Tumor oxygen microenvironment-tailored electron transfer-type photosensitizers for precise cancer therapy

Abstract

The oxygen level in a tumor typically exhibits complex characteristics, ranging from mild hypoxia to moderate and even severe hypoxia. This poses significant challenges for the efficacy of photodynamic therapy, where oxygen is an essential element. Herein, we propose a novel therapeutic strategy and develop a series of lipid droplet-targeting photosensitive dyes (Ser-TPAs), i.e., in situ synergistic activation of two different electron transfer-type reactions. Based on this strategy, Ser-TPAs can synergistically generate O₂˙⁻ and nitrogen radicals regardless of the oxygen content, which results in a sustained high concentration of strongly oxidizing substances in the lipid droplets of cancer cells. As such, Ser-TPAs exhibited inhibitory activity against tumor growth in vivo, resulting in a significant reduction in tumor volume (V_{experimental group} : V_{control group} ≈ 0.07). This strategy offers a conceptual framework for the design of innovative photosensitive dyes that are suitable for cancer therapy in complex oxygen environments.