RGD-POLYMER TARGETING PLASMID TO ANGIOGENIC ENDOTHELIUM

描述（由申请人提供）。 在本申请中，合成并表征了PEI-PEG-RGD靶向基因载体。将构建的编码sFllt-1的质粒携带至血管生成真皮微血管内皮细胞。体内实验表明，表达的sFlt-1可延缓肿瘤的生长，提高动物的存活率。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和sFlk-1的组合质粒。体外和体内研究证明了优异的抗肿瘤活性效率。在该更新申请中，我们提出递送siRNA以沉默VEGF和VEGF受体。RGD将与可还原的聚合物聚（CBA-DAH）缀合，聚（CBA-DAH）已知是无毒的，并且极大地增强了几种细胞系中的转染。还将合成RGD-chol-R9 C，因为chol-R9 C已证明siRNA的高转染。另外，本实验室还设计了RGD-PEG-水溶性脂质聚合物（WSLP）载体。将用这些与siRNA复合的RGD缀合的聚合物进行广泛的体外和体内动物研究。将在结果中证明对鼠前列腺和乳腺癌模型中肿瘤生长的抑制。所获得的数据可用于设计siRNA递送以治疗癌症患者。公共卫生相关性：三种新设计的聚合物将与RGD结合。预期体外和体内研究都将呈现siRNA递送的积极结果，其可应用于肿瘤治疗。

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. PUBLIC HEALTH RELEVANCE: Three newly designed polymers will be conjugated with RGD. It is expected that both in vitro and in vivo studies will present positive results for siRNA delivery, which can be applied to tumor treatment.