Department of Pharmacology and Toxicology, Philipps-University School of Medicine, D-35032 Marburg, Germany.
J Gene Med. 2010 Mar;12(3):287-300. doi: 10.1002/jgm.1431.
RNA interference is a powerful method for the knockdown of pathologically relevant genes. The in vivo delivery of siRNAs, preferably through systemic, nonviral administration, poses the major challenge in the therapeutic application of RNAi. Small interfering RNA (siRNA) complexation with polyethylenimines (PEI) may represent a promising strategy for siRNA-based therapies and, recently, the novel branched PEI F25-LMW has been introduced in vitro. Vascular endothelial growth factor (VEGF) is frequently overexpressed in tumors and promotes tumor growth, angiogenesis and metastasis and thus represents an attractive target gene in tumor therapy.
In subcutaneous tumor xenograft mouse models, we established the therapeutic efficacy and safety of PEI F25-LMW/siRNA-mediated knockdown of VEGF. In biodistribution and siRNA quantification studies, we optimized administration strategies and, employing chemically modified siRNAs, compared the anti-tumorigenic efficacies of: (i) PEI/siRNA-mediated VEGF targeting; (ii) treatment with the monoclonal anti-VEGF antibody Bevacizumab (Avastin); and (iii) a combination of both.
Efficient siRNA delivery is observed upon systemic administration, with the biodistribution being dependent on the mode of injection. Toxicity studies reveal no hepatotoxicity, proinflammatory cytokine induction or other side-effects of PEI F25-LMW/siRNA complexes or polyethylenimine, and tumor analyses show efficient VEGF knockdown upon siRNA delivery, leading to reduced tumor cell proliferation and angiogenesis. The determination of anti-tumor effects reveals that, in pancreas carcinoma xenografts, single treatment with PEI/siRNA complexes or Bevacizumab is already highly efficacious, whereas, in prostate carcinoma, synergistic effects of both treatments are observed.
PEI F25-LMW/siRNA complexes, which can be stored frozen as opposed to many other carriers, represent an efficient, safe and promising avenue in anti-tumor therapy, and PEI/siRNA-mediated, therapeutic VEGF knockdown exerts anti-tumor effects.
RNA 干扰是一种强大的病理性相关基因敲低方法。siRNA 的体内递送，最好通过全身非病毒给药，是 RNAi 治疗应用中的主要挑战。小干扰 RNA（siRNA）与聚乙烯亚胺（PEI）的复合物可能是 siRNA 治疗的一种有前途的策略，最近，新型支化 PEI F25-LMW 在体外得到了介绍。血管内皮生长因子（VEGF）在肿瘤中经常过表达，并促进肿瘤生长、血管生成和转移，因此是肿瘤治疗中有吸引力的靶基因。
在皮下肿瘤异种移植小鼠模型中，我们建立了 PEI F25-LMW/siRNA 介导的 VEGF 敲低的治疗效果和安全性。在生物分布和 siRNA 定量研究中，我们优化了给药策略，并使用化学修饰的 siRNA，比较了以下三种治疗方法的抗肿瘤效果：（i）PEI/siRNA 介导的 VEGF 靶向；（ii）贝伐单抗（阿瓦斯汀）单克隆抗 VEGF 抗体治疗；（iii）两者的联合治疗。
系统给药时观察到有效的 siRNA 递释，其生物分布取决于注射方式。毒性研究显示，PEI F25-LMW/siRNA 复合物或聚乙烯亚胺没有肝毒性、促炎细胞因子诱导或其他副作用，肿瘤分析显示 siRNA 递送后 VEGF 有效敲低，导致肿瘤细胞增殖和血管生成减少。抗肿瘤效果的测定表明，在胰腺癌细胞异种移植中，单独使用 PEI/siRNA 复合物或贝伐单抗已经非常有效，而在前列腺癌细胞异种移植中，两种治疗方法的联合治疗具有协同作用。
PEI F25-LMW/siRNA 复合物可以冷冻储存，与许多其他载体不同，是一种高效、安全且有前途的抗肿瘤治疗方法，PEI/siRNA 介导的治疗性 VEGF 敲低具有抗肿瘤作用。
