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 CeO(2) nanoparticles (H-CeO(2) NPs) were synthesized using a staged shape templating sol-gel protocol. Chlorin e6 (Ce6) was adsorbed onto H-CeO(2) NPs, and a thin polydopamine (PDA) layer was formed on Ce6-adsorbed H-CeO(2) NPs. Glucose oxidase (GOx) was bound onto PDA-coated Ce6-adsorbed H-CeO(2) NPs to obtain the targeted STA (H-CeO(2)@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-CeO(2) 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 O(2) 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.