Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
J Control Release. 2022 Jan;341:300-313. doi: 10.1016/j.jconrel.2021.11.029. Epub 2021 Nov 23.
Acute kidney injury (AKI) is characterized by a sudden loss of renal function and is associated with high morbidity and mortality. Tumor suppressor p53 and chemokine receptor CXCR4 were both implicated in the AKI pathology. Here, we report on the development and evaluation of polymeric CXCR4 antagonist (PCX) siRNA carrier for selective delivery to injured kidneys in AKI. Our results show that PCX/siRNA nanoparticles (polyplexes) provide protection against cisplatin injury to tubule cells in vitro when both CXCR4 and p53 are inhibited. The polyplexes selectively accumulate and are retained in the injured kidneys in cisplatin and bilateral ischemia reperfusion injury models of AKI. Treating AKI with the combined CXCR4 inhibition and p53 gene silencing with the PCX/sip53 polyplexes improves kidney function and decreases renal damage. Overall, our results suggest that the PCX/sip53 polyplexes have a significant potential to enhance renal accumulation in AKI and deliver therapeutic siRNA.
急性肾损伤（AKI）的特征是肾功能突然丧失，与高发病率和死亡率相关。肿瘤抑制因子 p53 和趋化因子受体 CXCR4 都与 AKI 病理有关。在这里，我们报告了用于选择性递送至 AKI 中受损肾脏的聚合物 CXCR4 拮抗剂（PCX）siRNA 载体的开发和评估。我们的结果表明，当同时抑制 CXCR4 和 p53 时，PCX/siRNA 纳米颗粒（聚合物）在体外对顺铂损伤的肾小管细胞提供保护。聚合物在顺铂和双侧缺血再灌注损伤 AKI 模型中选择性地积聚并保留在受损的肾脏中。用 PCX/sip53 聚合物联合抑制 CXCR4 和 p53 基因沉默治疗 AKI 可改善肾功能并减少肾损伤。总的来说，我们的结果表明，PCX/sip53 聚合物具有增强 AKI 中肾脏积累和递送治疗性 siRNA 的巨大潜力。
