Abstract
The development of resistance against photodamage triggered by photodynamic therapy (PDT) is ascribed mainly to the cellular redox defenses and repair. If the tumor tissue is not promptly eliminated by the first few PDT sessions, PDT-resistance can be favored, challenging the efficacy of the treatment. Although the mechanism of PDT resistance is still unclear, in vitro assays have evidenced that it can be developed through the PARP damage-repair signaling pathway. Therefore, inhibition of poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) has the potential to increase PDT efficacy. This work reports on the synthesis of a controlled release system of a photosensitizer, methylene blue (MB) and a PARP-inhibitor, the veliparib. MB and veliparib were co-encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (VMB-NPs). A colloidal stable aqueous suspension of nanoparticles was obtained. The average hydrodynamic diameter was 90 nm and a narrow size distribution was obtained, with a polydispersity index (PDI) of 0.08. The release kinetics of MB and veliparib from VMB-NPs showed an initial burst of 8.7% and 58.3% release of the total amounts of MB and veliparib respectively, in the first 6 h, and a delayed release of up to 11.3% and 70%, in 19 days, for MB and veliparib, respectively. The VMB-NPs showed no cytotoxicity in the dark but the viability of B16F10-Nex2 cells decreased by 36% when the cells were irradiated (102 J/cm(2), 660 nm) and treated with VMB-NPs containing 1.0 µM of MB and 8.3 µM of veliparib. Considering the increased photoactivity even at low MB and veliparib concentrations and the absence of cytotoxicity in dark, the co-encapsulation of MB and veliparib was shown to be a promising strategy to improve the PDT efficacy.