Mitochondrial Targeted Doxorubicin-Triphenylphosphonium Delivered by Hyaluronic Acid Modified and pH Responsive Nanocarriers to Breast Tumor: <i>in Vitro</i> and <i>in Vivo</i> Studies

Multidrug resistance (MDR) is the major obstacle for chemotherapy. In a previous study, we have successfully synthesized a novel doxorubicin (DOX) derivative modified by triphenylphosphonium (TPP) to realize mitochondrial delivery of DOX and showed the potential of this compound to overcome DOX resistance in MDA-MB-435/DOX cells. To introduce specificity for DOX-TPP to cancer cells, here we report on the conjugation of DOX-TPP to hyaluronic acid (HA) by hydrazone bond with adipic acid dihydrazide (ADH) as the acid-responsive linker, producing HA-<i>hydra</i>-DOX-TPP nanoparticles. Hyaluronic acid (HA) is a natural water-soluble linear glycosaminoglycan, which was hypothesized to increase the accumulation of nanoparticles containing DOX-TPP in the mitochondria of tumor cells upon systemic administration, overcoming DOX resistance, <i>in vivo</i>. Our results showed HA-<i>hydra</i>-DOX-TPP to self-assemble to core/shell nanoparticles of good dispersibility and effective release of DOX-TPP from the HA-<i>hydra</i>-DOX-TPP conjugate in cancer cells, which was followed by enhanced DOX mitochondria accumulation. The HA-<i>hydra</i>-DOX-TPP nanoparticles also showed improved anticancer effects, better tumor cell apoptosis, and better safety profile compared to free DOX in MCF-7/ADR bearing mice