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脂质体包裹的 Pin1 抑制剂增强肝癌中的 microRNA 生成。

MicroRNA Biogenesis is Enhanced by Liposome-Encapsulated Pin1 Inhibitor in Hepatocellular Carcinoma.

机构信息

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.

Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China.

出版信息

Theranostics. 2019 Jul 9;9(16):4704-4716. doi: 10.7150/thno.34588. eCollection 2019.

DOI:10.7150/thno.34588
PMID:31367251
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6643437/
Abstract

Hepatocellular carcinoma (HCC) is in an urgent need of new, effective therapies to reduce morbidity and mortality. We have previously demonstrated that peptidyl-prolyl cis/trans isomerase Pin1 is a potential target for HCC therapy, due to its pivotal role in HCC development through regulating miRNA biogenesis, and discovered the small molecule API-1 as a novel and specific Pin1 inhibitor. Despite its significant anti-HCC activity, the low water solubility and bioavailability of API-1 limit its clinical application. To address these issues, we herein developed a liposomal formulation of API-1 to improve API-1 delivery and enhance its anti-HCC efficacy. : We designed and developed a nanoscale liposomal formulation of API-1, named as API-LP. Subsequently, the mean diameter, polydispersity, zeta potential, encapsulation efficiency and thermal properties of the optimization API-LP were characterized. The enhanced anti-HCC activity and the molecular mechanism of API-LP were investigated both and . Finally, the safety and pharmacokinetic property of API-LP were evaluated systematically. : API-LP had good formulation characteristics and exhibited an enhanced activity of suppressing proliferation and migration of HCC cells when compared with free API-1. The mechanism study showed that API-LP upregulated miRNA biogenesis via inhibiting Pin1 activity followed by restoring the nucleus-to-cytoplasm export of XPO5. Because of the increased delivery efficiency, API-LP displayed a stronger ability to promote miRNA biogenesis than free API-1. Importantly, API-LP displayed higher systemic exposure than free API-1 in mice without apparent toxicity, resulting in an enhanced tumor inhibition in xenograft mice. : The development and assessment of API-LP provide an attractive and safe anti-HCC agent, highlighting the miRNA-based treatment for human cancers.

摘要

肝细胞癌 (HCC) 迫切需要新的、有效的治疗方法来降低发病率和死亡率。我们之前已经证明，肽基脯氨酰顺/反异构酶 Pin1 是 HCC 治疗的一个潜在靶点，因为它通过调节 miRNA 生物发生在 HCC 发展中起关键作用，并发现小分子 API-1 是一种新的、特异性的 Pin1 抑制剂。尽管 API-1 具有显著的抗 HCC 活性，但它的低水溶性和生物利用度限制了其临床应用。为了解决这些问题，我们开发了一种 API-1 的脂质体剂型，以改善 API-1 的递送并增强其抗 HCC 疗效。

我们设计并开发了一种名为 API-LP 的 API-1 的纳米级脂质体剂型。随后，对优化后的 API-LP 的平均粒径、多分散性、Zeta 电位、包封效率和热性能进行了表征。通过体内外实验研究了 API-LP 的增强抗 HCC 活性及其分子机制。最后，系统评价了 API-LP 的安全性和药代动力学特性。

API-LP 具有良好的剂型特征，与游离 API-1 相比，显示出更强的抑制 HCC 细胞增殖和迁移的活性。机制研究表明，API-LP 通过抑制 Pin1 活性，上调 miRNA 生物发生，随后恢复 XPO5 的核质输出。由于递送效率的提高，API-LP 比游离 API-1 具有更强的促进 miRNA 生物发生的能力。重要的是，API-LP 在小鼠中显示出比游离 API-1 更高的系统暴露量，而没有明显的毒性，导致异种移植小鼠的肿瘤抑制作用增强。

API-LP 的开发和评估为 HCC 提供了一种有吸引力和安全的治疗药物，强调了基于 miRNA 的人类癌症治疗方法。

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