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Overcoming Doxorubicin Resistance with Lipid-Polymer Hybrid Nanoparticles Photoreleasing Nitric Oxide.

This contribution reports the use of tailored lipid-polymer hybrid nanoparticles (NPs) delivering nitric oxide (NO) under visible light stimuli, for overcoming Doxorubicin (DOX) resistance. The NPs consist of a polymeric core and a coating. They are appropri-ately designed to entrap, respectively, DOX in the poly(lactide-co-glycolide) core and a NO photodonor (NOPD) in the phospho-lipid shell, to avoid their mutual interaction both in the ground as well as in the excited state. The typical red fluorescence of DOX, useful for its tracking in cells, is well preserved upon incorporation within the NPs, and it is not affected by the co-presence of the NOPD. The NPs scaffold enhances the NO photoreleasing efficiency of the entrapped NOPD when compared with the free compound, and the co-presence of DOX does not significantly affect such enhanced photochemical performance. Besides, the de-livery of DOX and NOPD from NPs is also not mutually influenced. Experiments carried out in M14 DOX-resistant melanoma cells demonstrate that NO release from the multi-cargo NPs can be finely-tuned by visible light stimuli, at doses that are not toxic to cells but that inhibit several efflux pumps which are mainly responsible for the efflux of DOX. This results in an increased cellu-lar retention of DOX with a consequent enhancement of its antitumor activity. This approach, in principle, is not dependent on the type of chemotherapeutic used and may pave the way for new treatment modalities based on the photoregulated release of NO to overcome multidrug resistance phenomena and improve cancer chemotherapies.