In Vitro Synergistic Photodynamic, Photothermal, Chemodynamic, and Starvation Therapy Performance of Chlorin e6 Immobilized, Polydopamine-Coated Hollow, Porous Ceria-Based, Hypoxia-Tolerant Nanozymes Carrying a Cascade System

A synergistic therapy agent (STA) with photothermal, photodynamic, chemodynamic, and starvation therapy (PTT, PDT, CDT, and ST) functions was developed. Hollow, mesoporous, and nearly uniform CeO₂ nanoparticles (H-CeO₂ NPs) were synthesized using a staged shape templating sol-gel protocol. Chlorin e6 (Ce6) was adsorbed onto H-CeO₂ NPs, and a thin polydopamine (PDA) layer was formed on Ce6-adsorbed H-CeO₂ NPs. Glucose oxidase (GOx) was bound onto PDA-coated Ce6-adsorbed H-CeO₂ NPs to obtain the targeted STA (H-CeO₂@Ce6@PDA@GOx NPs). A reversible photothermal conversion behavior with the temperature elevations up to 34 °C was observed by NIR laser irradiation at 808 nm. A cascade enzyme system based on immobilized GOx and intrinsic catalase-like activity of H-CeO₂ NPs was rendered on STA for enhancing the effectiveness of PDT by elevation of ROS generation and alleviation of hypoxia in a tumor microenvironment. Glucose-mediated generation of highly toxic hydroxyl radicals (^·OH) was evaluated for CDT. The effectiveness of PDT on glioblastoma T98G cells was markedly enhanced by O₂ generation started by the decomposition of glucose. A similar increase in cell death was also observed when ST and CDT functions were enhanced by photothermal action. The viability of T98G cells decreased to 10.6% by in vitro synergistic action including ST, CDT, PDT, and PTT without using any antitumor agent.