Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
Int J Nanomedicine. 2011;6:1661-73. doi: 10.2147/IJN.S22293. Epub 2011 Aug 11.
Small interfering RNA (siRNA) can silence target genes in the cytoplasm and be a major tool in gene therapy. Vascular endothelial growth factor (VEGF), a potent regulator of angiogenesis, is overexpressed in most tumors and is closely associated with tumor growth and metastasis. It has been shown that inhibition of VEGF expression by siRNA is an effective and useful method for antiangiogenic tumor therapy.
In the present study, we synthesized a targeted delivery system of PEI-PEG-APRPG incorporating angiogenic vessel-homing Ala-Pro-Arg-Pro-Gly (APRPG) peptide into cationic polyethylenimine (PEI) via a hydrophilic poly(ethylene glycol) (PEG) spacer.
PEI-PEG-APRPG effectively condensed siRNA into 20-50 nm nanoparticles with a positive surface charge using a suitable N/P ratio. The siRNA/PEI-PEG-APRPG complex effectively enhanced the stability of siRNA in RNase A, and improved the proliferation-inhibiting ability and transfection efficiency of siRNA in vitro and tumor accumulation in vivo. In addition, the siRNA/PEI-PEG-APRPG complex exhibited high efficiency as antitumor therapy with regard to tumor growth, microvessel density, and VEGF protein and mRNA levels.
These findings suggest that PEI-PEG-APRPG effectively delivers siRNA to tumors overexpressing VEGF and thereby inhibits tumor growth.
小干扰 RNA（siRNA）可在细胞质中沉默靶基因，是基因治疗的主要工具。血管内皮生长因子（VEGF）是血管生成的有力调节剂，在大多数肿瘤中过度表达，与肿瘤生长和转移密切相关。研究表明，通过 siRNA 抑制 VEGF 表达是一种有效的抗血管生成肿瘤治疗方法。
在本研究中，我们合成了一种靶向递送系统，将含有血管生成血管靶向 Ala-Pro-Arg-Pro-Gly（APRPG）肽的聚乙二醇（PEG）接枝到阳离子聚乙烯亚胺（PEI）上。
PEI-PEG-APRPG 在合适的 N/P 比下，能有效地将 siRNA 凝聚成 20-50nm 的带有正表面电荷的纳米颗粒。siRNA/PEI-PEG-APRPG 复合物能有效提高 siRNA 在 RNase A 中的稳定性，并提高 siRNA 在体外的增殖抑制能力和转染效率以及体内肿瘤积累。此外，siRNA/PEI-PEG-APRPG 复合物在肿瘤生长、微血管密度以及 VEGF 蛋白和 mRNA 水平方面具有高效的抗肿瘤治疗作用。
这些发现表明，PEI-PEG-APRPG 能有效地将 siRNA 递送到过度表达 VEGF 的肿瘤中，从而抑制肿瘤生长。
