Physical Dissolution Combined with Photodynamic Depletion: A Two-Pronged Nanoapproach for Deoxygenation-Driven and Hypoxia-Activated Prodrug Therapy

Hypoxia may enhance the chemoresistance of cancer cells and can significantly compromise the effectiveness of chemotherapy. Many efforts have been made to relieve or reverse hypoxia by introducing more oxygen into the tumor microenvironment (TME). Acting in a diametrically opposite way, in the current study, a novel nanocarrier was designed to further exhaust the oxygen level of the hypoxic TME. By creating such an oxygen depleted TME, the hypoxia-selective cytotoxin can work effectively, and oxygen exhaustion triggered chemotherapy can be achieved. Herein, deoxygenation agent, FDA-approved perfluorocarbon (PFC) and photosensitizer indocyanine green (ICG) for oxygen depletion, along with the hypoxia-activating drug tirapazamine (TPZ), were coincorporated within the poly(lactic-co-glycolic acid) (PLGA) nanoemulsion (ICG/TPZ@PPs) for the treatment of hypoxic tumors. Following hypoxia amplifying through physical oxygen dissolution and photodynamic depletion in tumors, hypoxic chemotherapy could be effectively activated to improve multitreatment synergy. After achieving local tumor enrichment, PFC-mediated oxygen dissolution combined with further ICG-mediated photodynamic therapy (PDT) under near-infrared (NIR) laser irradiation could induce enhanced hypoxia, which would activate the antitumor activity of codelivered TPZ to synergize cytotoxicity. Remarkably, in vivo experimental results exhibited that deoxygenated ICG/TPZ@PPs-based photothermal therapy (PTT), PDT, and hypoxia activated chemotherapy have an excellent synergistic ablation of tumors without obvious side effects, and therefore, a broad prospect of application of this nanocarrier could be expected.