Modular Dendritic Integrin Antagonists for Cancer Therapy

描述：整合素是介导内皮细胞和细胞外基质之间相互作用的异二聚体跨膜受体。它们参与许多基本的细胞内过程，如细胞-基质粘附、分化、应激反应和凋亡。在整合素中，？V3受体在经历血管生成的内皮细胞中过表达，尽管它们通常不在静止细胞中发现。这使得它们成为有吸引力的抗肿瘤靶点，因为这种受体的拮抗剂与其天然配体有效竞争，导致增殖血管中的细胞凋亡。我们研究的目的是检查多价模块化树突状整合素拮抗剂（MDIA）作为癌症成像工具，硼中子捕获治疗（BNCT）和血管生成抑制剂的疗效。特别是，整合多个整合素识别结构域的模块化构建体可能显示出对血管生成内皮细胞的亲和力和特异性增加。除了作为新生血管成像剂，这种多价物种可能能够干扰内吞周期？V3整合素或血管生成过程本身。血管生成是作为现有血管系统的萌芽形成新血管的过程，对于实体肿瘤的生长和转移扩散至关重要。我们的项目旨在发现选择性识别细胞表面受体的新化学方法-整合素在经历血管生成的内皮细胞表面上过表达。新设计的多价整联蛋白配体可以允许基于不同的受体表达模式靶向细胞或组织并阻断血管生成而不影响正常血管细胞。

DESCRIPTION: Integrins are heterodimeric transmembrane receptors that mediate the interactions between endothelial cells and the extracellular matrix. They are involved in a large number of fundamental intracellular processes, such as cell-matrix adhesion, differentiation, stress response and apoptosis. Among the integrins, ?v¿3 receptors are overexpressed in endothelial cells undergoing angiogenesis, although they are not typically found on quiescent cells. This renders them attractive antitumor targets, since antagonists of this receptor that effectively compete with its natural ligands cause apoptosis in proliferating vessels. The objective of our study is to examine the efficacy of multivalent modular dendritic integrin antagonists (MDIA) as tools in cancer imaging, in boron neutron capture therapy (BNCT) and as inhibitors of angiogenesis. In particular, modular constructs incorporating multiple integrin recognition domains might show increased affinity and specificity for angiogenic endothelial cells. In addition to acting as agents for imaging of neovasculature, such multivalent species might be capable of interfering with the endocytic cycle of ?v¿3 integrins or the angiogenic process itself. Angiogenesis, the process of formation of new blood vessels as sprouts of the existing vasculature, is critical for growth and metastatic spread of solid tumors. Our project aims to uncover new chemical approach for selective recognition of cell surface receptors - integrins that are overexpressed on the surface of endothelial cells undergoing angiogenesis. The new class of designed multivalent integrin ligands may allow cells or tissues to be targeted based on distinct receptor expression patterns and blocking angiogenesis without affecting normal blood vessel cells.