Lymphoma-Specific Ligands; Pharmacokinetics, Radioimaging and Therpeutics

淋巴瘤特异性配体；

• 批准号: 6934089
• 负责人: SALLY J DENARDO
• 金额: $ 20.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934089
• 关键词: antineoplastics; athymic mouse; bioimaging /biomedical imaging; chemical conjugate; contrast media; copper; dogs; dosage; drug design /synthesis /production; human genetic material tag; laboratory mouse; lymphoma; neoplasm /cancer radiodiagnosis; neoplasm /cancer radionuclide therapy; neoplasm /cancer transplantation; peptide analog; pharmacokinetics; positron emission tomography; radionuclides; radiopharmacology; radiotracer; yttrium

The overall goal of this program is the translational development of radioisotope targeting molecules and strategies to achieve more specific and sensitive detection with PET and delivery of enhanced systemic radiotherapy to cancer. Program 3 is central to the development and the translation of these molecules by in vivo evaluation of selected peptidomimetics as oligomers, to imaging or therapeutic agents. Program 3 will (1) prepare the selected DOTA-peptidomimetic oligomers as radioconjugates; (2) assure in vitro pharmaceutical quality; (3) perform in vivo mouse pharmacokinetic and microPET imaging studies in mice and dogs, as well as (4) perform selected therapeutic studies in these animals. These key issues will be addressed in a systematic approach. If needed further strategies will be developed to achieve the overall goal of this program. Five specific aims have been delineated. 1) The initial careful selection of 2 molecular formats for radiolabeled peptidomimetic will be made, #1 providing an effective target to normal tissue ratio (T/NT) for imaging and #2, an effective therapeutic index (Tl) for radionuclide therapy. These 2 oligomeric formats will be chosen from oligomers in several multimeric forms using in vivo pharmacokinetics and PET/CT imaging in mice. 2) The peptidomimetics will be selected by study in these oligomeric forms, and determination of those, which have the best potential for effective PET imaging and/or systemic radionuclide radiotherapy. This determination wil be made by quantitative in vivo pharmacokinetic studies and dosimetry calculations of the various peptidomimetic oligomers as radioconjugates using microPET/CT and biodistribution studies in nude mice bearing lymphoma xenografts, and PET/CT studies in dogs having spontaneous canine lymphoma. 3) Selected peptidomimetic as radioconjugate oligomers will be evaluated in therapy protocols in mice bearing human xenograft models and the MTD and efficacy will be compared to calculated dosimetry. 4) 64Cu peptidomimetic oligomers will be evaluated for their ability to provide the in vivo targeting signal leading to sensitive tumor detection by PET imaging of micrometastases in larger animals (dogs) with spontaneous lymphoma. Further study of the pharmacokinetics of these agents in PET quantitative imaging Canine protocols will be used to determine the Tl and calculated dosimetry for selected peptidomimetic oligomers, so as to predict and perform safe 90Y-peptidomimetic oligomer MTD therapy in these animals. 5) Selection will be made of a 64Cu and/or 111ln/90Y-peptidomimetic oligomer(s) with characteristics likely to substantially enhance T/NT and /or Tl over current lymphoma agents, for future human protocol trials. Preliminary microPET imaging in mice has demonstrated obvious tumor targeting of an initial 64Cu peptidomimetic. This Program is considered to have a high likelihood of success.

该计划的总体目标是放射性同位素靶向分子和策略的转化发展，以实现PET更特异和灵敏的检测，并对癌症进行增强的全身放射治疗。程序3是通过体内评价选择的肽模拟物作为寡聚体，将这些分子开发和翻译成成像剂或治疗剂的核心。程序3将（1）制备选定的DOTA-肽模拟物低聚物作为放射性缀合物;（2）确保体外药物质量;（3）在小鼠和犬中进行体内小鼠药代动力学和microPET成像研究，以及（4）在这些动物中进行选定的治疗研究。这些关键问题将以系统的方式加以解决。如有必要，将制定进一步的战略，以实现该方案的总体目标。已经确定了五个具体目标。1)将进行放射性标记的肽模拟物的2种分子形式的初步仔细选择，#1提供有效的 用于成像的靶与正常组织比率（T/NT）和#2，用于放射性核素治疗的有效治疗指数（TI）。使用小鼠体内药代动力学和PET/CT成像，从几种多聚体形式的寡聚体中选择这2种寡聚体形式。2)肽模拟物将通过这些寡聚体形式的研究来选择，并确定那些具有有效PET成像和/或全身放射性核素放疗的最佳潜力的肽模拟物。该测定将通过使用microPET/CT和在携带淋巴瘤异种移植物的裸鼠中的生物分布研究以及在患有自发性犬淋巴瘤的犬中的PET/CT研究对作为放射性缀合物的各种肽模拟物寡聚体进行定量体内药代动力学研究和剂量测定计算来进行。3)将在携带人异种移植物模型的小鼠的治疗方案中评价作为放射性缀合物低聚物的所选肽模拟物，并将MTD和功效与计算的剂量测定法进行比较。4)将评价64 Cu拟肽寡聚体提供体内靶向信号的能力，从而通过患有自发性淋巴瘤的较大动物（犬）中微转移的PET成像实现灵敏的肿瘤检测。在PET定量成像犬方案中对这些药剂的药代动力学的进一步研究将用于确定选定的拟肽寡聚体的Tl和计算的剂量测定，以便预测和在这些动物中进行安全的90 Y-拟肽寡聚体MTD治疗。5)将选择具有可能相对于当前淋巴瘤剂显著增强T/NT和/或Tl的特征的64 Cu和/或111 In/90 Y-肽模拟物寡聚体，用于未来的人类方案试验。小鼠中的初步microPET成像已经证明了初始64 Cu肽模拟物的明显肿瘤靶向。该计划被认为具有很高的成功可能性。