Modular Dendritic Integrin Antagonists for Cancer Therapy

描述：整合素是异二聚体跨膜受体，介导内皮细胞和细胞外基质之间的相互作用。它们参与大量基本的细胞内过程，如细胞-基质粘附、分化、应激反应和凋亡。在整合素中，？V¿3受体在血管生成的内皮细胞中过度表达，但在静止细胞中并不常见。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它的天然配体有效竞争，导致增殖血管的细胞凋亡。我们的研究目的是检验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功效。特别是，包含多个整合素识别域的模块化构建可能对血管生成内皮细胞显示出更高的亲和力和特异性。除了作为新血管显像剂外，这些多价物种可能能够干扰？V¿3整合素或血管生成过程本身血管生成（Angiogenesis）是指在现有血管系统上形成新血管的过程，对实体瘤的生长和转移扩散至关重要。我们的项目旨在发现新的化学方法来选择性识别细胞表面受体-在血管生成的内皮细胞表面过表达的整合素。新一类设计的多价整合素配体可以根据不同的受体表达模式靶向细胞或组织，并在不影响正常血管细胞的情况下阻断血管生成。

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.