Small Molecules and Gene Delivery in Tumor Angiogenesis

血管生成依赖于内皮细胞（EC）与血管重构的相互作用， 细胞外基质（ECM）是主要由称为整合素的细胞表面受体介导的事件。 在这个更新的建议中，我们将探讨小分子整合素的三个相关应用 拮抗剂，每一种都被设计为靶向并由此抑制动物中血管生成血管和产生的实体瘤的生长。第一个应用是在我们发现整合素α v β 3在血管生成EC上特异性表达并作为ECM和细胞表面蛋白酶基质金属蛋白酶2（MMP-2）的受体之后。在最初的目标中，将合成阻断MMP-2与alphavbeta 3结合的化合物的类似物（TSRI-265，在本提案的前一个资助周期期间首次发现），并在小鼠肿瘤模型中测试其增加的药代动力学和治疗活性。在目标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α v β 3特异性靶向药物（包括TSRI-265）的特异性和有效性。有效的靶向剂将被用来提供促凋亡基因，破坏小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合素α 3 β 1的抑制剂，我们在这里将其定义为在EC侵袭和血管生成中发挥核心作用。有证据表明，EC整合素α 3 β 1与选择性剪接（结构域外B或含ED-B）癌胚形式的纤连蛋白（BFN）相互作用。 B-FN聚集在血管生成血管周围，但迄今为止，其在血管生成中的作用已被证实。 仍然不清楚。我们将检验α 3 β 1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的假设。我们与斯克里普斯研究所的合成有机化学家Boger博士和Nicolaou博士持续密切的互动促进了这一提案的目标。预计这些研究将导致几种靶向特定EC整联蛋白的新型化合物的开发，从而破坏血管生成和肿瘤生长。

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.