Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, 35100, Bornova, Izmir, Turkey.
Department of Biotechnology, Graduate School of Science, Ege University, 35100, Bornova, Izmir, Turkey.
Mol Biotechnol. 2019 Jul;61(7):489-497. doi: 10.1007/s12033-019-00178-2.
Escape from apoptosis, one of the characteristic features of cancer cells, is a case that reduces the therapeutic efficacy of apoptosis-inducing molecules used in the cancer treatment. Stabilization of the P53 protein, which is responsible for the regulation of apoptosis mechanism in the cell, is therefore an important therapeutic goal. Nutlin3a inhibits the degradation of the P53 protein, triggers P53-mediated apoptosis in cancer cells and enhances the effectiveness of chemotherapeutics. However, its low aqueous solubility is the major disadvantage when it comes to in vivo administration. In order to facilitate an aqueous formulation of Nutlin3a and to enhance its apoptotic activity on cancer cells, Nutlin3a was encapsulated in solid lipid nanoparticles (SLNs) prepared by Ouzo method. Physicochemical characterization was performed and activity of apoptosis induction on wild-type P53 expressing LNCaP prostate cancer cell line was evaluated. Nutlin3a-loaded cationic solid lipid nanoparticles were found to stabilize functional P53 at protein level. In addition, induction rate of apoptosis by nanoparticles was higher than Nutlin3a solution in DMSO, proving this nanoparticle formulation is a promising candidate for increasing the efficiency of Nutlin3a for P53(+) cancer cases. Thus, it is anticipated that the results will contribute to evaluate the use of lipid-based nanocarriers to enhance the therapeutic potential of small molecules that are important in cancer cure.
逃避细胞凋亡是癌细胞的特征之一，这会降低用于癌症治疗的诱导细胞凋亡分子的治疗效果。因此，稳定负责调节细胞凋亡机制的 P53 蛋白是一个重要的治疗目标。Nutlin3a 抑制 P53 蛋白的降解，在癌细胞中引发 P53 介导的细胞凋亡，并增强化疗药物的有效性。然而，其低水溶性是体内给药的主要缺点。为了便于 Nutlin3a 的水性配方，并增强其对癌细胞的凋亡活性，将 Nutlin3a 包封在通过 Ouzo 方法制备的固体脂质纳米粒 (SLN) 中。进行了理化特性表征，并评估了对表达野生型 P53 的 LNCaP 前列腺癌细胞系的细胞凋亡诱导活性。发现负载 Nutlin3a 的阳离子固体脂质纳米粒在蛋白质水平上稳定了功能性 P53。此外，纳米粒制剂诱导细胞凋亡的比率高于 DMSO 中的 Nutlin3a 溶液，证明这种纳米粒制剂是提高 P53(+)癌症情况下 Nutlin3a 效率的有前途的候选物。因此，可以预期这些结果将有助于评估使用基于脂质的纳米载体来增强在癌症治疗中重要的小分子的治疗潜力。
