Development of GRP Receptor-Avid Radiopharmaceuticals

描述（由申请方提供）：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的胃泌素释放肽（GRP）受体亲和放射性药物的潜力。我们建议，这些放射性药物将是有效的定点药物，用于治疗和/或诊断患者的局部，以及转移性乳腺癌。GRP受体存在于原发性和转移性组织中发现的雌激素受体阳性（ER+）和阴性（ER-）乳腺癌细胞上。我们以前已经证明，在我们的实验室中开发的选定的放射性标记的蛙皮素（BBN）类似物以高亲和力和特异性靶向GRP受体。我们的初步工作已经导致99 mTc-和111 In-BBN类似物的开发，其在表达GRP受体的肿瘤（包括ER+，T47 D人乳腺癌异种移植物模型）中表现出高GRP受体特异性和延长的体内保留。我们的研究计划集中在四个主要领域：1）评估111 In-BBN类似物靶向和分期ER+和ER-人乳腺肿瘤异种移植物的诊断能力。这将涉及评估这些诊断剂用于监测放疗和化疗治疗过程的适用性; 2）确定111 In、90 Y、149 Pm和177 Lu-BBN类似物在人乳腺癌异种移植模型中的内部辐射剂量测定; 3）评估90 Y、149 Pm和177 Lu-BBN类似物在乳腺癌异种移植模型中的治疗功效。这将涉及确定每种同位素-BBN类似物的最大耐受剂量估计值，并随后进行单剂量和多剂量放疗试验评价; 4）评价靶向放疗和化疗在治疗人乳腺癌的ER+和ER-异种移植模型中的协同作用。在拟议的研究中使用的实验方法将利用111 In-BBN类似物的药代动力学和体内肿瘤靶向能力与使用Micro-CT获得的相关数据的免疫学评价。体内乳腺癌SCID小鼠肿瘤模型（T47 D和MDA-MB-231细胞来源）将成为分析111 In、90 Y、149 Pm和177 Lu-BBN类似物在治疗和诊断应用中疗效的主要评估工具。本提案中采用的方法将继续开发一类独特的高选择性诊断和治疗BBN放射性药物，靶向原发性和转移性乳腺癌。利用这种选择性的放射性靶向方法，无论是单独或与其他化疗药物相结合，可以提供新的机会来管理和治疗乳腺癌。

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.