Targeted Gene Delivery Against Glioblastoma multiforme

描述（申请人提供）：多形性胶质母细胞瘤（GBM）是一种恶性脑肿瘤，其发展依赖于血管生成。我们建议研究一种新的抗血管生成策略。它靶向整合素avb3，这是一种细胞表面蛋白，在参与肿瘤（如GBMs）血管生成的内皮细胞上显著表达。我们创造了一种阳离子纳米颗粒（NP），其中包含avb3配体和raf突变版本的质粒，ATP/M-Raf，血管生成中Ras-Raf-MEK-ERK激酶途径的核心成分。ATPM-Raf以显性负性方式抑制血管生成。在啮齿动物黑色素瘤模型中，静脉注射该构建物可破坏肿瘤血管，使血管附近的肿瘤细胞凋亡，改善肿瘤控制，提高生存率。我们的中心假设是抑制血管生成将提高GBMs患者的生存率。我们调查这一假设的目的是：1。建立avb3在我们的大鼠胶质瘤模型RT2内皮细胞上的存在。2. 建立avb3-NP对RT2肿瘤内皮细胞的定位。3. 在ATP/m-Raf附着的avb3-NP治疗后，在RT2模型中显示肿瘤控制和大鼠生存改善。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a malignant brain tumor whose development depends on angiogenesis. We propose to investigate a novel antiangiogenic strategy. It targets the integrin avb3, a cell surface protein markedly expressed on endothelial cells involved in angiogenesis of tumors such as GBMs. We have created a cationic nanoparticle (NP) containing an avb3 ligand and a plasmid for a mutant version of raf, ATP/M-Raf, a central component of the Ras-Raf-MEK-ERK kinase pathways in angiogenesis. ATPM-Raf, acts in a dominant negative fashion to suppress angiogenesis. The construct injected intravenously resulted in destruction of tumor vasculature, apoptosis of tumor cells adjacent to vessels, improved tumor control and increased survival of a rodent melanoma model. Our central hypothesis is that inhibiting angiogenesis will improve the survival of patients with GBMs. Our aims for investigating this hypothesis are: 1. Establish the presence of avb3 on endothelial cells of our rat glioma model, RT2. 2. Establish localization of avb3-NP for endothelial cells of the RT2 tumor. 3. Demonstrate tumor control and improved rat survival in the RT2 model following treatment with avb3-NP affixed to ATP/m-Raf.