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

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.