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首页> 美国卫生研究院文献>International Journal of Nanomedicine >A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy
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A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

机译：形成自携式氧化还原反应性伏立诺他纳米药物的有效途径，可用于有效的实体瘤治疗

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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.
机译：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，由于其独特的性能，已被认为是下一代纳米药物的有希望的候选者。伏立诺他（SAHA）是美国食品药品监督管理局批准的典型组蛋白脱乙酰基酶（HDAC）抑制剂，用于治疗皮肤T细胞淋巴瘤。然而，缺乏针对实体瘤的功效阻碍了其在临床应用中的进展。在此，基于二硫键连接的前药SAHA-S-S-VE，开发了新型的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 NP，并通过分子动力学模拟进行了验证。在减少的条件下，研究了SAHA-S-S-VE的氧化还原响应行为，并且HDAC抑制结果证实了游离SAHA的有效释放。通过具有生物相容性的d-α-生育酚聚乙二醇琥珀酸酯（TPGS）功能化，SAHA-S-S-VE / TPGS NPs的临界聚集浓度低至4.5μM，在体外具有出色的稳定性，载药量为24％。体外生物学评估表明，SAHA-S-S-VE / TPGS NP对HepG2具有显着的抗癌活性。进一步的体内评价表明，所产生的NP可以积累在肿瘤区域中并有效地抑制肿瘤的生长。该方法将SAHA转变为自组装的氧化还原反应性纳米药物，为在实体瘤治疗中使用HDAC抑制剂提供了新渠道。

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