Dual pH/Redox-Responsive Mixed Polymeric Micelles for Anticancer Drug Delivery and Controlled Release

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.

Stimulus-Responsive Nanomedicines for Disease Diagnosis and Treatment

“…With low pH and high GSH levels in tumor cells, a strong controlled release effect can be achieved. Recently, pH/redox-responsive mixed polymeric micelles formed by self-assembly of two amphiphilic diblock copolymers (poly(ethylene glycol) methyl ether-b-poly(β-amino ester)) (mPEG-b-PAE) and poly(ethylene glycol) methyl ether-grafted disulfide bond-poly(β-amino ester) (PAE-ss-mPEG) have been developed, which released drugs at low pH and high GSH concentration in tumor cells [ 211 ]. In addition, there are also many combinations, such as pH/ROS responsive system [ 212 , 213 ], pH/enzyme responsive system [ 214 , 215 ] and others.…”

pH-Sensitive Mixed Micelles Assembled from PDEAEMA-PPEGMA and PCL-PPEGMA for Doxorubicin Delivery: Experimental and DPD Simulations Study

“…Furthermore, as a promising and effective drug delivery vehicle, nanoscopic polymeric micelles should also have the ability to remain stable in normal tissues and release the majority of the loaded drug into the diseased tissues in a well-controlled manner. Consequently, more and more attention has been paid to stimuli-responsive nanocarriers in the last few years [10][11][12][13]. Thereinto, it is confirmed that the pH-sensitive amphiphilic polymers micelles have smart abilities in drug-controlled release, which can change their conformation upon pH variation easily, thus offering a targeted and controlled method for the delivery of wrapped drugs [14,15].…”

Docetaxel-Loaded Disulfide Cross-Linked Nanoparticles Derived from Thiolated Sodium Alginate for Colon Cancer Drug Delivery

“…Disulfide bond-containing polymers promptly degrade in cancer cells and release drug at intended site due to the reducing environment of cancer cells. The concentration of glutathione (GSH) was higher in cancerous cells than that in normal cells, providing an intracellular reductive environment for the polymer [17][18][19]. Therefore, nanocarriers derived from disulfide bond-containing polymers are stable in normal cells, in which the drug will not leak from the nanocarriers along the route to the targeted site, thus reducing the toxicity and side effects of drug to the normal cells.…”