A pH-Responsive Controlled Release Platform Based on Honeycomb MnO/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 (hMnO) 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. The hMnO can convert the optical energy of near-infrared (NIR) light into heat for photothermal therapy (PTT). Additionally, the hMnO can be reduced to Mn at low pH and high glutathione (GSH) level, and the produced Mn can further react with HO to generate hydroxyl radicals (·OH) through a Fenton-like reaction for chemodynamic therapy (CDT). ICG can be simultaneously released during the reduction of hMnO, which can catalyze the conversion of oxygen to singlet oxygen (O) upon exposure to NIR light for photodynamic therapy (PDT). Due to the synergistic effects of chemotherapy, PTT, CDT, and PDT, the developed ICG/hMnO/5-FU/CMCS/OHA hydrogels can significantly inhibit the growth of the 4T1 mouse breast cancer cell line.