Near-infrared light switching nitric oxide nanoemitter for triple-combination therapy of multidrug resistant cancer.

The multidrug resistance (MDR) of tumor cells often leads to the failure of chemotherapy against cancer. It is urgently needed to develop a safe and effective strategy of overcoming MDR for enhancing chemotherapy efficiency. In this work, one type of new folic acid-polyethylene glycol (FA-PEG) modified polydopamine nanoparticles (FAPPs) was synthesized for gas/chemo/photothermal triple-combination therapy of multidrug resistant cancer. The nanoparticles loaded nitric oxide (NO) donor act as a NO nanoemitter to generate NO via a NIR light irradiation switch, which has a great capacity of reversing MDR via inhibiting the overexpression of P-glycoprotein (P-gp) and cell respiration with the reduction of both the adenosine triphosphate (ATP) content and mitochondrial membrane potential (ΔΨm) in MDR tumor cells. Moreover, the amount of generated NO can be regulated by changing the action time of the nanoparticles. After that, the nanoparticles loaded chemotherapeutic agent (DOX) act as a photothermal-chemotherapy nanomedicine, which can release DOX with a high concentration in tumor cell for chemotherapy and simultaneously produce a large amount of heat for photothermal therapy under NIR irradiation. Finally, the gas/chemo/photothermal triple-combination therapy with the nanomedicines displays an excellent therapeutic efficacy in nude mice bearing MDR tumors. STATEMENT OF SIGNIFICANCE: The multidrug resistance (MDR) of tumor cells frequently leads to the failure of chemotherapy against cancer. It is urgently needed to develop a safe and effective strategy of overcoming MDR for enhancing chemotherapy efficiency. In this paper, a NIR light switching nitric oxide nanoemitter is successfully developed for gas/chemo/photothermal triple-combination therapy of multidrug resistant cancer. The controllably generated NO under NIR irradiation can effectively reverse multidrug resistance by inhibiting the overexpression of P-gp and cell respiration, significantly enhancing the chemotherapeutic agent concentration in tumor cells, and simultaneously a large amount of heat is produced for photothermal therapy.