Cyclo-RGD Truncated Polymeric Nanoconstruct with Dendrimeric Templates for Targeted HDAC4 Gene Silencing in a Diabetic Nephropathy Mouse Model,Molecular Pharmaceutics

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Cyclo-RGD Truncated Polymeric Nanoconstruct with Dendrimeric Templates for Targeted HDAC4 Gene Silencing in a Diabetic Nephropathy Mouse Model
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-05-26 , DOI: 10.1021/acs.molpharmaceut.0c00094
Nidhi Raval ₁ , Hardi Jogi ₁ , Piyush Gondaliya ₁ , Kiran Kalia ₁ , Rakesh K Tekade ₁

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Diabetic nephropathy (DN), a chronic progressive kidney disease, is a significant complication of diabetes mellitus. Dysregulation of the histone deacetylases (HDACs) gene has been implicated in the pathogenesis of DN. Hence, the HDAC-inhibitors have emerged as a critical class of therapeutic agents in DN; however, the currently available HDAC4-inhibitors are mostly nonselective in nature as well as inhibit multiple HDACs. RNA interference of HDAC4 (HDAC4 siRNA) has shown immense promise, but the clinical translation has been impeded due to lack of a targeted, specific, and in vivo applicable delivery modality. In the present investigation, we examined Cyclo(RGDfC) (cRGD) truncated polymeric nanoplex with dendrimeric templates for targeted HDAC4 Gene Silencing. The developed nanoplex exhibited enhanced encapsulation of siRNA and offered superior protection against serum RNase nucleases degradation. The nanoplex was tested on podocytes (in vitro), wherein it showed selective binding to the αvβ3 integrin receptor, active cellular uptake, and significant in vitro gene silencing. The in vivo experiments showed remarkable suppression of the HDAC4 and inhibition in the progression of renal fibrosis in the Streptozotocin (STZ) induced DN C57BL/6 mice model. Histopathological and toxicological studies revealed nonsignificant abnormality/toxicity with the nanoplex. Conclusively, nanoplex was found as a promising tactic for targeted therapy of podocytes and could be extended for other kidney-related ailments.

中文翻译：

在糖尿病肾病小鼠模型中用于靶向 HDAC4 基因沉默的带有树枝状模板的 Cyclo-RGD 截短聚合物纳米结构

糖尿病肾病 (DN) 是一种慢性进行性肾脏疾病，是糖尿病的重要并发症。组蛋白去乙酰化酶 (HDAC) 基因的失调与 DN 的发病机制有关。因此，HDAC 抑制剂已成为 DN 中一类重要的治疗剂。然而，目前可用的 HDAC4 抑制剂本质上大多是非选择性的，并且会抑制多种 HDAC。HDAC4 (HDAC4 siRNA) 的 RNA 干扰显示出巨大的前景，但由于缺乏靶向、特异性和体内适用的交付方式。在本研究中，我们检查了 Cyclo(RGDfC) (cRGD) 截短的聚合物纳米复合物和树枝状模板，用于靶向 HDAC4 基因沉默。开发的纳米复合物表现出增强的 siRNA 封装，并提供了对血清 RNase 核酸酶降解的卓越保护。纳米复合物在足细胞（体外）上进行了测试，其中它显示出与 αvβ3 整联蛋白受体的选择性结合、活跃的细胞摄取和显着的体外基因沉默。在体内实验表明，在链脲佐菌素 (STZ) 诱导的 DN C57BL/6 小鼠模型中，HDAC4 的显着抑制和肾纤维化进展的抑制作用。组织病理学和毒理学研究揭示了纳米复合物的非显着异常/毒性。最后，发现纳米复合物是一种很有前途的足细胞靶向治疗策略，可以扩展到其他肾脏相关疾病。

更新日期：2020-05-26

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