Near-Infrared Light-Initiated Molecular Superoxide Radical Generator: Rejuvenating Photodynamic Therapy against Hypoxic Tumors

TLDR

Hypoxia is a universal feature of solid tumors that severely limits the efficacy of conventional photodynamic therapy. The authors designed a near‑infrared‑triggered molecular superoxide generator, ENBS‑B, to overcome hypoxia‑induced resistance and evaluate its therapeutic potential in hypoxic tumors. ENBS‑B produces superoxide via type I photoreactions even at 2 % O₂, and the superoxide is further converted to highly toxic hydroxyl radicals through a SOD‑mediated cascade. The generated radicals damage lysosomes, trigger apoptosis, and, owing to biotin‑mediated targeting, ENBS‑B achieves 87‑fold higher cancer‑cell uptake, suppresses tumor growth at low light doses, and demonstrates robust hypoxic‑PDT efficacy, suggesting clinical promise.

Abstract

Hypoxia, a quite universal feature in most solid tumors, has been considered as the "Achilles' heel" of traditional photodynamic therapy (PDT) and substantially impairs the overall therapeutic efficacy. Herein, we develop a near-infrared (NIR) light-triggered molecular superoxide radical (O2-•) generator (ENBS-B) to surmount this intractable issue, also reveal its detailed O2-• action mechanism underlying the antihypoxia effects, and confirm its application for in vivo targeted hypoxic solid tumor ablation. Photomediated radical generation mechanism study shows that, even under severe hypoxic environment (2% O2), ENBS-B can generate considerable O2-• through type I photoreactions, and partial O2-• is transformed to high toxic OH· through SOD-mediated cascade reactions. These radicals synergistically damage the intracellular lysosomes, which subsequently trigger cancer cell apoptosis, presenting a robust hypoxic PDT potency. In vitro coculture model shows that, benefiting from biotin ligand, ENBS-B achieves 87-fold higher cellular uptake in cancer cells than normal cells, offering opportunities for personalized medicine. Following intravenous administration, ENBS-B is able to specifically target to neoplastic tissues and completely suppresses the tumor growth at a low light-dose irradiation. As such, we postulated this work will extend the options of excellent agents for clinical cancer therapy.