Department of Clinical Vascular Regeneration, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan.
Mol Pharm. 2010 Apr 5;7(2):501-9. doi: 10.1021/mp9002317.
In this study, a polyplex micelle was developed as a potential formulation for antiangiogenic gene therapy of subcutaneous pancreatic tumor model. Poly(ethylene glycol)-poly(l-lysine) block copolymers (PEG-PLys) with thiol groups in the side chain of the PLys segment were synthesized and applied for preparation of disulfide cross-linked polyplex micelles through ion complexation with plasmid DNA (pDNA) encoding the soluble form of vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), which is a potent antiangiogenic molecule. Antitumor activity and gene expression of polyplex micelles with various cross-linking rates were evaluated in mice bearing subcutaneously xenografted BxPC3 cell line, derived from human pancreatic adenocarcinoma, and polyplex micelles with optimal cross-linking rate achieved effective suppression of tumor growth. Significant gene expression of this micelle was detected selectively in tumor tissue, and its antiangiogenic effect was confirmed by decreased vascular density inside the tumor. Therefore, the disulfide cross-linked polyplex micelle loading sFlt-1 pDNA has a great potential for antiangiogenic therapy against subcutaneous pancreatic tumor model by systemic application.
在这项研究中，开发了一种多聚物胶束作为用于皮下胰腺肿瘤模型的抗血管生成基因治疗的潜在制剂。聚（乙二醇）-聚（L-赖氨酸）嵌段共聚物（PEG-PLys）在 PLys 段的侧链中具有巯基，通过与编码可溶性形式血管内皮生长因子（VEGF）受体-1（sFlt-1）的质粒 DNA（pDNA）进行离子复合，应用于制备二硫键交联的多聚物胶束，sFlt-1 是一种有效的抗血管生成分子。在携带皮下异种移植的 BxPC3 细胞系（源自人胰腺腺癌）的小鼠中，评估了具有不同交联率的多聚物胶束的抗肿瘤活性和基因表达，具有最佳交联率的多聚物胶束可有效抑制肿瘤生长。该胶束的基因表达在肿瘤组织中被选择性检测到，其抗血管生成作用通过肿瘤内血管密度的降低得到证实。因此，通过全身应用，负载 sFlt-1 pDNA 的二硫键交联多聚物胶束具有用于皮下胰腺肿瘤模型的抗血管生成治疗的巨大潜力。
