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 twocomponent 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.
In this study, the structure–activity relationship of amphiphilic block copolymer micelles as nanosized drug delivery system was revealed. Firstly, a biodegradable triblock polymers PEG-DiHyd-PLA containing hydrazone bond was synthesized through the ring-opening polymerization. In this method, PEG-DiHyd-Phenol was used as the initiator and L-lactide as the monomer. Then, the polymeric micelles were formed and used as nano-drug carriers with pH sensitivity. The structure and composition of the polymer were characterized by infrared (IR), nuclear magnetic resonance (1H-NMR), and gel permeation chromatography (GPC), we characterized the self-assembling process of the triblock polymers and the pH sensitivity of the micelles by the means of transmission electron microscopy (TEM), dynamic light scattering method (DLS). Doxorubicin (DOX) acts as the model drug, and we researched the capacities of drug loading and release in vitro of the micelles. MTT experiments showed that the blank micelles of PEG-DiHyd-PLA were not cytotoxic to tumor cells (HepG-2, MCF-7) and normal cell (L-02 cells), but the DOX loaded ones displayed more toxicity than the ones without hydrazone, which was consistent to the further confocal laser scanning microscopy and flow cytometry study.
Biodegradable pH-sensitive amphiphilic block polymer (mPEG-Hyde-PLGA) was synthesized via ring-opening polymerization, initiated from a hydrazone-containing macro-initiator. In this way, a pH-sensitive hydrazone bond was inserted into the backbone of block copolymer, linking hydrophilic poly(ethylene glycol) segment and hydrophobic poly(lactic-co-glycolic acid) segment. The copolymer self-assembled to form stable micelles with mean diameters below 100 nm and served as a drug delivery system for doxorubicin, with drug loading content of 5.3%. pH sensitivity of the hydrazone-containing micelles was investigated by changes in diameter and size distribution observed by dynamic light scattering measurements when the micelles were encountered to acidic medium. Small pieces and larger aggregates were found by transmission electron microscopy resulting from the disassociation of the micelles in acidic conditions. It was also noted that doxorubicin release from the pH-sensitive micelles is significantly faster at pH 4.0 and pH 5.0 compared to pH 7.4, while almost no difference was detected in the case of pH non-sensitive micelles. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays on HepG-2 and MCF-7 cells revealed that doxorubicin-loaded pH-sensitive micelles had higher antitumor activity than pH-insensitive ones. This pH-sensitive drug delivery system based on hydrazonecontaining block copolymer has been proved as a promising drug formulation for cancer therapy.
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