A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy.
A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy.
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一种形成自载氧化还原响应伏立诺他纳米药物的简便途径，用于有效的实体瘤治疗
DOI：
10.2147/ijn.s118727
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发表时间：
2016
影响因子：
8
通讯作者：
Zhang N
中科院分区：
文献类型：
--
作者：
Han L;Wang T;Wu J;Yin X;Fang H;Zhang N
具有主要由小分子组成的纳米颗粒（NPs）的基于小分子的纳米药物由于其独特的性质而被认为是下一代纳米药物的有希望的候选者。伏立诺他（SAHA）是美国食品和药物管理局批准的用于治疗皮肤T细胞淋巴瘤的组蛋白脱乙酰酶（HDAC）抑制剂。然而，缺乏对实体瘤的疗效阻碍了其在临床应用中的进展。本文以二硫键连接的前药SAHA-S-S-VE为基础，开发了一种新型的SAHA纳米药物。SAHA-S-S-VE可以通过二硫键诱导的机制自组装成148 nm的纳米粒子，分子动力学模拟验证了这一点。在还原条件下，研究了SAHA-S-S-VE的氧化还原响应行为，HDAC抑制结果证实了游离SAHA的有效释放。SAHA-S-S-VE/TPGS纳米粒具有良好的生物相容性，其临界聚集浓度为4.5 μM，体外稳定性好，载药量为24%。体外生物学活性评价表明，SAHA-S-S-VE/TPGS纳米粒对HepG 2细胞具有显著的抗癌活性。进一步的体内评价表明，所得的NPs可以在肿瘤区域积聚并有效地抑制肿瘤生长。这种方法将SAHA转化为自组装的氧化还原响应性纳米药物，为HDAC抑制剂在实体瘤治疗中的应用提供了新的渠道。
Small molecule-based nanodrugs with nanoparticles (NPs) that are mainly composed of small molecules, have been considered as a promising candidate for a next-generation nanodrug, owing to their unique properties. Vorinostat (SAHA) is a canonical US Food and Drug Administration-approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma. However, the lack of efficacy against solid tumors hinders its progress in clinical use. Herein, a novel nanodrug of SAHA was developed based on disulfide-linked prodrug SAHA-S-S-VE. SAHA-S-S-VE could self-assemble into 148 nm NPs by disulfide-induced mechanisms, which were validated by molecular dynamics simulations. Under reduced conditions, the redox-responsive behavior of SAHA-S-S-VE was investigated, and the HDAC inhibition results verified the efficient release of free SAHA. With a biocompatible d-a-tocopheryl polyethylene glycol succinate (TPGS) functionalization, the SAHA-S-S-VE/TPGS NPs exhibited low critical aggregation concentration of 4.5 μM and outstanding stability in vitro with drug-loading capacity of 24%. In vitro biological assessment indicated that SAHA-S-S-VE/TPGS NPs had significant anticancer activity against HepG2. Further in vivo evaluation demonstrated that the resulting NPs could be accumulated in the tumor region and inhibit the tumor growth effectively. This approach, which turned SAHA into a self-assembled redox-responsive nanodrug, provided a new channel for the use of HDAC inhibitor in solid tumor therapy.