Small Molecules and Gene Delivery in Tumor Angiogenesis

肿瘤血管生成中的小分子和基因传递

• 批准号: 6990219
• 负责人: DAVID A CHERESH
• 金额: $ 17.56万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-12 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6990219
• 关键词: SCID mouse; angiogenesis inhibitors; antineoplastics; apoptosis; athymic mouse; biomimetics; biotechnology; cell migration; collagenase; combinatorial chemistry; drug discovery /isolation; drug screening /evaluation; fibronectins; gene delivery system; integrins; neoplasm /cancer blood supply; neoplastic growth; pharmacokinetics; receptor binding; small molecule; vascular endothelium

Angiogenesis is dependent on the interaction of endothelial cells (ECs) with the remodeling extracellular matrix (ECM), an event primarily mediated by cell surface receptors termed integrins. In this renewal proposal we will explore three related applications of small molecule integrin antagonists, each designed to target and thereby inhibit the growth of angiogenic blood vessels and resulting solid tumors in animals. The first application follows our discovery that the integrin alphavbeta3 is expressed specifically on angiogenic ECs and serves as a receptor for the ECM and the cell surface protease matrix metalloproteinase 2 (MMP-2). In the initial aim, analogs of a compound that blocks MMP-2 binding to alphavbeta3 (TSRI-265, first discovered during the previous funding cycle of this proposal), will be synthesized and tested in murine tumor models for increased pharmacokinetic and therapeutic activity. In Aim 2, we will extend our recently developed nanoparticle gene delivery technology to examine specificity and efficacy of different alphavbeta3-specific targeting agents (including TSRI-265). Efficient targeting agents will be used to deliver proapoptotic genes to disrupt angiogenic blood vessels in murine tumor growth models. In the final two aims, we will develop and test inhibitors of integrin alpha3beta1, which we define here as playing a central role in EC invasion and angiogenesis. Evidence is provided that EC integrin alpha3beta1 interacts with an alternatively spliced (extra-domain B, or ED-B containing) oncofetal form of fibronectin (BFN). B-FN accumulates around angiogenic blood vessels, but to date, its role in angiogenesis has remained unclear. We will test the hypothesis that antagonists of alpha3beta1 block endothelial cell interaction with ED-B, and disrupt early stages of tumor-mediated angiogenesis. The goals of this proposal are facilitated by our continued close interactions with Drs Boger and Nicolaou, synthetic organic chemists at The Scripps Research Institute. It is anticipated that these studies will result in the development of several novel compounds that target specific EC integrins, thereby disrupting angiogenesis and tumor growth.

血管生成取决于内皮细胞（EC）与重塑的相互作用 细胞外基质（ECM），这一事件主要由称为整联蛋白的细胞表面受体介导。 在此续签建议中，我们将探索小分子整合素的三个相关应用 拮抗剂，每个拮抗剂旨在靶向，从而抑制血管生成血管的生长和导致动物的实体瘤的生长。第一个应用是我们发现的，整联蛋白alphavbeta3专门在血管生成ECS上表达，并用作ECM和细胞表面蛋白酶基质基质金属蛋白酶2（MMP-2）的受体。在最初的目的中，将在鼠肿瘤模型中合成和测试，该化合物的类似物阻断了与Alphavbeta3结合的MMP-2结合（TSRI-265，最初是在该提案的先前资助周期中发现的），以增加药物代动力学和治疗活性。在AIM 2中，我们将扩展我们最近开发的纳米颗粒基因递送技术，以检查不同Alphavbeta3特异性靶向剂（包括TSRI-265）的特异性和功效。有效的靶向剂将用于输送促凋亡基因，以破坏鼠肿瘤生长模型中的血管生成血管。在最后两个目标中，我们将开发和测试整联蛋白alpha3beta1的抑制剂，我们在这里将其定义为在EC侵袭和血管生成中起着核心作用。有证据表明，EC整联蛋白alpha3beta1与纤连蛋白（BFN）的替代剪接（外域B或含有ED-B的）形式相互作用。 B-FN在血管生成血管周围积聚，但迄今为止，其在血管生成中的作用 仍然不清楚。我们将检验以下假设：α3BETA1的拮抗剂阻断内皮细胞与ED-B的相互作用，并破坏肿瘤介导的血管生成的早期阶段。我们与Scripps Research Institute的合成有机化学家Nicolaou的持续密切互动促进了该提案的目标。可以预料，这些研究将导致靶向特定EC整合素的几种新型化合物的发展，从而破坏血管生成和肿瘤生长。