A pH-Responsive Controlled Release Platform Based on Honeycomb MnO₂/Carboxymethyl Chitosan/Oxidized Hyaluronic Acid...

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 MnO₂ (hMnO₂) 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/hMnO₂. The hMnO₂ can convert the optical energy of near-infrared (NIR) light into heat for photothermal therapy (PTT). Additionally, the hMnO₂ can be reduced to Mn²⁺ at low pH and high glutathione (GSH) level, and the produced Mn²⁺ can further react with H₂O₂ to generate hydroxyl radicals (·OH) through a Fenton-like reaction for chemodynamic therapy (CDT). ICG can be simultaneously released during the reduction of hMnO₂, which can catalyze the conversion of oxygen to singlet oxygen (¹O₂) upon exposure to NIR light for photodynamic therapy (PDT). Due to the synergistic effects of chemotherapy, PTT, CDT, and PDT, the developed ICG/hMnO₂/5-FU/CMCS/OHA hydrogels can significantly inhibit the growth of the 4T1 mouse breast cancer cell line.