Improved\nControl of Triple-Negative Breast Cancer\nTumor and Metastasis with a pH-Sensitive Hyaluronic Acid Nanocarrier\nfor Doxorubicin Delivery

Polymer based nanoformulations offer\nsubstantial prospects\nfor\nefficacious chemotherapy delivery. Here, we developed a pH-responsive\npolymeric nanoparticle based on acidosis-triggered breakdown of boronic\nester linkers. A biocompatible hyaluronic acid (HA) matrix served\nas a substrate for carrying a doxorubicin (DOX) prodrug which also\npossesses natural affinity for CD44<sup>+</sup> cells. DOX was functionalized\nwith a boronic acid group, which was covalently linked with the HA\npolymer, resulting in a stable chemical linker at neutral pH. Under\nacidic conditions, the boronic ester linker is degraded, dissociating\nDOX. Compared to free DOX, the DOX HA NPs exhibited preferential accumulation\nin 4T1 cells. In a BALB/c mouse model, DOX HA NPs improved antitumor\nactivity, dramatically improved control of lung metastases, and ultimately\nled to enhanced survival. The pH-sensitive HA nanocarriers provide\na promising approach to enhance therapeutic outcomes and reduce toxicity\nin chemotherapy.