Targeted Molecular Probes for Tumor Imaging

用于肿瘤成像的靶向分子探针

• 批准号: 7171729
• 负责人: Henry F. VanBrocklin
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-05 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7171729
• 关键词: SDS polyacrylamide gel electrophoresis; athymic mouse; epidermal growth factor; growth factor receptors; high performance liquid chromatography; imaging /visualization /scanning; neoplasm /cancer; pharmacokinetics; polymerase chain reaction; positron emission tomography; protein tyrosine kinase; radiotracer; receptor binding; technology /technique development; thin layer chromatography

DESCRIPTION (provided by applicant): The goal of this R01, a competing continuation of our R21, is to further develop and validate labeled probes as imaging agents for the epidermal growth factor receptor (EGFR). Growth factor receptors are important diagnostic and prognostic indicators as well as significant therapeutic targets. EGFR, one of the first growth factors discovered and the basis for many current therapeutic drug development programs, is a member of the ErbB family of receptor tyrosine kinases. Overexpression of these cell surface receptors plays a significant role in the progression of a variety of human tumors of the breast, ovary, lung and prostate. EGFR, over expressed in nearly 45% of breast tumors, ranges in concentration from 0-3600 fmol/mg membrane protein compared to 0- 1500 fmol/mg cytosol for the estrogen receptor. Additionally, tumor EGFR concentration is up to 100 times that of normal tissue, providing good target-to-background selectivity. Many active drug screening programs have identified potent small molecule inhibitors of the EGFR intracellular tyrosine-kinase domain. This is currently the only growth factor receptor where nM and sub-nM small molecule inhibitors have been found. Our approach is to synthesize receptor-binding molecules for the intracellular tyrosine-kinase domain as well as for the extra cellular binding domain, suitable for labeling with positron-emitting isotopes. The binding characteristics, specificity, lipophilicity and stability will be measured in vitro. Based on the in vitro characteristics, select compounds will be radiolabeled. Measures of hepatocyte metabolism will be performed in vitro using the labeled compounds. The biodistribution of select labeled probes will be carried out in tumor-bearing mice. These xenografts will have varying concentrations of EGFR. The uptake of labeled probe in the tumor tissues will be correlated with receptor content and probe metabolism will be determined. Small animal imaging will be used to follow the distribution time course and to obtain dosimetry information for the potential translation of some of these agents to human studies (not part of this proposal). These EGFR tracers may ultimately be important diagnostic probes, but more than likely they will be I invaluable tools for the development of new therapeutic drugs.

描述（由申请人提供）：本R 01（R21的竞争性延续）的目标是进一步开发和验证标记探针作为表皮生长因子受体（EGFR）的成像剂。生长因子受体是重要的诊断和预后指标以及重要的治疗靶点。EGFR是最早发现的生长因子之一，也是目前许多治疗药物开发计划的基础，是受体酪氨酸激酶ErbB家族的成员。这些细胞表面受体的过表达在乳腺、卵巢、肺和前列腺的多种人类肿瘤的进展中起重要作用。EGFR在近45%的乳腺肿瘤中过表达，其浓度范围为0-3600 fmol/mg膜蛋白，而雌激素受体的浓度范围为0- 1500 fmol/mg胞质溶胶。此外，肿瘤EGFR浓度高达正常组织的100倍，提供了良好的靶向背景选择性。许多活跃的药物筛选程序已经确定了EGFR细胞内酪氨酸激酶结构域的有效小分子抑制剂。这是目前唯一的生长因子受体，其中nM和亚nM的小分子抑制剂已被发现。 我们的方法是合成细胞内酪氨酸激酶结构域以及细胞外结合结构域的受体结合分子，适合用正电子发射同位素标记。将在体外测定结合特性、特异性、亲脂性和稳定性。根据体外特征，将对选定化合物进行放射性标记。将使用标记化合物在体外进行肝细胞代谢测定。选择标记探针的生物分布将在荷瘤小鼠中进行。这些异种移植物将具有不同浓度的EGFR。标记探针在肿瘤组织中的摄取将与受体含量相关，并将确定探针代谢。小动物成像将用于跟踪分布时间过程，并获得剂量测定信息，以便将其中一些制剂转化为人体研究（不属于本提案的一部分）。 这些EGFR示踪剂最终可能成为重要的诊断探针，但更有可能的是，它们将成为开发新治疗药物的宝贵工具。