Light-responsive polyphosphoester nanocarriers for cascade-amplified synergistic photodynamic-chemotherapy of colon cancer

Early-stage colorectal cancer is often asymptomatic, many patients are diagnosed at advanced stages (III-IV) and require systemic therapy, which is frequently compromised by nonspecific biodistribution and severe systemic toxicity. To address these clinical challenges, we developed a biocompatible poly (ethylene glycol)-polyphosphoester (PEG-b-PPE) block copolymer-based nanocarrier for the co-delivery of the photosensitizer chlorin e6 (Ce6) and chemotherapeutic drugs, obtaining a drug-loaded nanomedicine termed S-PCD. Following intravenous administration, S-PCD passively accumulated in tumor, and the encapsulated Ce6 could generate reactive oxygen species (ROS) upon near-infrared light irradiation. The produced ROS further induced an oxidative hydrophilic-hydrophobic transition of the polyphosphoester backbone. This process rapidly destabilized the nanoparticles and triggers the release of the encapsulated chemotherapeutic agents. As a result, the S-PCD system enables an ROS-triggered cascade process leading to synergistic photodynamic-chemotherapy. In vivo studies demonstrated that S-PCD enabled efficient delivery of broad-spectrum anticancer drugs, such as doxorubicin and oxaliplatin, resulting in effective tumor growth inhibition in a CT26 colorectal cancer model. These results indicated that the ROS-responsive polyphosphoester-based nanoplatform represented a versatile and scalable strategy for systemic chemotherapy in colorectal cancer.