Acute kidney injury (AKI) increases the risk of in-hospital death, adds to expense of care, and risk of early chronic kidney disease. AKI often follows an acute event such that timely treatment could ameliorate AKI and potentially reduce the risk of additional disease. Despite therapeutic success of dexamethasone in animal models, clinical trials have not demonstrated broad success. To improve the safety and efficacy of dexamethasone for AKI, we developed and characterized a novel, kidney-specific nanoparticle enabling specific within-kidney targeting to proximal tubular epithelial cells provided by the megalin ligand cilastatin. Cilastatin and dexamethasone were complexed to H-Dot nanoparticles, which were constructed from generally recognized as safe components. Cilastatin/Dexamethasone/H-Dot nanotherapeutics were found to be stable at plasma pH and demonstrated salutary release kinetics at urine pH. , they were specifically biodistributed to the kidney and bladder, with 75% recovery in the urine and with reduced systemic toxicity compared to native dexamethasone. Cilastatin complexation conferred proximal tubular epithelial cell specificity within the kidney and enabled dexamethasone delivery to the proximal tubular epithelial cell nucleus . The Cilastatin/Dexamethasone/H-Dot nanotherapeutic improved kidney function and reduced kidney cellular injury when administered to male C57BL/6 mice in two translational models of AKI (rhabdomyolysis and bilateral ischemia reperfusion). Thus, our design-based targeting and therapeutic loading of a kidney-specific nanoparticle resulted in preservation of the efficacy of dexamethasone, combined with reduced off-target disposition and toxic effects. Hence, our study illustrates a potential strategy to target AKI and other diseases of the kidney.

中文翻译：

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纳米治疗肾细胞特异性靶向治疗，以改善急性肾损伤


急性肾损伤 （AKI） 会增加院内死亡的风险，增加护理费用，并增加早期慢性肾病的风险。AKI 通常发生在急性事件之后，因此及时治疗可以改善 AKI 并可能降低其他疾病的风险。尽管地塞米松在动物模型中的治疗取得了成功，但临床试验并未显示出广泛的成功。为了提高地塞米松治疗 AKI 的安全性和有效性，我们开发并表征了一种新型的肾脏特异性纳米颗粒，能够特异性地在肾内靶向由 megalin 配体 cilastatin 提供的近端肾小管上皮细胞。西司他丁和地塞米松与 H-Dot 纳米颗粒复合，H-Dot 纳米颗粒由公认的安全成分构成。发现西司他丁/地塞米松/H-Dot 纳米治疗药物在血浆 pH 值下稳定，并在尿液 pH 值下显示出有益的释放动力学。，它们专门生物分布于肾脏和膀胱，与天然地塞米松相比，尿液中回收率为 75%，全身毒性降低。Cilastatin 复合物赋予肾脏内近端肾小管上皮细胞特异性，并使地塞米松能够递送至近端肾小管上皮细胞核。西司他丁/地塞米松/H-Dot 纳米疗法在两种 AKI 翻译模型 （横纹肌溶解和双侧缺血再灌注） 中对雄性 C57BL/6 小鼠给药时，改善了肾功能并减少了肾细胞损伤。因此，我们基于设计的肾脏特异性纳米颗粒的靶向和治疗负载导致保留了地塞米松的疗效，同时减少了脱靶处置和毒性作用。 因此，我们的研究说明了一种针对 AKI 和其他肾脏疾病的潜在策略。