Multifunctional mixed micelles loaded with doxorubicin for enhanced photodynamic-chemo cancer therapy

Combined use of photodynamic therapy (PDT) and chemotherapeutic drugs has attracted extensive attention. The solubility of hydrophobic photosensitizers, the lack of accumulation and the release problem of chemotherapeutic drugs have limited its application. Herein, we designed a multifunctional mixed micelles loaded with doxorubicin (DOX) to solve aforementioned problems. Hyaluronic acid (HA) and hypoxia-responsive nitroimidazole (NI) was bonded to form HA-NI polymers. D-alpha tocopherol polyethylene glycol 1000 succinate (TPGS) and Chlorin e6 (Ce6) was connected to obtain TPGS-Ce6 polymers. Then, HA-NI and TPGS-Ce6 could be selfassembled obtaining mixed micelles and encapsulate DOX. TPGS could increase the water solubility of Ce6, HA could interact specifically with CD44 receptors endowing the mixed micelles the ability to target tumor cells. Upon laser irradiation, Ce6 was activated and generated reactive oxygen species (ROS) to kill cancer cells. Moreover, under hypoxic conditions, overexpression of nitroreductase could decrease nitroimidazole (NI) by depleting glutathione (GSH) and thioredoxin (Trx) - the frontline defenses against ROS-induced oxidative stress during photodynamic therapy. This resulted in swift cargo release and increased effectiveness. In addition, TPGS could also induce additional ROS production. This work highlights the role of multifunctional mixed micelles for active target capability, triggered drug release and enhanced antitumor PDT efficacy.