Introduction

Chronic kidney disease (CKD) affects approximately 13% of the world’s population and will lead to dialysis or kidney transplantation. Unfortunately, clinically available drugs for CKD show limited efficacy and toxic extrarenal side effects. Hence, there is a need to develop targeted delivery systems with enhanced kidney specificity that can also be combined with a patient-compliant administration route for such patients that need extended treatment. Towards this goal, kidney-targeted nanoparticles administered through transdermal microneedles (KNP/MN) is explored in this study.

Methods

A KNP/MN patch was developed by incorporating folate-conjugated micelle nanoparticles into polyvinyl alcohol MN patches. Rhodamine B (RhB) was encapsulated into KNP as a model drug and evaluated for biocompatibility and binding with human renal epithelial cells. For MN, skin penetration efficiency was assessed using a Parafilm model, and penetration was imaged via scanning electron microscopy. In vivo, KNP/MN patches were applied on the backs of C57BL/6 wild type mice and biodistribution, organ morphology, and kidney function assessed.

Results

KNP showed high biocompatibility and folate-dependent binding in vitro, validating KNP’s targeting to folate receptors in vitro. Upon transdermal administration in vivo, KNP/MN patches dissolved within 30 min. At varying time points up to 48 h post-KNP/MN administration, higher accumulation of KNP was found in kidneys compared with MN that consisted of the non-targeting, control-NP. Histological evaluation demonstrated no signs of tissue damage, and kidney function markers, serum blood urea nitrogen and urine creatinine, were found to be within normal ranges, indicating preservation of kidney health.

Conclusions

Our studies show potential of KNP/MN patches as a non-invasive, self-administrable platform to direct therapies to the kidneys.

中文翻译：

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使用可溶性微针透皮递送靶向肾脏的纳米颗粒

 介绍

慢性肾病 (CKD) 影响着世界上大约 13% 的人口，将导致透析或肾移植。不幸的是，临床上可用的 CKD 药物显示出有限的疗效和肾外毒性副作用。因此，需要开发具有增强的肾脏特异性的靶向递送系统，该系统还可以与需要延长治疗的患者的患者依从性给药途径相结合。为了实现这一目标，本研究探索了通过透皮微针（KNP/MN）施用的肾脏靶向纳米颗粒。

 方法

KNP/MN 贴片是通过将叶酸缀合的胶束纳米颗粒掺入聚乙烯醇 MN 贴片中而开发的。将罗丹明 B (RhB) 作为模型药物封装到 KNP 中，并评估其生物相容性以及与人肾上皮细胞的结合。对于 MN，使用封口膜模型评估皮肤渗透效率，并通过扫描电子显微镜对渗透进行成像。在体内，将 KNP/MN 贴片贴在 C57BL/6 野生型小鼠的背部，并评估生物分布、器官形态和肾功能。

 结果

KNP在体外表现出高度的生物相容性和叶酸依赖性结合，验证了 KNP 在体外针对叶酸受体的靶向性。体内透皮给药后，KNP/MN 贴剂在 30 分钟内溶解。在 KNP/MN 给药后 48 小时内的不同时间点，与由非靶向对照 NP 组成的 MN 相比，肾脏中 KNP 的积累量更高。组织学评估显示没有组织损伤的迹象，肾功能标志物、血清血尿素氮和尿肌酐均在正常范围内，表明肾脏健康得以保存。

 结论

我们的研究表明 KNP/MN 贴片作为一种非侵入性、可自我给药的平台来直接治疗肾脏的潜力。