A kidney-selective biopolymer for targeted drug delivery
A kidney-selective biopolymer for targeted drug delivery
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DOI：
10.1152/ajprenal.00143.2016
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发表时间：
2017-01-01
影响因子：
4.2
通讯作者：
Chade, Alejandro R.
中科院分区：
文献类型：
--
作者：
Bidwell, Gene L., III;Mahdi, Fakhri;Chade, Alejandro R.
利用肾脏靶向治疗改善药物输送到肾脏是一个有希望但不发达的领域。我们的目标是开发一种针对肾脏特异性药物递送的肾脏靶向结构。弹性蛋白样多肽（ELPs）是一种非免疫原性蛋白载体，可以稳定附着的小分子和肽治疗药物。我们在ELP的nh2末端用一个环，7个氨基酸的肾靶向肽（KTP）修饰，在cooh末端用半胱氨酸残基修饰，用于示踪剂偶联。在大鼠和猪模型中进行了体内药代动力学和生物分布的比较，并利用人肾细胞进行了体外细胞结合研究。在两种动物模型中，KTP-ELP的血浆半衰期都比ELP长，并且在肾脏中积累的水平同样比非靶向ELP高5倍，肾脏中的水平比其他主要器官高15至150倍以上。肾荧光组织学显示近端小管和血管内皮高度积聚KTP-ELP。此外，与盐水处理的对照组相比，高剂量ELP或KTP-ELP输注14天不会影响体重、肾小球滤过率或蛋白尿，也不会引起肾组织损伤。体外实验表明，与未靶向的ELP相比，KTP-ELP与人足细胞、近端小管上皮细胞和肾小球微血管内皮细胞的结合更高。这些结果显示了KTP-ELP的高肾选择性，支持了该结构不是物种特异性的概念，并证明它不会引起急性肾毒性。ELP附着于任何一类治疗药物的可塑性，开启了在未来研究中将ELP技术应用于肾脏疾病靶向治疗的可能性。
Improving drug delivery to the kidney using renal-targeted therapeutics is a promising but underdeveloped area. We aimed to develop a kidney-targeting construct for renal-specific drug delivery. Elastin-like polypeptides (ELPs) are nonimmunogenic protein-based carriers that can stabilize attached small-molecule and peptide therapeutics. We modified ELP at its NH2-terminus with a cyclic, seven-amino acid kidney-targeting peptide (KTP) and at its COOH-terminus with a cysteine residue for tracer conjugation. Comparative in vivo pharmacokinetics and biodistribution in rat and swine models and in vitro cell binding studies using human renal cells were performed. KTP-ELP had a longer plasma half-life than ELP in both animal models and was similarly accumulated in kidneys at levels fivefold higher than untargeted ELP, showing renal levels 15- to over 150-fold higher than in other major organs. Renal fluorescence histology demonstrated high accumulation of KTP-ELP in proximal tubules and vascular endothelium. Furthermore, a 14-day infusion of a high dose of ELP or KTP-ELP did not affect body weight, glomerular filtration rate, or albuminuria, or induce renal tissue damage compared with saline-treated controls. In vitro experiments showed higher binding of KTP-ELP to human podocytes, proximal tubule epithelial, and glomerular microvascular endothelial cells than untargeted ELP. These results show the high renal selectivity of KTP-ELP, support the notion that the construct is not species specific, and demonstrate that it does not induce acute renal toxicity. The plasticity of ELP for attachment of any class of therapeutics unlocks the possibility of applying ELP technology for targeted treatment of renal disease in future studies.