RGD-POLYMER TARGETING PLASMID TO ANGIOGENIC ENDOTHELIUM

描述（由申请人提供）。摘要在目前的应用中，合成并表征了PEI-PEG-RGD靶向基因载体。将构建的编码sFllt-1的质粒转染到血管生成的真皮微血管内皮细胞。体内研究表明，该递送系统携带表达的sFlt-1可延缓肿瘤生长，提高动物存活率。因此，PEI-PEG-RGD/pCMV- sFlt-1复合物可用于开发肿瘤特异性抗血管生成基因治疗。此外，构建了IL-2与sFlk-1质粒的组合。体外和体内研究表明其具有良好的抗肿瘤活性。在这个更新申请中，我们建议递送siRNA来沉默VEGF和VEGF受体。RGD将与可还原的聚合物聚（CBA-DAH）偶联，聚（CBA-DAH）已知是无毒的，并大大增强了几种细胞系的转染。我们还将合成rgd - choll - r9c，因为choll - r9c具有高siRNA转染能力。此外，RGD- peg -水溶性脂聚合物（WSLP）将被设计，因为WSLP在本实验室已被证明是一种优秀的载体。广泛的体外和体内动物研究将用这些rgd共轭聚合物与siRNA络合进行。抑制小鼠前列腺和乳腺腺癌模型的肿瘤生长将在结果中得到证实。所获得的数据可用于设计siRNA递送以治疗癌症患者。

DESCRIPTION (provided by applicant). PROJECT SUMMARY ABSTRACT In the current application, PEI-PEG-RGD targeted gene carrier was synthesized and characterized. The constructed plasmid encoding sFllt-1 was carried to angiogenic dermal microvascular endothelial cells. The in vivo studies demonstrated that expressed sFlt-1 carried by this delivery system delayed tumor growth and increased survival rate of animal. Therefore, PEI-PEG-RGD/pCMV- sFlt-1 complex can be useful to develop tumor specific anti-angiogenic gene therapy. In addition, combination of IL-2 and sFlk-1 plasmid was constructed. The in vitro and in vivo studies demonstrated excellent efficiency of anti-tumor activity. In this renewal application, we propose to deliver siRNA for silencing VEGF and VEGF receptors. RGD will be conjugated to the reducible polymer, poly (CBA-DAH), which is known to be non-toxic and greatly enhances transfection in several cell lines. RGD-chol-R9C will also be synthesized, since chol-R9C has demonstrated high transfection of siRNA. In addition, RGD- PEG-water soluble lipopolymer (WSLP) will be designed as WSLP has been proven an excellent carrier in this laboratory. Extensive in vitro and in vivo animal studies will be carried out with these RGD-conjugated polymers complexed with siRNA. Inhibition of tumor growth in murine prostate and breast adenocarcinoma models will be proven in the results. The obtained data can be utilized for the design of siRNA delivery to treat cancer patients.