Dual cellular stimuli-responsive hydrogel nanocapsules for delivery of anticancer drugs

In this work, we report dual cellular environmental stimuli-responsive hydrogel nanocapsules (HA-NCs) for delivery of an anticancer drug (doxorubicin, DOX). This nanocapsule drug delivery system was specially designed to be triggered by stimuli in intra-cellular environments, specifically high glutathione (GSH) concentration and low pH. Biocompatible hyaluronan was used as the basic nanocapsule shell building material. Chemical modifications were conducted in order to functionalize it; specifically, GSH cleavable crosslinking sites and pH responsive expansion sites were introduced. After passive delivery to tumor sites via an enhanced permeation and retention (EPR) effect and cellular uptake, the nanocapsule shells underwent a swelling/disassembly process due to high GSH concentration (e.g., 10 mM), which induced cleavage of disulfide (S-S) bonds, and low pH (e.g., pH 5), which caused water influx associated with deprotection of the acetal groups. This process enabled rupture of the hydrogel nanocapsules and therefore resulted in release of the encapsulated payloads. This hydrogel nanocapsule system exhibited a great ability to release the vast majority of the encapsulated DOX in tumor cells, as proven by the remarkably (4.7-fold) accelerated drug release rate within tumor cells (pH 5.0, GSH 10 mM), in sharp contrast to the drug release rate under physiological conditions (pH 7.4, GSH 0). In vitro bio-evaluation showed the good biocompatibility of the nanocapsule carriers and their efficient cancer cell growth inhibition activity after drug encapsulation. In vivo studies confirmed that the DOX containing nanocapsules (DOX/HA-NCs) had comparable antitumor efficiency and greatly reduced side effects as compared with free DOX (DOX·HCl).