MicroRNA Biogenesis is Enhanced by Liposome-Encapsulated Pin1 Inhibitor in Hepatocellular Carcinoma
MicroRNA Biogenesis is Enhanced by Liposome-Encapsulated Pin1 Inhibitor in Hepatocellular Carcinoma
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脂质体封装的 Pin1 抑制剂可增强肝细胞癌中的 MicroRNA 生物合成
DOI：
10.7150/thno.34588
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发表时间：
2019
期刊：
影响因子：
12.4
通讯作者：
Yong Peng
中科院分区：
文献类型：
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作者：
Dan Sun;Shuangyan Tan;Yanli Xiong;Wenchen Pu;Jiao Li;Wei Wei;Canhua Huang;Yu-Quan Wei;Yong Peng
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Pin 1是HCC治疗的潜在靶点，由于其通过调节miRNA生物合成在HCC发展中起关键作用，并且发现小分子API-1是一种新的特异性Pin 1抑制剂。尽管API-1具有显著的抗HCC活性，但其低水溶性和体内生物利用度限制了其临床应用。为了解决这些问题，我们在此开发了API-1的脂质体制剂以改善API-1递送并增强其抗HCC功效。方法：设计并制备API-1纳米脂质体制剂，命名为API-LP。对优化后的API-LP的平均粒径、多分散性、Zeta电位、包封率和热性能进行了表征。研究了API-LP在体内外的抗肝癌作用及其分子机制。最后，对API-LP的安全性和药动学特性进行了系统评价。结果如下：API-LP具有良好的制剂特性，与游离API-1相比，其体外抑制HCC细胞增殖和迁移的活性增强。机制研究表明，API-LP通过抑制Pin 1活性，随后恢复XPO 5的核质输出，从而上调miRNA的生物合成。由于递送效率增加，API-LP显示出比游离API-1更强的促进miRNA生物合成的能力。重要的是，API-LP在小鼠中显示出比游离API-1更高的全身暴露，而没有明显的毒性，导致异种移植小鼠中增强的肿瘤抑制。结论：API-LP的开发和评估提供了一种有吸引力和安全的抗HCC药物，突出了基于miRNA的人类癌症治疗。
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 in vivo 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. Methods: 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 in vitro and in vivo. Finally, the safety and pharmacokinetic property of API-LP were evaluated systematically. Results: API-LP had good formulation characteristics and exhibited an enhanced in vitro 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. Conclusion: The development and assessment of API-LP provide an attractive and safe anti-HCC agent, highlighting the miRNA-based treatment for human cancers.