Yoshio Funahashi, Seung Hun Park, Jessica F Hebert, Mahaba B Eiwaz, Adam C Munhall, Tahnee Groat, Lingxue Zeng, Jonghan Kim, Hak Soo Choi, Michael P Hutchens
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引用次数: 0
摘要
急性肾损伤(AKI)会增加院内死亡风险、增加护理费用和早期慢性肾病的风险。急性肾损伤通常发生在急性事件之后,因此及时治疗可改善急性肾损伤,并有可能降低其他疾病的风险。尽管地塞米松在动物模型中取得了治疗效果,但临床试验并未取得广泛成功。为了提高地塞米松治疗 AKI 的安全性和疗效,我们开发并鉴定了一种新型肾脏特异性纳米粒子,通过巨球蛋白配体西司他丁实现肾脏内对近端肾小管上皮细胞的特异性靶向。Cilastatin和地塞米松与H-Dot纳米粒子复合,H-Dot纳米粒子由公认安全的成分制成。研究发现,西司他丁(Cilastatin)/地塞米松(Dexamethasone)/H-Dot 纳米治疗药物在血浆 pH 值下稳定,在尿液 pH 值下表现出有益的释放动力学。在体内,它们被特异性地生物分布到肾脏和膀胱,在尿液中的回收率为 75%,与原生地塞米松相比,全身毒性降低。Cilastatin 复合物在体内赋予肾脏近端肾小管上皮细胞特异性,在体外使地塞米松输送到近端肾小管上皮细胞核。雄性 C57BL/6 小鼠在两种急性肾损伤转化模型(横纹肌溶解和双侧缺血再灌注)中接受西司他丁/地塞米松/H-Dot 纳米治疗后,肾功能得到改善,肾细胞损伤也有所减轻。因此,我们设计的肾脏特异性纳米粒子的靶向性和治疗负载既保留了地塞米松的疗效,又减少了脱靶处置和毒性效应。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。
Nanotherapeutic kidney cell-specific targeting to ameliorate acute kidney injury.
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. In vivo, 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 in vivo and enabled dexamethasone delivery to the proximal tubular epithelial cell nucleus in vitro. 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.
期刊介绍:
Kidney International (KI), the official journal of the International Society of Nephrology, is led by Dr. Pierre Ronco (Paris, France) and stands as one of nephrology's most cited and esteemed publications worldwide.
KI provides exceptional benefits for both readers and authors, featuring highly cited original articles, focused reviews, cutting-edge imaging techniques, and lively discussions on controversial topics.
The journal is dedicated to kidney research, serving researchers, clinical investigators, and practicing nephrologists.