Development of GRP Receptor-Avid Radiopharmaceuticals

GRP受体-Avid放射性药物的开发

• 批准号: 6710603
• 负责人: TIMOTHY J. HOFFMAN
• 金额: $ 21.53万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-03 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710603
• 关键词: SCID mouse; antineoplastics; bombesin; breast neoplasm /cancer diagnosis; breast neoplasms; drug design /synthesis /production; gastrin releasing peptide; laboratory mouse; neoplasm /cancer radionuclide diagnosis; neoplasm /cancer radionuclide therapy; neoplasm /cancer transplantation; neuropeptide receptor; nonhuman therapy evaluation; peptide analog; radiation dosage; radionuclides; radiopharmacology; radiotracer; receptor binding; synthetic peptide

DESCRIPTION (provided by applicant):The research project outlined in this proposal holds the potential for development of one or more radiolabeled Gastrin Releasing Peptide (GRP) receptor-avid radiopharmaceuticals. We propose that these radiopharmaceuticals will be effective site-directed agents, for the treatment and/or diagnosis of patients with localized, as well as metastasized breast cancer. GRP receptors are present on estrogen receptor positive (ER+) and negative (ER-) breast cancer cells found in primary and metastatic tissue. We have previously demonstrated that selected radiolabeled bombesin (BBN) analogs developed in our laboratory target the GRP receptor with high affinity and specificity. Our initial work has resulted in the development of 99mTc- and 111In-BBN analogs which demonstrate high GRP receptor specificity and prolonged retention in vivo in GRP receptor expressing tumors including the ER+, T47D human breast cancer xenograft model. Our research plan focuses on four primary areas: 1) evaluate the diagnostic capabilities of 111In-BBN analogs to target and stage ER+ and ER- human breast tumor xenografts. This will involve assessing the applicability of these diagnostic agents for use in monitoring the course of radiotherapy and chemotherapy treatment; 2) determine the internal radiation dosimetry of 111In, 90Y, 149Pm, and 177Lu-BBN analogs in xenograft models of human breast cancer; 3) evaluate the therapeutic efficacy of 90Y, 149Pm, and 177Lu-BBN analogs in xenograft models of breast cancer. This will involve the determination of a maximum tolerable dose estimate for each isotope-BBN analog evaluated with subsequent single dose and multi-dose radiotherapy trial evaluation; 4) evaluate the synergism of targeted radiotherapy and chemotherapy in the treatment of ER+ and ER-xenograft models of human breast cancer. The experimental approaches used in the proposed research will utilize scintigraphic evaluation of 111In-BBN analog pharmacokinetics and in vivo tumor targeting capabilities with correlative data obtained using a Micro-CT. In vivo breast cancer SCID mouse tumor models (T47D and MDA-MB-231 cell origin), will be the primary assessment tool for analysis of 111In, 90Y, 149Pm, and 177Lu-BBN analog efficacy in therapeutic and diagnostic applications. The approach taken in this proposal will continue our development of a unique class of highly selective diagnostic and therapeutic BBN radiopharmaceuticals that target primary and metastatic breast cancer. Utilizing this selective radiotherapeutic targeting approach, either alone or combined with other chemotherapeutics, may provide new opportunities to manage and treat breast cancer.

描述（由申请人提供）：本提案中概述的研究项目具有开发一种或多种放射性标记胃泌素释放肽（GRP）受体亲和的放射性药物的潜力。我们建议这些放射性药物将成为有效的定点药物，用于治疗和/或诊断患有局部以及转移性乳腺癌的患者。 GRP 受体存在于原发组织和转移组织中的雌激素受体阳性 (ER+) 和阴性 (ER-) 乳腺癌细胞上。我们之前已经证明，我们实验室开发的选定的放射性标记铃蟾肽 (BBN) 类似物以高亲和力和特异性靶向 GRP 受体。我们的初步工作导致了 99mTc- 和 111In-BBN 类似物的开发，这些类似物在表达 GRP 受体的肿瘤（包括 ER+、T47D 人乳腺癌异种移植模型）中表现出高 GRP 受体特异性和长期体内保留。我们的研究计划侧重于四个主要领域：1) 评估 111In-BBN 类似物对 ER+ 和 ER- 人类乳腺肿瘤异种移植物的靶向和分期的诊断能力。这将涉及评估这些诊断剂在监测放疗和化疗过程中的适用性； 2)测定人乳腺癌异种移植模型中111In、90Y、149Pm和177Lu-BBN类似物的内辐射剂量测定； 3)评价90Y、149Pm和177Lu-BBN类似物在乳腺癌异种移植模型中的治疗效果。这将涉及确定每个同位素-BBN类似物的最大耐受剂量估计值，并通过随后的单剂量和多剂量放射治疗试验评估进行评估； 4）评价靶向放疗和化疗在治疗人乳腺癌ER+和ER-异种移植模型中的协同作用。拟议研究中使用的实验方法将利用 111In-BBN 类似药代动力学和体内肿瘤靶向能力的闪烁照相评估以及使用 Micro-CT 获得的相关数据。体内乳腺癌 SCID 小鼠肿瘤模型（T47D 和 MDA-MB-231 细胞来源）将成为分析 111In、90Y、149Pm 和 177Lu-BBN 类似物在治疗和诊断应用中功效的主要评估工具。该提案中采用的方法将继续我们开发一类独特的高选择性诊断和治疗性 BBN 放射性药物，针对原发性和转移性乳腺癌。单独使用这种选择性放射治疗靶向方法或与其他化疗药物联合使用，可能会为管理和治疗乳腺癌提供新的机会。