Hypoxia alleviating platinum(IV)/chlorin e6-based combination chemotherapeutic-photodynamic nanomedicine for oropharyngeal carcinoma

Hypoxia is an important pathological hallmark of the tumor microenvironment, associated with metabolic alterations, cell proliferation, aggressiveness, metastasis, and therapy resistance in cancers. Hypoxia impedes the outcome of photodynamic therapy (PDT), which is largely dependent on molecular oxygen to generate cytotoxic 1O2. Here, a near-infrared light activatable, oxygen-generating nanomicellar PDT-chemotherapy system (mPPCPN Ms) constituted of amphiphilic mPEG-PLA, photosensitizer Ce6, and tetravalent platinum prodrug Pt(IV)-diazide was developed for oral squamous cell carcinoma. The polymer conjugate self-assemble to nanosize (115 ± 2.35 nm) micelles, which, upon irradiation (660 nm laser), activated Ce6, and photodecomposed to produce cytotoxic Pt(II), azidyl radical, and molecular oxygen. The strategically fabricated PDT-chemotherapy produced a strong antitumor response in vitro using oral squamous cell carcinoma and in vivo in oral cancer-xenografted mouse models, revealing its significant potential in chemo-photodynamic combination therapy with the benefit of reversing hypoxia.