pH-Responsive Nanosuspension Based on an Orthoester for Synergistic Chemodynamic and Photothermal Therapy in Localized Cancer Treatment

This study aims to develop a pH-responsive nanosuspension for localized cancer therapy by integrating photothermal therapy (PTT) and chemodynamic therapy (CDT). Initially, we synthesized a compound containing two five-membered cyclic orthoester bonds (OE) as a liquid pharmaceutical excipient. This OE was subsequently coloaded with the photothermal agent indocyanine green (ICG) and iron oxide nanoparticles (Fe₃O₄), forming a stable nanosuspension (OE/ICG/Fe₃O₄). OE exhibits acid-sensitive degradation, enabling controlled drug release in the tumor microenvironment. The Fe₃O₄ nanoparticles can induce the generation of reactive oxygen species (ROS) through the Fenton reaction, which synergizes effectively with the photothermal effect of ICG. Additionally, the OE/ICG/Fe₃O₄ formulation prolongs drug retention in tumor tissues and enhances drug penetration. Furthermore, the formulation induces immune modulation via Fe₃O₄, thereby enhancing the overall therapeutic efficacy. Under 808 nm near-infrared laser irradiation, a tumor suppression rate of 84.6% was achieved through the combination of photothermal and chemodynamic therapies and immunotherapy. This study highlights the potential of OE-based nanosuspensions for localized cancer treatment, offering a multifunctional strategy to improve treatment outcomes while minimizing systemic toxicity.