymer Journal (2018), 105 (), 26-37CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)

    Well-defined homopolymers of 2-deoxy-2-methacrylamido-D-glucose (MAG) were synthesized via reversible addn.-fragmentation chain transfer (RAFT) polymn. using 4-cyanopentanoic acid-4-dithiobenzoate as chain transfer agent (CTA) and 2,2'-azobisisobutyronitrile (AIBN) as initiator. The effect of polymn. conditions such as molar ratio of RAFT agent to initiator and monomer to RAFT agent on conversion and mol. mass characteristics of prepd. polymers was estd. Kinetics of the polymn. under various reaction conditions was studied as a function of time and conversion using in situ1H NMR spectroscopy. The living character of polymn. was demonstrated by carriyng out the further chain extension expts. using isolated PMAG-CTA as a macroRAFT agent. For that, the PMAG with higher mol. wt., as well as block copolymer with acrylic acid were synthesized and characterized using 1H NMR and SEC anal. A novel amphiphilic copolymer representing a hybrid of glycopolymer and polypeptide fragments was synthesized using RAFT and ring-opening polymn. (ROP). In this case, dithiobenzoate end-group of PMAG was transformed via simultaneous redn. and in situ thiol capping reaction by cysteamine hydrochloride into amino functionality suitable for polymn. of N-carboxyanhydrides (NCA). Two block copolymers of MAG with poly-L-phenylalanine (PPhe) differed with hydrophobic block length were synthesized, characterized and used for prepn. of particles via copolymer self-assembly. The hydrodynamic diam., morphol. and cytotoxicity of polymer particles based on PMAG-b-PPhe were evaluated using DLS, TEM and MTT-assay, resp. Moreover, the encapsulation of model compd. (fluorescent dye rhodamine 6G) inside PMAG-b-PPhe micelles, as well as its release, were also tested.
62. 62

    Yang, C.; Xue, Z.; Liu, Y.; Xiao, J.; Chen, J.; Zhang, L.; Guo, J.; Lin, W. Delivery of anticancer drug using pH-sensitive micelles from triblock copolymer MPEG-b-PBAE-b-PLA. Mater. Sci. Eng., C 2018, 84, 254– 262,  DOI: 10.1016/j.msec.2017.12.003

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    62

    Delivery of anticancer drug using pH-sensitive micelles from triblock copolymer MPEG-b-PBAE-b-PLA

    Yang, Chufen; Xue, Zhaolin; Liu, Yinglin; Xiao, Jiayu; Chen, Jingrui; Zhang, Lijuan; Guo, Jianwei; Lin, Wenjing

    Materials Science & Engineering, C: Materials for Biological Applications (2018), 84 (), 254-262CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)

    To improve the drug release rate in well-controlled manner, a new pH-sensitive triblock amphiphilic copolymer Me poly(ethylene glycol) ether-b-poly(β-amino esters)-b-poly lactic acid (MPEG-b-PBAE-b-PLA) and its self-assembled micelles were developed for anticancer drug delivery. The av. mol. wt. and mol. structure of MPEG-b-PBAE-b-PLA were confirmed by gel permeation chromatog. (GPC) and 1H NMR. The formation of self-assembled micelles, the microstructures at different pH values, and the distribution of doxorubicin (DOX) were investigated by dissipative particle dynamics (DPD) simulation combined with exptl. techniques. The copolymers formed stable core-shell-type micelles in water. The crit. micelle concn. (CMC) values, particle sizes and zeta potentials of the blank micelles increased along with globule-extended conformational transitions when the pH values decreased from 7.4 to 5.0, due to the protonation of amine groups of PBAE. Obvious increases in the particle sizes and the drug loading content of micelles were obsd. with increasing DOX. The in vitro release behavior of DOX from the micelles was pH-dependent. The DOX release rate was improved obviously as pH decreased from pH 7.4 to pH 5.0, with over 96% of DOX was released within 48 h. The drug release mechanism under different conditions was also analyzed using theor. formulas. All the results suggest that the pH-sensitive MPEG-b-PBAE-b-PLA micelles might be a prospective candidate as anticancer drug delivery carrier with well-controlled release behavior.
63. 63

    Kulkarni, B.; Surnar, B.; Jayakannan, M. Dual Functional Nanocarrier for Cellular Imaging and Drug Delivery in Cancer Cells Based on π-Conjugated Core and Biodegradable Polymer Arms. Biomacromolecules 2016, 17, 1004– 1016,  DOI: 10.1021/acs.biomac.5b01654

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    63

    Dual Functional Nanocarrier for Cellular Imaging and Drug Delivery in Cancer Cells Based on π-Conjugated Core and Biodegradable Polymer Arms

    Kulkarni, Bhagyashree; Surnar, Bapurao; Jayakannan, Manickam

    Biomacromolecules (2016), 17 (3), 1004-1016CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    Multipurpose polymer nanoscaffolds for cellular imaging and delivery of anticancer drug are urgently required for the cancer therapy. The present investigation reports a new polymer drug delivery concept based on biodegradable polycaprolactone (PCL) and highly luminescent π-conjugated fluorophore as dual functional nanocarrier for cellular imaging and delivery vehicles for anticancer drug to cancer cells. To accomplish this goal, a new substituted caprolactone monomer was designed, and it was subjected to ring opening polymn. using a blue luminescent bishydroxyloligo-phenylenevinylene (OPV) fluorophore as an initiator. A series of A-B-A triblock copolymer building blocks with a fixed OPV π-core and variable chain biodegradable PCL arm length were tailor-made. These triblocks self-assembled in org. solvents to produce well-defined helical nanofibers, whereas in water they produced spherical nanoparticles (size ∼150 nm) with blue luminescence. The hydrophobic pocket of the polymer nanoparticle was found to be an efficient host for loading water insol. anticancer drug such as doxorubicin (DOX). The photophys. studies revealed that there was no cross-talking between the OPV and DOX chromophores, and their optical purity was retained in the nanoparticle assembly for cellular imaging. In vitro studies revealed that the biodegradable PCL arm was susceptible to enzymic cleavage at the intracellular lysosomal esterase under physiol. conditions to release the loaded drugs. The nascent nanoparticles were found to be nontoxic to cancer cells, whereas the DOX-loaded nanoparticles accomplished more than 80% killing in HeLa cells. Confocal microscopic anal. confirmed the cell penetrating ability of the blue luminescent polymer nanoparticles and their accumulation preferably in the cytoplasm. The DOX loaded red luminescent polymer nanoparticles were also taken up by the cells, and the drug was found to be accumulated at the perinuclear environment. The new nanocarrier approach reported in the present manuscript accomplishes both cellular imaging and delivering drugs to intracellular compartments in a single polymer system. The present investigation is one of the first examples to demonstrate the dual functional biodegradable luminescence nanocarrier concept in the literature, and the studies established this proof-of-concept in cellular imaging and drug delivery in cancer cells.
64. 64

    Pearson, S.; Vitucci, D.; Khine, Y. Y.; Dag, A.; Lu, H.; Save, M.; Billon, L.; Stenzel, M. H. Light-responsive azobenzene-based glycopolymer micelles for targeted drug delivery to melanoma cells. Eur. Polym. J. 2015, 69, 616– 627,  DOI: 10.1016/j.eurpolymj.2015.04.001

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    Light-responsive azobenzene-based glycopolymer micelles for targeted drug delivery to melanoma cells

    Pearson, Samuel; Vitucci, Dylan; Khine, Yee Yee; Dag, Aydan; Lu, Hongxu; Save, Maud; Billon, Laurent; Stenzel, Martina H.

    European Polymer Journal (2015), 69 (), 616-627CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)

    Light-responsive glycopolymer micelles were produced by the self-assembly of amphiphilic block copolymers contg. azobenzene and β-galactose units. These well-defined block copolymers were synthesized firstly by the RAFT polymn. of an azobenzene methacrylate monomer (AzoMA) to produce two short azobenzene macroRAFT agents contg. 7 and 15 monomer units. Chain extension with a second block of ∼150 or ∼250 sugar units comprising of a protected β-galactose monomer (β-AcGalEtMA) generated four block copolymers, which were converted to amphiphilic structures by deprotection of the acetyl groups on the sugar units. Micelles with well-defined sizes of 26-50 nm were produced by self-assembly in water. The azobenzene units isomerized very rapidly to their more polar cis isomers under UV irradn., reaching the photostationary state within 2 min, with reversion to the trans state taking several hours in the dark. This transition to the more polar cis state is an important criteria for aiding expulsion of a hydrophobic payload. In cell studies, unloaded micelles showed low cytotoxicity, and micelles loaded with the model hydrophobic compd. Nile red demonstrated high cellular uptake in human melanoma A375 cells, demonstrating their suitability as a potential drug delivery system for melanoma.
65. 65

    Surnar, B.; Sharma, K.; Jayakannan, M. Core–shell polymer nanoparticles for prevention of GSH drug detoxification and cisplatin delivery to breast cancer cells. Nanoscale 2015, 7, 17964– 17979,  DOI: 10.1039/C5NR04963F

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    Core-shell polymer nanoparticles for prevention of GSH drug detoxification and cisplatin delivery to breast cancer cells

    Surnar, Bapurao; Sharma, Kavita; Jayakannan, Manickam

    Nanoscale (2015), 7 (42), 17964-17979CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

    Platinum drug delivery against the detoxification of cytoplasmic thiols is urgently required for achieving efficacy in breast cancer treatment that is over expressed by glutathione (GSH, thiol-oligopeptide). GSH-resistant polymer-cisplatin core-shell nanoparticles were custom designed based on biodegradable carboxylic functional polycaprolactone (PCL)-block-poly(ethylene glycol) diblock copolymers. The core of the nanoparticle was fixed as 100 carboxylic units and the shell part was varied using various mol. wt. poly(ethylene glycol) monomethyl ethers (MW of PEGs = 100-5000 g mol-1) as initiator in the ring-opening polymn. The complexation of cisplatin aquo species with the diblocks produced core-shell nanoparticles of 75 nm core with precise size control the particles up to 190 nm. The core-shell nanoparticles were found to be stable in saline soln. and PBS and they exhibited enhanced stability with increase in the PEG shell thickness at the periphery. The hydrophobic PCL layer on the periphery of the cisplatin core behaved as a protecting layer against the cytoplasmic thiol residues (GSH and cysteine) and exhibited <5% of drug detoxification. In vitro drug-release studies revealed that the core-shell nanoparticles were ruptured upon exposure to lysosomal enzymes like esterase at the intracellular compartments. Cytotoxicity studies were performed both in normal wild-type mouse embryonic fibroblast cells (Wt-MEFs), and breast cancer (MCF-7) and cervical cancer (HeLa) cell lines. Free cisplatin and polymer drug core-shell nanoparticles showed similar cytotoxicity effects in the HeLa cells. In MCF-7 cells, the free cisplatin drug exhibited 50% cell death whereas complete cell death (100%) was accomplished by the polymer-cisplatin core-shell nanoparticles. Confocal microscopic images confirmed that the core-shell nanoparticles were taken up by the MCF-7 and HeLa cells and they were accumulated both at the cytoplasm as well at peri-nuclear environments. The present investigation lays a new foundation for the polymer-based core-shell nanoparticles approach for overcoming detoxification in platinum drugs for the treatment of GSH over-expressed breast cancer cells.
66. 66

    Wu, H.; Yang, J.; Šečkuṫ, J.; Devaraj, N. K. In Situ Synthesis of Alkenyl Tetrazines for Highly Fluorogenic Bioorthogonal Live-Cell Imaging Probes. Angew. Chem., Int. Ed. 2014, 53, 5805– 5809,  DOI: 10.1002/anie.201400135

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    In Situ Synthesis of Alkenyl Tetrazines for Highly Fluorogenic Bioorthogonal Live-Cell Imaging Probes

    Wu, Haoxing; Yang, Jun; Seckute, Jolita; Devaraj, Neal K.

    Angewandte Chemie, International Edition (2014), 53 (23), 5805-5809CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    In spite of the wide application potential of 1,2,4,5-tetrazines, particularly in live-cell and in vivo imaging, a major limitation has been the lack of practical synthetic methods. Here we report the in situ synthesis of (E)-3-substituted 6-alkenyl-1,2,4,5-tetrazine derivs. through an elimination-Heck cascade reaction. By using this strategy, we provide 24 examples of π-conjugated tetrazine derivs. that can be conveniently prepd. from tetrazine building blocks and related halides. These include tetrazine analogs of biol. small mols., highly conjugated buta-1,3-diene-substituted tetrazines, and a diverse array of fluorescent probes suitable for live-cell imaging. These highly conjugated probes show very strong fluorescence turn-on (up to 400-fold) when reacted with dienophiles such as cyclopropenes and trans-cyclooctenes, and we demonstrate their application for live-cell imaging. This work provides an efficient and practical synthetic methodol. for tetrazine derivs. and will facilitate the application of conjugated tetrazines, particularly as fluorogenic probes for live-cell imaging.
67. 67

    Lee, Y.-J.; Kurra, Y.; Yang, Y.; Torres-Kolbus, J.; Deiters, A.; Liu, W. R. Genetically encoded unstrained olefins for live cell labeling with tetrazine dyes. Chem. Commun. 2014, 50, 13085– 13088,  DOI: 10.1039/C4CC06435F

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    Genetically encoded unstrained olefins for live cell labeling with tetrazine dyes

    Lee, Yan-Jiun; Kurra, Yadagiri; Yang, Yanyan; Torres-Kolbus, Jessica; Deiters, Alexander; Liu, Wenshe R.

    Chemical Communications (Cambridge, United Kingdom) (2014), 50 (86), 13085-13088CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

    A no. of non-canonical amino acids (NCAAs) with unstrained olefins are genetically encoded using mutant pyrrolysyl-tRNA synthetase-tRNAPylCUA pairs. These NCAAs readily undergo inverse electron-demand Diels-Alder cycloaddns. with tetrazine dyes, leading to selective labeling of proteins bearing these NCAAs in live cells.
68. 68

    Devaraj, N. K.; Weissleder, R.; Hilderbrand, S. A. Tetrazine-Based Cycloadditions: Application to Pretargeted Live Cell Imaging. Bioconjugate Chem. 2008, 19, 2297– 2299,  DOI: 10.1021/bc8004446

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    Tetrazine-Based Cycloadditions: Application to Pretargeted Live Cell Imaging

    Devaraj, Neal K.; Weissleder, Ralph; Hilderbrand, Scott A.

    Bioconjugate Chemistry (2008), 19 (12), 2297-2299CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    Bioorthogonal tetrazine cycloaddns. have been applied to live cell labeling. Tetrazines react irreversibly with the strained dienophile norbornene forming dihydropyrazine products and dinitrogen. The reaction is high yielding, selective, and fast in aq. media. Her2/neu receptors on live human breast cancer cells were targeted with a monoclonal antibody modified with a norbornene. Tetrazines conjugated to a near-IR fluorochrome selectively and rapidly label the pretargeted antibody in the presence of serum. These findings indicate that this chem. is suitable for in vitro labeling expts., and suggests that it may prove a useful strategy for in vivo pretargeted imaging under numerous modalities.
69. 69

    Peterson, V. M.; Castro, C. M.; Lee, H.; Weissleder, R. Orthogonal Amplification of Nanoparticles for Improved Diagnostic Sensing. ACS Nano 2012, 6, 3506– 3513,  DOI: 10.1021/nn300536y

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    Orthogonal Amplification of Nanoparticles for Improved Diagnostic Sensing

    Peterson, Vanessa M.; Castro, Cesar M.; Lee, Hakho; Weissleder, Ralph

    ACS Nano (2012), 6 (4), 3506-3513CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

    There remains an ongoing need for fast, highly sensitive, and quant. technologies that can detect and profile rare cells in freshly harvested samples. Recent developments in nanomaterial-based detection platforms provide advantages over traditional approaches in terms of signal sensitivity, stability, and the possibility for performing multiplexed measurements. Here, the authors describe a bioorthogonal, nanoparticle amplification technique capable of rapid augmentation of detection sensitivities by up to 1-2 orders of magnitude over current methods. This improvement in sensitivity was achieved by (i) significantly reducing background noise arising from nonspecific nanoparticle binding, (ii) increasing nanomaterial binding through orthogonal rounds of amplification, and (iii) implementing a cleavage step to improve assay robustness. The developed method allowed sensitive detection and mol. profiling of scant tumor cells directly in unpurified human clin. samples such as ascites. With its high sensitivity and simplified assay steps, this technique will likely have broad utility in nanomaterial-based diagnostics.
70. 70

    Liong, M.; Fernandez-Suarez, M.; Issadore, D.; Min, C.; Tassa, C.; Reiner, T.; Fortune, S. M.; Toner, M.; Lee, H.; Weissleder, R. Specific Pathogen Detection Using Bioorthogonal Chemistry and Diagnostic Magnetic Resonance. Bioconjugate Chem. 2011, 22, 2390– 2394,  DOI: 10.1021/bc200490r

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    70

    Specific Pathogen Detection Using Bioorthogonal Chemistry and Diagnostic Magnetic Resonance

    Liong, Monty; Fernandez-Suarez, Marta; Issadore, David; Min, Changwook; Tassa, Carlos; Reiner, Thomas; Fortune, Sarah M.; Toner, Mehmet; Lee, Hakho; Weissleder, Ralph

    Bioconjugate Chemistry (2011), 22 (12), 2390-2394CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    The development of faster and more sensitive detection methods capable of identifying specific bacterial species and strains has remained a longstanding clin. challenge. Thus to date, the diagnosis of bacterial infections continues to rely on the performance of time-consuming microbiol. cultures. Here, the authors demonstrate the use of bioorthogonal chem. for magnetically labeling specific pathogens to enable their subsequent detection by NMR. Antibodies against a bacterial target of interest were first modified with trans-cyclooctene and then coupled to tetrazine-modified magnetic nanoprobes, directly on the bacteria. This labeling method was verified by surface plasmon resonance as well as by highly specific detection of Staphylococcus aureus using a miniaturized diagnostic magnetic resonance system. Compared to other copper-free bioorthogonal chemistries, the cycloaddn. reaction reported here displayed faster kinetics and yielded higher labeling efficiency. Considering the short assay times and the portability of the necessary instrumentation, it is feasible that this approach could be adapted for clin. use in resource-limited settings.
71. 71

    Oliveira, B. L.; Guo, Z.; Bernardes, G. J. L. Inverse electron demand Diels-Alder reactions in chemical biology. Chem. Soc. Rev. 2017, 46, 4895– 4950,  DOI: 10.1039/C7CS00184C

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    Inverse electron demand Diels-Alder reactions in chemical biology

    Oliveira, B. L.; Guo, Z.; Bernardes, G. J. L.

    Chemical Society Reviews (2017), 46 (16), 4895-4950CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

    The emerging inverse electron demand Diels-Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biol., imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concns. of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chem. biol., radiochem. and materials science.
72. 72

    Kang, K.; Park, J.; Kim, E. Tetrazine ligation for chemical proteomics. Proteome Sci. 2017, 15, 15,  DOI: 10.1186/s12953-017-0121-5

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73. 73

    Seo, J.; Park, S. H.; Kim, M. J.; Ju, H. J.; Yin, X. Y.; Min, B. H.; Kim, M. S. Injectable Click-Crosslinked Hyaluronic Acid Depot To Prolong Therapeutic Activity in Articular Joints Affected by Rheumatoid Arthritis. ACS Appl. Mater. Interfaces 2019, 11, 24984– 24998,  DOI: 10.1021/acsami.9b04979

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    73

    Injectable Click-Crosslinked Hyaluronic Acid Depot To Prolong Therapeutic Activity in Articular Joints Affected by Rheumatoid Arthritis

    Seo, Jiyoung; Park, Seung Hun; Kim, Min Ju; Ju, Hyeon Jin; Yin, Xiang Yun; Min, Byoung Hyun; Kim, Moon Suk

    ACS Applied Materials & Interfaces (2019), 11 (28), 24984-24998CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

    The aim of this study was to design a click-crosslinked hyaluronic acid (HA) (Cx-HA) depot via a click crosslinking reaction between tetrazine-modified HA and trans-cyclooctene-modified HA for direct intra-articular injection into joints affected by rheumatoid arthritis (RA). The Cx-HA depot had significantly more hydrogel-like features and a longer in vivo residence time than the HA depot. Methotrexate (MTX)-loaded Cx-HA (MTX-Cx-HA)-easily prepd. as an injectable formulation-quickly formed an MTX-Cx-HA depot that persisted at the injection site for an extended period. In vivo MTX biodistribution in MTX-Cx-HA depots showed that a high concn. of MTX persisted at the intra-articular injection site for an extended period, with little distribution of MTX to normal tissues. In contrast, direct intra-articular injection of MTX alone or MTX-HA resulted in rapid clearance from the injection site. After intra-articular injection of MTX-Cx-HA into rats with RA, we noted the most significant RA reversal, measured by an articular index score, increased cartilage thickness, extensive generation of chondrocytes and glycosaminoglycan deposits, extensive new bone formation in the RA region, and suppression of tumor necrosis factor-α or interleukin-6 expression. Therefore, MTX-Cx-HA injected intra-articularly persists at the joint site in therapeutic MTX concns. for an extended period, thus increasing the duration of RA treatment, resulting in an improved relief of RA.
74. 74

    Heo, J. Y.; Noh, J. H.; Park, S. H.; Ji, Y. B.; Ju, H. J.; Kim, D. Y.; Lee, B.; Kim, M. S. An Injectable Click-Crosslinked Hydrogel that Prolongs Dexamethasone Release from Dexamethasone-Loaded Microspheres. Pharmaceutics 2019, 11, 438,  DOI: 10.3390/pharmaceutics11090438

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    74

    An injectable click-crosslinked hydrogel that prolongs dexamethasone release from dexamethasone-loaded microspheres

    Heo, Ji Yeon; Noh, Jung Hyun; Park, Seung Hun; Ji, Yun Bae; Ju, Hyeon Jin; Kim, Da Yeon; Lee, Bong; Kim, Moon Suk

    Pharmaceutics (2019), 11 (9), 438CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)

    Our purpose was to test whether a prepn. of injectable formulations of dexamethasone (Dex)-loaded microspheres (Dex-Ms) mixed with click-crosslinked hyaluronic acid (Cx-HA) (or Pluronic (PH) for comparison) prolongs therapeutic levels of released Dex. Dex-Ms were prepd. using a monoaxial-nozzle ultrasonic atomizer with an 85% yield of the Dex-Ms prepn., encapsulation efficiency of 80%, and av. particle size of 57 μm. Cx-HA was prepd. via a click reaction between transcyclooctene (TCO)-modified HA (TCO-HA) and tetrazine (TET)-modified HA (TET-HA). The injectable formulations (Dex-Ms/PH and Dex-Ms/Cx-HA) were fabricated as suspensions and became a Dex-Ms-loaded hydrogel drug depot after injection into the s.c. tissue of Sprague Dawley rats. Dex-Ms alone also formed a drug depot after injection. The Cx-HA hydrogel persisted in vivo for 28 days, but the PH hydrogel disappeared within six days, as evidenced by in vivo near-IR fluorescence imaging. The in vitro and in vivo cumulative release of Dex by Dex-Ms/Cx-HA was much slower in the early days, followed by sustained release for 28 days, compared with Dex-Ms alone and Dex-Ms/PH. The reason was that the Cx-HA hydrogel acted as an external gel matrix for Dex-Ms, resulting in the retarded release of Dex from Dex-Ms. Therefore, we achieved significantly extended duration of a Dex release from an in vivo Dex-Ms-loaded hydrogel drug depot formed by Dex-Ms wrapped in an injectable click-crosslinked HA hydrogel in a minimally invasive manner. In conclusion, the Dex-Ms/Cx-HA drug depot described in this work showed excellent performance on extended in vivo delivery of Dex.
75. 75

    Dicker, K. T.; Moore, A. C.; Garabedian, N. T.; Zhang, H.; Scinto, S. L.; Akins, R. E.; Burris, D. L.; Fox, J. M.; Jia, X. Q. Spatial Patterning of Molecular Cues and Vascular Cells in Fully Integrated Hydrogel Channels via Interfacial Bioorthogonal Cross-Linking. ACS Appl. Mater. Interfaces 2019, 11, 16402– 16411,  DOI: 10.1021/acsami.9b04383

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    75

    Spatial Patterning of Molecular Cues and Vascular Cells in Fully Integrated Hydrogel Channels via Interfacial Bioorthogonal Cross-Linking

    Dicker, Kevin T.; Moore, Axel C.; Garabedian, Nikolay T.; Zhang, Han; Scinto, Samuel L.; Akins, Robert E.; Burris, David L.; Fox, Joseph M.; Jia, Xinqiao

    ACS Applied Materials & Interfaces (2019), 11 (18), 16402-16411CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)

    Fully integrated hydrogel channels were fabricated via interfacial bioorthogonal crosslinking, a diffusion-controlled method for the creation and patterning of synthetic matrixes based on the rapid bioorthogonal reaction between s-tetrazines (Tz) and trans-cyclooctene (TCO) dienophiles. Injecting an aq. soln. of a bisTCO cross-linker into a reservoir of tetrazine-modified hyaluronic acid (HA-Tz), while simultaneously drawing the syringe needle through the reservoir, yielded a cross-linked hydrogel channel that was mech. robust. Fluorescent tags and biochem. signals were spatially patterned into the channel wall through time-dependent perfusion of TCO-conjugated mols. into the lumen of the channel. Different cell populations were spatially encapsulated in the channel wall via temporal alteration of cells in the HA-Tz reservoir. The interfacial approach enabled the spatial patterning of vascular cells, including human abdominal aorta endothelial cells, aortic vascular smooth muscle cells, and aortic adventitial fibroblasts, into the hydrogel channels with high viability and proper morphol. in the anatomical order found in human arteries. The bioorthogonal platform does not rely on external triggers and represents the first step toward the engineering of functional and implantable arteries.
76. 76

    Jain, S.; Neumann, K.; Zhang, Y.; Geng, J.; Bradley, M. Tetrazine-Mediated Postpolymerization Modification. Macromolecules 2016, 49, 5438– 5443,  DOI: 10.1021/acs.macromol.6b00867

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    Tetrazine-Mediated Postpolymerization Modification

    Jain, Sarthak; Neumann, Kevin; Zhang, Yichuan; Valero, Elsa; Geng, Jin; Bradley, Mark

    Macromolecules (Washington, DC, United States) (2016), 49 (15), 5438-5443CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)

    A new and highly efficient polymer, postpolymn., modification platform based on an inverse electron demand Diels-Alder reaction is reported. Well-defined polymers were synthesized from allyl glycidyl ether and glycidol by anionic ring-opening polymn. with postpolymn. modifications conducted with a no. of tetrazine derivs. that carried functional groups spanning from carboxylates and esters to primary amines. Anal. of polymn. kinetics by real-time 1H NMR, and GPC revealed a rapid and high degree of side-chain conversion (>99%), with the generation of well-defined functional polymers, in both org. and aq. solvents, without the need for additives or catalysts.
77. 77

    Çetinkaya, A.; Sadak, A. E.; Ayhan, M. M.; Zorlu, Y.; Kahveci, M. U. Porphyrin-based covalent organic polymer by inverse electron demand Diels-Alder reaction. Eur. Polym. J. 2021, 157, 110664  DOI: 10.1016/j.eurpolymj.2021.110664

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    77

    Porphyrin-based covalent organic polymer by inverse electron demand Diels-Alder reaction

    Cetinkaya, Ahmet; Sadak, Ali Enis; Ayhan, Mehmet Menaf; Zorlu, Yunus; Kahveci, Muhammet U.

    European Polymer Journal (2021), 157 (), 110664CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)

    Inverse electron demand Diels-Alder (IEDDA) reaction has been employed as a powerful ligation in several fields. In the current work, a synthetic approach relying on IEDDA reaction is developed for prepn. of a porphyrin based covalent org. polymer (PoTz-COP). A tetra-norbornene functional porphyrin is chosen as the core and a bis-tetrazine as the linker. The PoTz-COP is readily formed by just mixing the components without a catalyst and under mild conditions. Chem. structure, morphol. (XRD, SEM-EDX), porosity (BET), thermal stability (TGA), optical and gas sorption (CO2 uptake) and selectivity (CO2/N2) properties via Myers and Prausnitz's ideal adsorbed soln. theory (IAST) are investigated. PoTz-COP shows remarkably high adsorption selectivity of CO2 over N2 as found 80, 42, and 47 at 50/50 ratio; 84, 39 and 40 at 15/85 ratio; and 84, 39 and 38 at 05/95 ratio at temps. of 273 K, 298 K and 320 K at 1.1 bar pressure resp. The optical band gap is detd. relatively narrow as 1.66 eV.
78. 78

    Lorenzo, M. M.; Decker, C. G.; Kahveci, M. U.; Paluck, S. J.; Maynard, H. D. Homodimeric Protein-Polymer Conjugates via the Tetrazine-trans-Cyclooctene Ligation. Macromolecules 2016, 49, 30– 37,  DOI: 10.1021/acs.macromol.5b02323

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    Homodimeric Protein-Polymer Conjugates via the Tetrazine-trans-Cyclooctene Ligation

    Lorenzo, Maltish M.; Decker, Caitlin G.; Kahveci, Muhammet U.; Paluck, Samantha J.; Maynard, Heather D.

    Macromolecules (Washington, DC, United States) (2016), 49 (1), 30-37CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)

    Tetrazine end-functionalized telechelic polymers were synthesized by controlled radical polymn. (CRP) and employed to generate T4 lysozyme homodimers. Mutant T4 lysozyme (V131C), contg. a single surface-exposed cysteine, was modified with a protein-reactive trans-cyclooctene (T4L-TCO). Reversible addn.-fragmentation chain transfer (RAFT) polymn. yielded poly(N-isopropylacrylamide) (pNIPAAm) with a no.-av. mol. wt. (Mn by 1H NMR) of 2.0 kDa and a dispersity (D by GPC) of 1.05. pNIPAAm was then modified at both ends by postpolymn. with 6-methyltetrazine. For comparison, 2.0 kDa bis-tetrazine poly(ethylene glycol) (PEG) and 2.0 kDa bis-maleimide pNIPAAm were synthesized. Ligation of T4L-TCO to bis-tetrazine pNIPAAm or bis-tetrazine PEG resulted in protein homodimer in 38% yield and 37% yield, resp., after only 1 h, whereas bis-maleimide pNIPAAm resulted in only 5% yield of dimer after 24 h. This work illustrates the advantage of employing tetrazine ligation over maleimide thiol-ene chem. for the synthesis of protein homodimer conjugates.
79. 79

    Alge, D. L.; Azagarsamy, M. A.; Donohue, D. F.; Anseth, K. S. Synthetically Tractable Click Hydrogels for Three-Dimensional Cell Culture Formed Using Tetrazine-Norbornene Chemistry. Biomacromolecules 2013, 14, 949– 953,  DOI: 10.1021/bm4000508

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    Synthetically Tractable Click Hydrogels for Three-Dimensional Cell Culture Formed Using Tetrazine-Norbornene Chemistry

    Alge, Daniel L.; Azagarsamy, Malar A.; Donohue, Dillon F.; Anseth, Kristi S.

    Biomacromolecules (2013), 14 (4), 949-953CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    The implementation of bio-orthogonal click chemistries is a topic of growing importance in the field of biomaterials, as it is enabling the development of increasingly complex hydrogel materials capable of providing dynamic, cell-instructive microenvironments. Here, we introduce the tetrazine-norbornene inverse electron demand Diels-Alder reaction as a new crosslinking chem. for the formation of cell laden hydrogels. The fast reaction rate and irreversible nature of this click reaction allowed for hydrogel formation within minutes when a multifunctional PEG-tetrazine macromer was reacted with a dinorbornene peptide. In addn., the cytocompatibility of the polymn. led to high postencapsulation viability of human mesenchymal stem cells, and the specificity of the tetrazine-norbornene reaction was exploited for sequential modification of the network via thiol-ene photochem. These advantages, combined with the synthetic accessibility of the tetrazine mol. compared to other bio-orthogonal click reagents, make this crosslinking chem. an interesting and powerful new tool for the development of cell-instructive hydrogels for tissue engineering applications.
80. 80

    Kara, S. S.; Ateş, M. Y.; Deveci, G.; Cetinkaya, A.; Kahveci, M. U. Direct synthesis of tetrazine functionalities on polymer backbones. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 673– 680,  DOI: 10.1002/pola.29308

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    Direct synthesis of tetrazine functionalities on polymer backbones

    Kara, Sinem Sipahioglu; Ates, Mustafa Yasin; Deveci, Gozde; Cetinkaya, Ahmet; Kahveci, Muhammet U.

    Journal of Polymer Science, Part A: Polymer Chemistry (2019), 57 (6), 673-680CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)

    Tetrazine mediated inverse Electron Demand Diels-Alder Reaction (IEDDA) is an important modification technique due to its high selectivity and super-fast kinetics. Incorporation of tetrazine moieties on polymer chains requires multistep synthetic pathways and a post-polymn. step leading to functional polymeric materials. Such approaches involve sep. syntheses of polymer and the mol. which will be employed in modification. Herein, we introduce a straightforward synthetic approach for direct synthesis of tetrazine groups on polymers as side chains. As model systems, tetrazine functional poly(N-isopropylacrylamide) and poly(ethylene glycol) based polymers from corresponding precursor polymers with nitrile moieties as pendant groups are prepd. and IEDDA Click Reaction is achieved with trans-cyclooctene derivs. The click reaction is monitored by both NMR and UV-vis spectroscopies. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018.
81. 81

    Spencer, G. H., Jr.; Cross, P. C.; Wiberg, K. B. s-Tetrazine. II. Infrared Spectra. J. Chem. Phys. 1961, 35, 1939– 1945,  DOI: 10.1063/1.1732190

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    Wen, K.; Zhou, M.; Lu, H.; Bi, Y.; Ruan, L.; Chen, J.; Hu, Y. Near-Infrared/pH Dual-Sensitive Nanocarriers for Enhanced Intracellular Delivery of Doxorubicin. ACS Biomater. Sci. Eng. 2018, 4, 4244– 4254,  DOI: 10.1021/acsbiomaterials.8b01051

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    Near-Infrared/pH Dual-Sensitive Nanocarriers for Enhanced Intracellular Delivery of Doxorubicin

    Wen, Kaikai; Zhou, Mengxue; Lu, Huiru; Bi, Ying; Ruan, Lifo; Chen, Jun; Hu, Yi

    ACS Biomaterials Science & Engineering (2018), 4 (12), 4244-4254CODEN: ABSEBA; ISSN:2373-9878. (American Chemical Society)

    Herein, we designed near-IR (NIR)/pH dual-sensitive nanocarriers and evaluated its application to intracellular drug delivery. The nanocarriers were prepd. based on amphiphilic poly(β-amino ester) (PBAE) contg. o-nitrobenzyl moieties in the backbones and upconversion nanoparticles (UCNPs). UCNPs can convert NIR to UV that subsequently removes PEG segments from PBAE copolymers, which could enhance the protonation of PBAE in endo/lysosomes and facilitate the escape of the nanoparticles from lysosomes. In addn., we found the colocalization of the nanoparticles with mitochondria inside the cells, presumably resulting from high hydrophobicity and pos. charges of the nanoparticles. The results showed that the nanocarriers with the aid of NIR could enhance the intracellular delivery of DOX, as compared with free DOX and NIR-free control. Furthermore, PBAE@UCNPs-DOX with NIR potently inhibited tumor growth in mice. Therefore, the intelligent micellar nanoparticles might provide a simple yet effective nanoplatform to achieve mitochondrion-targeting drug delivery.
83. 83

    Liu, Y.; Li, Y.; Keskin, D.; Shi, L. Poly(β-Amino Esters): Synthesis, Formulations, and Their Biomedical Applications. Adv. Healthcare Mater. 2019, 8, 1801359  DOI: 10.1002/adhm.201801359

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    Iqbal, S.; Qu, Y.; Dong, Z.; Zhao, J.; Rauf Khan, A.; Rehman, S.; Zhao, Z. Poly (β-amino esters) based potential drug delivery and targeting polymer; an overview and perspectives (review). Eur. Polym. J. 2020, 141, 110097  DOI: 10.1016/j.eurpolymj.2020.110097

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    Poly (β-amino esters) based potential drug delivery and targeting polymer; an overview and perspectives (review)

    Iqbal, Sajid; Qu, Ying; Dong, Zhonghua; Zhao, Jianxiong; Rauf Khan, Abdur; Rehman, Shams; Zhao, Zhongxi

    European Polymer Journal (2020), 141 (), 110097CODEN: EUPJAG; ISSN:0014-3057. (Elsevier Ltd.)

    A review. Poly(β-amino ester)s (PβAE)s are considered as the most potent alternative to viral vectors, which has been increasingly proposed for targeting gene delivery, because of their excellent transfection performance. The self-assembled nanoparticles formed from interaction with nucleic acids showed good biodegradable and hydrophilic nature, which make PβAE superior over other polycationic polymers. PβAEs exhibit different kinetic profiles and tunable charge d., which can be fabricated using a diverse library of building blocks and binding various conjugates to improve transfection efficiency. The rational designing of PβAE is a crit. step to achieve various requirements of gene delivery, anticancer and antimicrobial drug delivery, and nanochaperones. This review presents a revised recapitulation of the synthesis protocols, formulation aspects, and biomedical applications of PβAEs. Within each of these titles, a crit. anal. of the design principles and strategies along with examples, opportunities, and challenges are discussed.
85. 85

    Zhou, X. X.; Jin, L.; Qi, R. Q.; Ma, T. pH-responsive polymeric micelles self-assembled from amphiphilic copolymer modified with lipid used as doxorubicin delivery carriers. R. Soc. Open Sci. 2018, 5, 171654  DOI: 10.1098/rsos.171654

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    The pH-responsive polymeric micelles self-assembled from amphiphilic copolymer modified with lipid used as doxorubicin delivery carriers

    Zhou, Xin Xin; Jin, Long; Qi, Rui Qun; Ma, Teng

    Royal Society Open Science (2018), 5 (3), 171654/1-171654/13CODEN: RSOSAV; ISSN:2054-5703. (Royal Society)

    In the present study, a novel pH-responsive amphiphilic copolymer, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[methoxy(polyethylene glycol)] conjugated poly(β-amino esters) (DSPE-b-PEG-b-PAE-b-PEG-b-DSPE), was designed and successfully synthesized via Michael-type step polymn. The chem. structure of the pentablock copolymer was confirmed with proton NMR (1H-NMR) and Fourier transform IR (FTIR) spectroscopy. The copolymer was able to self-assemble into core/shell polymeric micelles in aq. soln. at low concns., and its crit. micelle concn. (CMC) value was 4.5mgl-1 detd. by fluorescence spectrophotometry. The pKb value of the copolymer was about 6.5, confirmed by acid-base titrn., indicating the pH-sensitivity of the polymeric micelle. The hydrodynamic diam., distribution and zeta potential of the polymeric micelles at different pH conditions were monitored by dynamic light scattering (DLS). Doxorubicin (DOX) was encapsulated into the core of the micelles with a high drug loading content (15.9%) and entrapment efficacy (60.4%). In vitro expts. demonstrated that the release behavior of DOX from the DOX-loaded polymeric micelles (DOX-PMs) was pH-triggered. When the pH decreased from 7.4 to 5.0, the drug release rate was markedly accelerated. MTT assay showed that the copolymer had negligible cytotoxicity whereas the DOX-PMs displayed high toxicity for tumor cells such as B16F10, HepG2 and HeLa cell lines. The results demonstrated that these pH-sensitive polymeric micelles could be used as potential anti-cancer drug carriers for cancer chemotherapy with controlled release.