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WIREs Nanomed Nanobiotechnol

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Block copolymer prodrugs: Synthesis, self‐assembly, and applications for cancer therapy

Focus Article

Zhishen Ge, Min Zhou, Wei Yin, Longchang Xi, Wendong Ke, Debabrata Dutta

Published Online: Aug 26 2019

DOI: 10.1002/wnan.1585

Full article on Wiley Online Library: HTML PDF

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Abstract Block copolymer prodrugs (BCPs) have emerged as one of the most promising anticancer drug delivery strategies, which can self‐assemble into nanoparticles with optimal physicochemical properties including sizes, morphologies, surface properties, and integration of multifunction for improved in vivo applications. Moreover, the utility of stimuli‐responsive linkages to conjugate drugs onto the polymer backbones can achieve efficient and targeting drug release. Several BCP micellar delivery systems have been pushed ahead into the clinical trials, which showed great promising potentials for cancer therapy. In recent years, various novel and more efficient BCP systems have been developed for better in vivo performance. In this focus article, we focus on the recent advances of BCPs including the synthesis, self‐assembly, and applications for cancer therapy. The synthetic methods are first introduced, and the self‐assembly of BCPs for in vivo anticancer applications is discussed along the line of varying endogenous stimuli‐responsive linkages including amide or ester bonds, pH, reduction, and oxidation‐responsive linkages. Finally, conclusions along with the brief future perspectives are presented. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

(a) The self‐assembled morphologies of PEG‐b‐PCPTM BCPs including spherical micelles, smooth disks, flower‐like large compound vesicles, and staggered lamellae. The nanoparticles showed morphology‐dependent behaviors in blood circulation, cellular uptake, and intracellular distribution and degradation. (b) Synthetic routes for preparation of the reduction‐responsive CPT prodrug monomer and PEG‐b‐PCPTM BCPs, and the responsive drug release mechanism the BCPs. Source: Reprinted with permission from Hu, Hu, et al. (). Copyright 2013 American Chemical Society

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Schematic illustration for the process that the dual pH‐responsive BCPs self‐assemble into negatively charged micelles in aqueous solution (1), which turn out to be positively charged at the extracellular tumor pH (2) (6.5–6.8). The positive micelles are internalized by the cells via endocytosis (3, 4), followed by DOX release via cleavage of the hydrazone linkages under endosomal pH and diffusion into the cellular nuclei for cancer cell killing (5). Source: Reprinted with permission from Du, Du, Mao, and Wang (). Copyright 2011 American Chemical Society

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(a) Synthetic routes of PEG‐P(HEMASN38) through ATRP of CPT prodrug monomer. (b) Size distributions of the micelles self‐assembled from the BCP of PEG‐b‐P(HEMASN38) determined by DLS. (c) Photograph pictures of the micelle solutions with the sizes in the range of 22–300 nm. (d) Schematic illustration for tumor penetration of CPT BCP micelles with varying nanoparticle sizes. Source: Reprinted with permission from Wang et al. (). Copyright 2015 American Chemical Society

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(a) Synthesis of BCPs by the conjugation strategy between functionalized block copolymer precursors and functional drugs or prodrugs. (b) and (c) The chemical structure of the couples of block copolymer and the corresponding conjugated drug or prodrug, and the related references. The reactive sites on the block copolymers, drugs, and prodrugs were highlighted

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(a) Synthesis of BCPs by the polymerization strategy of prodrug monomers in the presence of the macro initiator. (b) The chemical structure and references were shown for every prodrug monomer

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Schematic illustration for the preparation of multifunctional BCP micelles to overcome cascade CARIR in vivo drug delivery barriers. The design with the distinct features in each step during the delivery journey including ➀ prolonged blood circulation based on the nanoscale particle size and neutral POEGMA surface, ➁ accumulation in the tumor, ➂ tumor mild acidity caused hydrophobic to hydrophilic transition of PC7A segments and exposure of RGD targets for improved tumor retention effect, ➃ improved cellular internalization finally realized intracellular GSH‐responsive ➄ CPT release. Source: Reprinted with permission from Wang, Yu, et al. (). Copyright 2018 Wiley

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(a) Schematic illustration for the preparation of glucose oxidase (GOD)‐loaded BCP nanoreactors. (b) and (c) the BCP nanoreactors were designed to respond to mildly acidic tumor pH for activation to produce H₂O₂ through improved membrane permeability which is favorable for glucose and oxygen diffusion, followed by free CPT release under the trigger by improved H₂O₂ level. Source: Reprinted with permission from Li et al. (). Copyright 2017 American Chemical Society

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