Conquering the Hypoxia Limitation for Photodynamic Therapy

Photodynamic therapy (PDT) has aroused great research interest in recent years owing to its high spatiotemporal selectivity, minimal invasiveness, and low systemic toxicity. However, due to the hypoxic nature characteristic of many solid tumors, PDT is frequently limited in therapeutic effect. Moreover, the consumption of O₂ during PDT may further aggravate the tumor hypoxic condition, which promotes tumor proliferation, metastasis, and invasion resulting in poor prognosis of treatment. Therefore, numerous efforts have been made to increase the O₂ content in tumor with the goal of enhancing PDT efficacy. Herein, these strategies developed in past decade are comprehensively reviewed to alleviate tumor hypoxia, including 1) delivering exogenous O₂ to tumor directly, 2) generating O₂ in situ, 3) reducing tumor cellular O₂ consumption by inhibiting respiration, 4) regulating the TME, (e.g., normalizing tumor vasculature or disrupting tumor extracellular matrix), and 5) inhibiting the hypoxia-inducible factor 1 (HIF-1) signaling pathway to relieve tumor hypoxia. Additionally, the O₂ -independent Type-I PDT is also discussed as an alternative strategy. By reviewing recent progress, it is hoped that this review will provide innovative perspectives in new nanomaterials designed to combat hypoxia and avoid the associated limitation of PDT.