Magalhães Jéssica A, Arruda Denise C, Baptista Maurício S, Tada Dayane B
Nanomaterials and Nanotoxicology Laboratory, Institute of Science and Technology, Federal University of São Paulo (UNIFESP), São Paulo 12231-280, Brazil.
Laboratory of Experimental Cancer Biology, University of Mogi das Cruzes (UMC), São Paulo 08780-911, Brazil.
Nanomaterials (Basel). 2021 Jun 8;11(6):1514. doi: 10.3390/nano11061514.
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, 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.
对光动力疗法（PDT）引发的光损伤产生抗性主要归因于细胞氧化还原防御和修复。如果肿瘤组织在前几次PDT疗程中未被及时清除，就可能形成PDT抗性，从而对治疗效果构成挑战。尽管PDT抗性的机制仍不清楚，但体外试验已证明其可通过PARP损伤修复信号通路形成。因此，抑制聚（腺苷二磷酸（ADP）-核糖）聚合酶（PARP）有可能提高PDT疗效。本研究报道了一种光敏剂亚甲蓝（MB）和PARP抑制剂维利帕尼的控释系统的合成。MB和维利帕尼被共包封在聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒（VMB-NPs）中。获得了纳米颗粒的胶体稳定水悬浮液。平均流体动力学直径为90nm，尺寸分布狭窄，多分散指数（PDI）为0.08。MB和维利帕尼从VMB-NPs中的释放动力学表明，在前6小时内，MB和维利帕尼的初始突释量分别为总量的8.7%和58.3%，在19天内，MB和维利帕尼的延迟释放量分别高达11.3%和70%。VMB-NPs在黑暗中无细胞毒性，但当用含有1.0μM MB和8.3μM维利帕尼的VMB-NPs照射（102 J/cm，660nm）并处理B16F10-Nex2细胞时，细胞活力下降了36%。考虑到即使在低浓度的MB和维利帕尼下也有增强的光活性以及在黑暗中无细胞毒性，MB和维利帕尼的共包封被证明是提高PDT疗效的一种有前景的策略。
