Molecularly Self-Engineered Nanoamplifier for Boosting Photodynamic Therapy via Cascade Oxygen Elevation and Lipid ROS Accumulation

Abstract

Photodynamic therapy (PDT) has been extensively explored as a noninvasive cancer treatment modality. However, the dilemma of tumor hypoxia and short half-life of singlet oxygen (¹O₂) severely restrict the therapeutic efficacy of PDT. Herein, we develop a facile three-in-one PDT nanoamplifier (AA@PPa/Hemin NPs) assembled by pyropheophorbide a (PPa), hemin, and arachidonic acid (AA). Interestingly, AA not only acts as an enabler to facilitate the assembly of PPa and hemin in the construction of ternary hybrid nanoassemblies but also acts as a lipid reactive oxygen species (ROS) amplifier for robust PDT. In tumor cells, hemin plays the role of a catalase-like catalyst that accelerates the production of oxygen (O₂) from hydrogen peroxide (H₂O₂), significantly alleviating tumor hypoxia. Under laser irradiation, vast amounts of ¹O₂ generated by PPa trigger the peroxidation of AA to produce large amounts of cytotoxic lipid ROS, immensely amplifying the efficiency of PDT by promptly eliciting cellular oxidative stress. As expected, AA@PPa/Hemin NPs exert potent antitumor activity in a 4T1 breast-tumor-bearing BALB/c mice xenograft model. Such a cascade nanohybrid amplifier provides a novel codelivery platform for accurate and effective PDT of cancer.

Keywords: cascade nanoamplifier; cytotoxic lipid ROS; hypoxia alleviation; molecularly self-engineered; photodynamic therapy.