A Carbon‐Caged Rhodamine Generating Nitrosoperoxycarbonate for Photoimmunotherapy

Abstract

Photoimmunotherapy is a promising cancer treatment modality. While potent 1‐e‐ oxidative species are known to induce immunogenic cell death (ICD), they are also associated with unspecific oxidation and collateral tissue damage. This difficulty may be addressed by post‐generation radical reinforcement. Namely, non‐oxidative radicals are first generated and subsequently activated into powerful oxidative radicals to induce ICD. Here, we developed a photo‐triggered molecular donor (NPCD565) of nitrosoperoxycarbonate (ONOOCO2‐), the first of its class to our knowledge, and further evaluated its feasibility for immunotherapy. Upon irradiation of NPCD565 by light within a broad spectral region from ultraviolet to red, ONOOCO2‐ is released along with a bright rhodamine dye (RD565), whose fluorescence is a reliable and convenient build‐in reporter for the localization, kinetics, and dose of ONOOCO2‐ generation. Upon photolysis of NPCD565 in 4T1 cells, damage‐associated molecular patterns (DAMPs) indicative of ICD were observed and confirmed to exhibit immunogenicity by induced maturation of dendritic cells. In vivo studies with a bilateral tumor‐bearing mouse model showcased the potent tumor‐killing capability of NPCD565 of the primary tumors and growth suppression of the distant tumors. This work unveils the potent immunogenicity of ONOOCO2‐, and its donor (NPCD565) has broad potential for photo‐immunotherapy of cancer.