Free Adriamycin-Loaded pH/Reduction Dual-Responsive Hyaluronic Acid–Adriamycin Prodrug Micelles for Efficient Cancer Therapy

Currently, tumor-targeted nanocarriers self-assembled from amphiphilic polymer-drug conjugates are of great demand. The appeal of these carriers arises mainly through their excellent loading efficiency of homologous drug molecules with microenvironment-triggered drug release. Herein, doxorubicin (DOX) was constructed to a hyaluronic acid (HA) backbone through hydrazone and disulfide linkages to construct pH and reduction coresponsive prodrug conjugates (HA-ss-DOX). During formulation, the amphipathic HA-ss-DOX spontaneously assembled into distinct core/shell micelles in aqueous media and showed conspicuous physical DOX loading capabilities (29.1%, DOX/HA-ss-DOX) based on homologous compatibility. DOX/HA-ss-DOX micelles were shown to be stable in normal physiological environments, while accomplishing selective, rapid DOX release at acidic pH and/or highly reducing conditions. The efficacy of DOX/HA-ss-DOX micelles was tested on A549 human lung cancer cells, wherein flow cytometry and confocal microscopy analysis revealed their HA receptor-mediated endocytosis mechanism. In comparison, DOX-loaded redox-insensitive micelles (DOX/HA-DOX) still demonstrated pH-dependent drug release. However, a more rapid intracellular DOX release profile was achieved in DOX/HA-ss-DOX micelles because of their sensitivity to both acidic and reducing environments. Resultantly, DOX/HA-ss-DOX exhibited the strongest cytotoxicity and apoptosis-inducing ability among all tested groups when tested on an A549 cell line and xenograft model.