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Bicomponent polymeric micelles for pH-controlled delivery of doxorubicin.

ABSTRACT: Stimuli-responsive drug delivery systems (DDSs) are expected to realize site-specific drug release and kill cancer cells selectively. In this study, a pH-responsive micelle was designed utilizing the pH-sensitivity of borate bonds formed between dopamine and boronic acid. First, methyl (polyethylene glycol)-block-polycaprolactone (mPEG-PCL) was conjugated with 4-cyano-4-(thiobenzoylthio)pentanoic acid (CTP) to obtain a macroinitiator. Two different segments poly(dopamine methacrylamide) (PDMA) and poly(vinylphenylboronic acid) (PVBA) were then grafted to the end of mPEG-PCL. Two triblock copolymers, mPEG-PCL-PDMA and mPEG-PCL-PVBA, were then obtained by reversible addition-fragmentation transfer (RAFT) polymerization. These copolymers and their mixture self-assembled in aqueous solution to form micelles that were able to load hydrophobic anticancer drug doxorubicin (DOX). These two-component micelles were found to be pH-sensitive, in contrast to the one-component micelles. Furthermore, MTT studies showed that the micelles were almost nontoxic. The DOX-loaded micelles showed cytotoxicity equivalent to that of DOX at high concentration. In vivo antitumor experiments showed that this pH-sensitive polymeric micellar system had an enhanced therapeutic effect on tumors. These two-component boronate-based pH micelles are universally applicable to the delivery of anticancer drugs, showing great potential for cancer therapy.

SUBMITTER: Wang C

PROVIDER: S-EPMC7054969 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RNA interference (RNAi) drugs have significant therapeutic potential, but delivery systems with appropriate efficacy and toxicity profiles are still needed. Here, we describe a neutral, ampholytic polymeric delivery system based on conjugatable diblock polymer micelles. The diblock copolymer contains a hydrophilic poly[N-(2-hydroxypropyl)methacrylamide-co-N-(2-(pyridin-2-yldisulfanyl)ethyl)methacrylamide) (poly[HPMA-co-PDSMA]) segment to promote aqueous stability and facilitate thiol-disulfide exchange reactions and a second ampholytic block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The poly[(HPMA-co-PDSMA)-b-(PAA-co-DMAEMA-co-BMA)] was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization with an overall molecular weight of 22 000 g/mol and a PDI of 1.88. Dynamic light scattering and fluorescence measurements indicated that the diblock copolymers self-assemble under aqueous conditions to form polymeric micelles with a hydrodynamic radius and critical micelle concentration of 25 nm and 25 μg/mL, respectively. Red blood cell hemolysis experiments show that the neutral hydrophilic micelles have potent membrane destabilizing activity at endosomal pH values. Thiolated siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was directly conjugated to the polymeric micelles via thiol exchange reactions with the pyridal disulfide groups present in the micelle corona. Maximum silencing activity in HeLa cells was observed at a 1:10 molar ratio of siRNA to polymer following a 48 h incubation period. Under these conditions 90% mRNA knockdown and 65% protein knockdown at 48 h was achieved with negligible toxicity. In contrast the polymeric micelles lacking a pH-responsive endosomalytic segment demonstrated negligible mRNA and protein knockdown under these conditions. The potent mRNA knockdown and excellent biocompatibility of the neutral siRNA conjugates demonstrate the potential utility of this carrier design for delivering therapeutic siRNA drugs.

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Bicomponent polymeric micelles for pH-controlled delivery of doxorubicin.

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