Pilot--Novel imaging agents targeted to tumor vasculatur

描述：(申请人提供) 血管生成过程直接影响肿瘤的生长和转移。 实体肿瘤的性质。临床上有用的创新成像技术 迫切需要检测血管生成活性的技术。近期 选择性结合肿瘤血管的新型多肽的发现 通过它们与增殖血管中的明胶酶相互作用 支持新放射性药物和放射学造影剂的开发 用于伽马闪烁和磁共振功能成像的材料 成像(MRI)。其中一个这样的肽，环十肽，CTTHWGFTLC，与 选择高亲和力的明胶酶A和明胶酶B。 我们建议在体内合成两个系列的多肽结合物作为靶点。 使用水溶性聚合物作为载体的显像剂 放射性同位素或用于顺磁性金属离子的药理优化 该多肽的性质和金属载量。 具体地说，我们将：(1)合成肽-聚乙二醇(PEG) 与连接到聚乙二醇链一端的111In-DTPA偶联，和(2) 嵌段共聚物连接的多肽与Gd-DTPA偶联物的合成 链接器。这种名为聚乙二醇-聚(L-谷氨酸)(聚乙二醇-PG)的共聚物将允许 多个Gd-DTPA分子偶联到PG区块的侧链。这个 这些试剂的生物分布和成像特性将在 裸鼠荷人MDA-MB435肿瘤。最后，我们将(3)验证 ~(111)In和~(111)Gd标记的多肽选择性显像肿瘤血管 未修饰/冷肽与标记物共注射的聚合物偶联物 多肽在我们的成像研究中。如果成功，这个开发项目 将扩大以评估各种抗血管生成剂对血管生成的影响 这种新的肿瘤血管特异性分子靶点的早期变化 多肽。

Description: (provided by applicant) The process of angiogenesis directly influences the growth and metastatic properties of solid tumors. Clinically useful, innovative imaging technologies for detecting angiogenic activity are urgently needed. Recent discoveries of novel peptides that selectively home to tumor vasculature through their interaction with gelatinases in proliferating blood vessels support the development of new radiopharmaceuticals and radiological contrast materials for functional imaging by gamma scintigraphy and magnetic resonance imaging (MRI). One such peptide, a cyclic decapeptide, CTTHWGFTLC, binds with MMP-2 (gelatinase A) and MMP-9 (gelatinase B) selectively with high affinity. We propose to synthesize two series of peptide conjugates as targeted in vivo imaging agents using water-soluble polymers as carriers for either radioisotope or for paramagnetic metal ions to optimize the pharmacological properties and metal loading capacity of this peptide. Specifically, we will: (1) synthesize peptide-polyethylene glycol (PEG) conjugate with 111In-DTPA attached to one end of the PEG chains, and (2) synthesize conjugate of peptide and Gd-DTPA linked through a block copolymer linker. The copolymer, PEG-poly(L-glutamic acid) (PEG-PG), will allow coupling of multiple Gd-DTPA molecules to the side chain of PG block. The biodistribution and imaging properties of these agents will be evaluated in nude mice bearing human MDA-MB435 tumor. Finally, we will (3) validate the selective imaging of tumor vasculature with 111In- and Gd-labeled peptide- polymer conjugates by co-injecting unmodified/cold peptide with labeled peptides in our imaging studies. If successful, this developmental project will be expanded to assess the effect of various anti angiogenic agents on the early changes of the molecular target of this novel tumor vascular-specific peptide.