Oxygen-independent combined photothermal/photodynamic therapy delivered by tumor acidity-responsive polymeric micelles

Tumor hypoxia strikingly restricts photodynamic therapy (PDT) efficacy and limits its clinical applications in cancer therapy. The ideal strategy to address this issue is to develop oxygen-independent PDT systems. Herein, the rationally designed tumor pH-responsive polymeric micelles are devised to realize oxygen-independent combined PDT and photothermal therapy (PTT) under near-infrared light (NIR) irradiation. The triblock copolymer, poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-(piperidin-1-yl)ethyl methacrylate) (PEG-b-PCL-b- PPEMA), was prepared to co-encapsulate cypate and singlet oxygen donor (diphenylanthracene endoperoxide, DPAE) via self-assembly to obtain the micellar delivery system (C/O@N-Micelle). C/O@N-Micelle showed remarkable tumor accumulation and improved cellular internalization (2.1 times) as the pH value was changed from 7.4 during blood circulation to 6.8 in tumor tissues. The micelles could produce a potent hyperthermia for PTT of cypate under 808 nm NIR irradiation, which simultaneously induced thermal cycloreversion of DPAE generating abundant singlet oxygen for PDT without participation of tumor oxygen. Finally, the photothermally triggered PDT and PTT combination achieved efficient tumor ablation without remarkable systemic toxicity in an oxygen-independent manner. This work represents an efficient strategy for oxygen-independent combined PDT and PTT of cancers under NIR irradiation through co-encapsulation of cypate and DPAE into tumor pH-responsive polymeric micelles.