Abstract
Stimuli-responsive polymeric micelles (PMs) have shown great potential in drug delivery and controlled release in cancer chemotherapy. Herein, inspired by the features of the tumor microenvironment, we developed dual pH/redox-responsive mixed PMs which are self-assembled from two kinds of amphiphilic diblock copolymers (poly(ethylene glycol) methyl ether-b-poly(β-amino esters) (mPEG-b-PAE) and poly(ethylene glycol) methyl ether-grafted disulfide-poly(β-amino esters) (PAE-ss-mPEG)) for anticancer drug delivery and controlled release. The co-micellization of two copolymers is evaluated by measurement of critical micelle concentration (CMC) values at different ratios of the two copolymers. The pH/redox-responsiveness of PMs is thoroughly investigated by measurement of base dissociation constant (pKb) value, particle size, and zeta-potential in different conditions. The PMs can encapsulate doxorubicin (DOX) efficiently, with high drug-loading efficacy. The DOX was released due to the swelling and disassembly of nanoparticles triggered by low pH and high glutathione (GSH) concentrations in tumor cells. The in vitro results demonstrated that drug release rate and cumulative release are obviously dependent on pH values and reducing agents. Furthermore, the cytotoxicity test showed that the mixed PMs have negligible toxicity, whereas the DOX-loaded mixed PMs exhibit high cytotoxicity for HepG2 cells. Therefore, the results demonstrate that the dual pH/redox-responsive PMs self-assembled from PAE-based diblock copolymers could be potential anticancer drug delivery carriers with pH/redox-triggered drug release, and the fabrication of stimuli-responsive mixed PMs could be an efficient strategy for preparation of intelligent drug delivery platform for disease therapy.
Highlights
With the rapid development of nanotechnology, a series of drug delivery systems (DDSs) such as liposomes [1], gels [2], polymeric micelles (PMs) [3,4], and nanoparticles (NPs) [5], etc., have been reported in cancer therapy [6]
Lee’s group developed redox/pH-responsive PMs self-assembled from amphiphilic copolymer poly(β-amino ester)-grafted disulfide methylene oxide poly(ethylene glycol) (PAE-g-DSMPEG), used as anticancer drug carriers in cancer chemotherapy [19]
Blank mixed PMs and DOX-loaded mixed PMs were prepared by the dialysis method
Summary
With the rapid development of nanotechnology, a series of drug delivery systems (DDSs) such as liposomes [1], gels [2], polymeric micelles (PMs) [3,4], and nanoparticles (NPs) [5], etc., have been reported in cancer therapy [6]. PMs, which are self-assembled from amphiphilic copolymers, have shown great potential in anticancer drug-targeted delivery and controlled release due to superior advantages of technical ease, high drug-loading efficacy and biocompatibility, low cytotoxicity, and reduced side-effects [10,11,12]. The cellular glutathione (GSH) levels in solid tumors are much higher (~1000-times) than in normal cells [19,20] Inspired by these specific features in the TME, a series of multi-functional stimuli-responsive PMs have been designed and prepared for drug targeted delivery and controlled release in cancer treatment [21,22,23,24,25]. Lee’s group developed redox/pH-responsive PMs self-assembled from amphiphilic copolymer poly(β-amino ester)-grafted disulfide methylene oxide poly(ethylene glycol) (PAE-g-DSMPEG), used as anticancer drug carriers in cancer chemotherapy [19]. After filtration and lyophilization as aforementioned, the DOX-PMs were obtained and stored at −20 ◦C for further experiments
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