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

Abstract

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 (ΔΨ_m) 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.