Oxygen-Abundant and pH/NIR Dual-Responsive Nanocarriers for Tumor Hypoxia Reduction Therapy

Pre-existing tumor hypoxia and oxygen consumption by photodynamic therapy (PDT) always generate an inadequate oxygen supply, which often contributes to other therapy resistance, especially for aerobic treatments such as chemotherapy. In order to overcome this problem, we synthesized a chitosan (CS)-capped pH-/NIR-dual responsive and perfluorocarbon-based oxygen self-enriching photodynamic therapy nanosystem which could codeliver oxygen, photosensitizer, and chemotherapeutic drug. Simultaneously, in vitro results revealed that DOX release was stimulated by the acidic pH value with CS as a pH-responsive layer and rising temperature caused by the photothermal effect with an 808 nm laser, which could effectively reduce the nonspecific toxicity caused by premature drug release. Furthermore, due to the higher oxygen-carrying capability of perfluorocarbon, the decreased expression of the hypoxia-inducible factor-1α (HIF-1α) of tumors, as well as the significantly intense photodynamic effect and longer singlet (1O2) lifetime of the loaded photosensitizer, the elevated cytotoxicity was improved. More importantly, both in vitro and in vivo results showed that drug-loaded nanoparticles with oxygen-abundant properties achieved a similar anticancer therapy in both normoxic and hypoxic conditions against the difficulty led by deficient oxygen, as well as a good cellular internalization. Summarily, all these results pointed out that such a pH-/NIR-dual responsive drug carrier could enhance the synergetic anticancer therapy of chemotherapy and PDT by alleviation of tumor hypoxia, which provided a tempting controllable and multifunctional therapeutic application.