A pH-Responsive Controlled Release Platform Based on Honeycomb MnO 2 /Carboxymethyl Chitosan/Oxidized Hyaluronic Acid for Multimodal Therapy of Breast Cancer

To enhance the therapeutic efficacy of breast cancer, multimodal therapy with the aid of a pH-responsive controlled release platform is proposed in this work. Indocyanine green (ICG) is loaded in honeycomb MnO 2 (hMnO 2 ) synthesized by a template method, which is coencapsulated with 5-fluorouracil (5-FU) in the hydrogels cross-linked between carboxymethyl chitosan (CMCS) and oxidized hyaluronic acid (OHA). The imine linkage (−HC═N−) between CMCS and OHA is hydrolyzed under weakly acidic conditions, leading to the release of 5-FU for chemotherapy and ICG/hMnO 2 . The hMnO 2 can convert the optical energy of near-infrared (NIR) light into heat for photothermal therapy (PTT). Additionally, the hMnO 2 can be reduced to Mn 2+ at low pH and high glutathione (GSH) level, and the produced Mn 2+ can further react with H 2 O 2 to generate hydroxyl radicals (·OH) through a Fenton-like reaction for chemodynamic therapy (CDT). ICG can be simultaneously released during the reduction of hMnO 2, which can catalyze the conversion of oxygen to singlet oxygen ( 1 O 2 ) upon exposure to NIR light for photodynamic therapy (PDT). Due to the synergistic effects of chemotherapy, PTT, CDT, and PDT, the developed ICG/hMnO 2 /5-FU/CMCS/OHA hydrogels can significantly inhibit the growth of the 4T1 mouse breast cancer cell line.