Integrin αvβ3, which is selectively targeted by cyclic arginine-glycine-aspartic acid (cRGD) peptides, is significantly upregulated in tumors. Previous studies showed that small interfering RNA (siRNA) modified with cRGD (cRGD-siRNA) could significantly inhibit tumor growth through RNAi with oncogene expression. However, cRGD-siRNA is partially reabsorbed and trapped in the kidneys, causing renal injury in an unpredictable manner. This study aimed to investigate the influence of Gelofusine on tubulointerstitial injury induced by cRGD-siRNA in vitro and in vivo. The effect of Gelofusine on the distribution of cRGD-siRNA in tumor-bearing nude mice and wild-type mice was also explored. We found that Gelofusine inhibited apoptosis and activation of the innate immune response of human tubular epithelial cells induced by cRGD-siRNA in vitro. In addition, co-injection of Gelofusine efficiently reduced renal retention of cRGD-siRNA without affecting its tumor targeting in vivo. Further in vivo studies indicated that Gelofusine significantly attenuated tubulointerstitial injury induced by cRGD-siRNA through regulating Toll-like receptor 3 (TLR3)-mediated activation of the nuclear factor κ B (NF-κB) and caspase-3 apoptotic pathway. In conclusion, Gelofusine, acting as a novel and effective renal protective agent, could form a compound preparation with siRNA drugs for future clinical applications.

被环状精氨酸-甘氨酸-天冬氨酸（cRGD）肽选择性靶向的整联蛋白αvβ3在肿瘤中显着上调。先前的研究表明，用cRGD（cRGD-siRNA）修饰的小干扰RNA（siRNA）可以通过具有癌基因表达的RNAi显着抑制肿瘤的生长。然而，cRGD-siRNA被部分重吸收并截留在肾脏中，以无法预测的方式引起肾脏损伤。这项研究旨在探讨明珠丝杉碱对cRGD-siRNA诱导的体外和体内肾小管间质损伤的影响。还研究了明矾碱对荷瘤裸鼠和野生型小鼠中cRGD-siRNA分布的影响。我们发现Gelofusine在体外可抑制cRGD-siRNA诱导的人肾小管上皮细胞凋亡并激活其固有的免疫反应。此外，共注射明洛芙碱可有效降低cRGD-siRNA的肾脏保留，而不会影响其体内肿瘤靶向性。进一步体内研究表明，通过调节Toll样受体3（TLR3）介导的核因子κB（NF-κB）和caspase-3凋亡途径的活化，明洛史滨显着减轻了cRGD-siRNA引起的肾小管间质损伤。综上所述，作为新的有效肾脏保护剂的Gelofusine可以与siRNA药物形成复合制剂，以用于未来的临床应用。