Department of Pediatrics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310006 China.
Department of Chemistry, Imperial College London, London, UK.
Int J Nanomedicine. 2018 Jun 19;13:3507-3527. doi: 10.2147/IJN.S166445. eCollection 2018.
Diabetic nephropathy (DN) is the primary root of morbidity and mortality in diabetic patients. Unfortunately, currently, no effective therapeutic strategies are available to ameliorate and reverse the progression of DN. Rhein (RH) is an anthraquinone derivative extracted from herbal medicines with various pharmacological effects on DN. However, its clinical administration is limited by its poor solubility, low bioavailability, reduced distribution into the kidney and adverse effects.
To improve the delivery of RH into kidney and the therapeutic effect on DN, we synthesized and utilized polyethyleneglycol--polycaprolactone--polyethylenimine triblock amphiphilic polymers to prepare RH-loaded polyethyleneglycol--polycaprolactone--polyethylenimine nanoparticles (PPP-RH-NPs). PPP-RH-NP size was optimized to 75 ± 25 nm for kidney-targeted drug delivery; the positive zeta potential allowed an effective cellular uptake and the polyethylenimine amine groups facilitate the endosomal escape quickly. The distribution and pharmacodynamics of PPP-RH-NPs were studied in a streptozocin-induced DN model, which explicitly demonstrated kidney-targeted distribution and improved the therapeutic effects of RH on DN by ameliorating several pathological indicators.
Therefore, this study not only stimulates further clinical research on RH but also, more importantly, proposes a promising DN therapy consisting of an effective kidney-targeted drug delivery.
糖尿病肾病（DN）是糖尿病患者发病率和死亡率的主要根源。不幸的是，目前尚无有效的治疗策略来改善和逆转 DN 的进展。大黄酸（RH）是从草药中提取的蒽醌衍生物，对 DN 具有多种药理作用。然而，其临床应用受到其溶解度差、生物利用度低、在肾脏中的分布减少和不良反应的限制。
为了提高 RH 向肾脏的传递和对 DN 的治疗效果，我们合成并利用聚乙二醇-聚己内酯-聚亚乙基亚胺三嵌段两亲聚合物制备 RH 负载的聚乙二醇-聚己内酯-聚亚乙基亚胺纳米粒（PPP-RH-NPs）。将 PPP-RH-NP 的尺寸优化为 75±25nm，以实现肾脏靶向药物传递；正的 ζ 电位允许有效的细胞摄取，并且聚亚乙基亚胺的胺基有助于快速进行内体逃逸。在链脲佐菌素诱导的 DN 模型中研究了 PPP-RH-NPs 的分布和药效学，明确表明 PPP-RH-NPs 具有肾脏靶向分布，并通过改善几种病理指标来提高 RH 对 DN 的治疗效果。
因此，本研究不仅激发了对 RH 的进一步临床研究，而且更重要的是提出了一种有前途的 DN 治疗方法，包括有效的肾脏靶向药物传递。
