Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
J Control Release. 2011 Jan 5;149(1):51-7. doi: 10.1016/j.jconrel.2010.02.002. Epub 2010 Feb 6.
Disulfide crosslinked polyplex micelles with RGD peptides were formed through ion complexation of thiolated c(RGDfK)-poly(ethylene glycol)-block-poly(L-lysine) (c(RGDfK)-PEG-P(Lys-SH)) and plasmid DNA encoding sFlt-1 and tested for their therapeutic effect in BxPC3 pancreatic adenocarcinoma tumor bearing mice. These micelles, systemically injected, demonstrated significant inhibition of tumor growth up to day 18, as a result of the antiangiogenic effect that was confirmed by vascular density measurements. Significant therapeutic activity of the 15% crosslinked micelle (c(RGDfK)-PEG-P(Lys-SH15)) was achieved by combined effect of increased tumor accumulation, interaction with endothelial cells and enhanced intracellular uptake through receptor-mediated endocytosis. These results suggest that RGD targeted crosslinked polyplex micelles can be effective plasmid DNA carriers for antiangiogenic gene therapy.
巯基化的 c(RGDfK)-聚乙二醇-嵌段-聚（L-赖氨酸）（c(RGDfK)-PEG-P(Lys-SH)）和编码 sFlt-1 的质粒 DNA 通过离子复合形成了带有 RGD 肽的二硫键交联的聚合物胶束，并在携带 BxPC3 胰腺腺癌肿瘤的小鼠中测试了它们的治疗效果。这些胶束经系统注射后，由于血管密度测量证实的抗血管生成作用，在第 18 天之前显著抑制了肿瘤生长。15%交联胶束（c(RGDfK)-PEG-P(Lys-SH15)）的显著治疗活性是通过增加肿瘤积累、与内皮细胞相互作用以及通过受体介导的内吞作用增强细胞内摄取的综合作用实现的。这些结果表明，RGD 靶向交联聚合物胶束可以成为用于抗血管生成基因治疗的有效质粒 DNA 载体。
