Redox-sensitive hyaluronic acid–paclitaxel conjugate micelles with high physical drug loading for efficient tumor therapy

Abstract

The design of targeted nanosized micelles self-assembled from polymer–drug conjugates which exhibit conspicuous physical drug-loading based on excellent hydrophobic compatibility as well as sufficient release of encapsulated drugs in targeted areas remains a benchmark for drug delivery systems. Herein, our 41.8% drug loaded redox-sensitive micelles exhibit not only significantly improved drug-loading capacities, but also sufficient drug release. Based on a hyaluronic acid–disulfide–paclitaxel (HA–ss–PTX) conjugate, these core–shell structural redox-sensitive micelles mediate the reduction-triggered release of PTX (chemically conjugated ones plus physically encapsulated ones) into the tumor intracellular matrix. The redox-sensitivity is verified by morphological changes of micelles alongside in vitro release profiles within simulated reducing environments. Flow cytometry, confocal microscopy analysis and cytotoxicity assays indicate that HA–ss–PTX micelles exhibit selective tumor uptake via HA-receptor mediated endocytosis. Through the disassembly of the redox-sensitive micelles, PTX is rapidly released into the cytoplasm, inducing enhanced cytotoxicity and apoptosis against MDA-MB-231 cells. In vivo investigations on tumor-bearing mice further confirm that PTX-loaded HA–ss–PTX micelles possess much higher tumor-targeting capacity over non-sensitive controls and exhibit enhanced anti-tumor efficacy with minimal collateral damage. All the results indicate that a redox-sensitive HA–ss–PTX micelle is a promising PTX intracellular delivery carrier for efficient tumor therapy.