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)受体亲和型放射性药物的潜力。我们认为，这些放射性药物将是有效的定点药物，用于治疗和/或诊断局限性和转移性乳腺癌。在原发和转移组织中发现的雌激素受体阳性(ER+)和阴性(ER-)乳腺癌细胞上存在GRP受体。我们以前已经证明，我们实验室开发的部分放射性标记蛙皮素(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，这些类似物显示了高GRP受体特异性和在表达GRP受体的肿瘤包括ER+，T47D人乳腺癌异种移植模型中的长时间体内保留。我们的研究计划集中在四个主要领域：1)评估111In-BBN类似物对ER+和ER-人乳腺肿瘤异种移植瘤的靶向和分期的诊断能力。这将包括评估这些诊断试剂用于监测放疗和化疗过程的适用性；2)确定111In、90Y、149 Pm和177Lu-BBN类似物在人乳腺癌异种移植模型中的内照射剂量学；3)评估90Y、149 Pm和177Lu-BBN类似物在乳腺癌异种移植模型中的治疗效果。这将包括确定每个同位素-BBN类似物的最大可耐受剂量估计，并在随后的单剂量和多剂量放射试验评估中进行评估；4)评估靶向放射治疗和化疗在治疗ER+和ER-异种移植模型中的协同作用。建议研究中使用的实验方法将利用111In-BBN模拟药代动力学和体内肿瘤靶向能力的闪烁成像评估，并使用Micro-CT获得相关数据。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、149 Pm和177Lu-BBN类似物在治疗和诊断应用中有效性的主要评估工具。这项提案中采用的方法将继续开发一种针对原发和转移性乳腺癌的独特的高选择性诊断和治疗BBN放射性药物。利用这种选择性放射治疗靶向方法，无论是单独使用还是与其他化疗药物联合使用，都可能为管理和治疗乳腺癌提供新的机会。