Department of Internal Medicine, National Taiwan University Hospital Hsinchu Biomedical Park Branch, Zhu Bei City 302, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu City 30059, Taiwan.
Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Chemical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.
J Control Release. 2022 Jun;346:169-179. doi: 10.1016/j.jconrel.2022.04.004. Epub 2022 Apr 23.
Fibrosis is an excessive accumulation of the extracellular matrix within solid organs in response to injury and a common pathway that leads functional failure. No clinically approved agent is available to reverse or even prevent this process. Herein, we report a nanotechnology-based approach that utilizes a drug carrier to deliver a therapeutic cargo specifically to fibrotic kidneys, thereby improving the antifibrotic effect of the drug and reducing systemic toxicity. We first adopted in vitro-in vivo combinatorial phage display technology to identify peptide ligands that target myofibroblasts in mouse unilateral ureteral obstruction (UUO)-induced fibrotic kidneys. We then engineered lipid-coated poly(lactic-co-glycolic acid) nanoparticles (NPs) with fibrotic kidney-homing peptides on the surface and sorafenib, a potent antineoplastic multikinase inhibitor, encapsulated in the core. Sorafenib loaded in the myofibroblast-targeted NPs significantly reduced the infiltration of α-smooth muscle actin-expressing myofibroblasts and deposition of collagen I in UUO-treated kidneys and enhanced renal plasma flow measured by Technetium-99m mercaptoacetyltriglycine scintigraphy. This study demonstrates the therapeutic potential of the newly identified peptide fragments as anchors to target myofibroblasts and represents a strategic advance for selective delivery of sorafenib to treat renal fibrosis. SIGNIFICANCE STATEMENT: Renal fibrosis is a pathological feature accounting for the majority of issues in chronic kidney disease (CKD), which may progress to end-stage renal disease (ESRD). This manuscript describes a myofibroblast-targeting drug delivery system modified with phage-displayed fibrotic kidney-homing peptides. By loading the myofibroblast-targeting nanoparticles (NPs) with sorafenib, a multikinase inhibitor, the NPs could suppress collagen synthesis in cultured human myofibroblasts. When given intravenously to mice with UUO-induced renal fibrosis, sorafenib loaded in myofibroblast-targeting NPs significantly ameliorated renal fibrosis. This approach provides an efficient therapeutic option to renal fibrosis. The myofibroblast-targeting peptide ligands and nanoscale drug carriers may be translated into clinical application in the future.
纤维化是固体器官在受伤后细胞外基质的过度积累，是导致功能衰竭的常见途径。目前尚无临床批准的药物可逆转甚至预防这一过程。在此，我们报告了一种基于纳米技术的方法，该方法利用药物载体将治疗性货物专门递送到纤维化的肾脏，从而提高药物的抗纤维化效果并降低系统毒性。我们首先采用体外-体内组合噬菌体展示技术鉴定靶向小鼠单侧输尿管梗阻（UUO）诱导的纤维化肾脏中的肌成纤维细胞的肽配体。然后，我们在表面工程化带有纤维化肾脏归巢肽的脂质包覆的聚（乳酸-共-乙醇酸）纳米颗粒（NPs），并将索拉非尼，一种有效的抗肿瘤多激酶抑制剂，封装在核心中。负载在肌成纤维细胞靶向 NPs 中的索拉非尼可显著减少 UUO 处理肾脏中表达α-平滑肌肌动蛋白的肌成纤维细胞的浸润和胶原 I 的沉积，并增强 Technetium-99m 巯基乙酰三甘氨酸闪烁扫描测量的肾血浆流量。这项研究表明，新鉴定的肽片段作为靶向肌成纤维细胞的锚定点具有治疗潜力，并代表了将索拉非尼选择性递送到治疗肾纤维化的战略进展。意义陈述：肾纤维化是导致慢性肾脏病（CKD）大多数问题的病理特征，其可能进展为终末期肾病（ESRD）。本文描述了一种用噬菌体展示的纤维化肾脏归巢肽修饰的肌成纤维细胞靶向药物传递系统。通过将肌成纤维细胞靶向纳米颗粒（NPs）负载索拉非尼，一种多激酶抑制剂，NPs 可以抑制培养的人肌成纤维细胞中的胶原合成。当静脉给予 UUO 诱导的肾纤维化小鼠时，负载在肌成纤维细胞靶向 NPs 中的索拉非尼可显著改善肾纤维化。这种方法为肾纤维化提供了有效的治疗选择。肌成纤维细胞靶向肽配体和纳米级药物载体可能在未来转化为临床应用。
