Lymphoma-Specific Ligands; Pharmacokinetics, Radioimaging and Therapeutics

该计划的总体目标是翻译开发放射性同位素靶向分子和策略，以实现通过PET进行更特异和更敏感的检测，并为癌症提供增强型全身放射治疗。程序3是这些分子的开发和翻译的中心，通过体内评估选定的肽仿制物作为低聚物，用于成像或治疗药物。计划3将(1)将选定的DOTA-肽仿制低聚物制备为放射性结合物；(2)保证体外药物质量；(3)在小鼠和狗身上进行小鼠体内药代动力学和microPET成像研究，以及(4)在这些动物上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。如果需要，将制定进一步的战略，以实现该方案的总体目标。已经勾勒出了五个具体目标。1)将对放射性标记多肽模拟物的两种分子形式进行初步仔细的选择，#1提供有效的 靶组织与正常组织的比率(T/NT)和#2，放射性核素治疗的有效治疗指数(TL)。这两种低聚形式将从几种多聚形式的低聚物中选择，使用在小鼠体内的药代动力学和PET/CT成像。2)将通过对这些寡聚形式的研究和确定哪些形式最有可能进行有效的PET成像和/或全身放射性核素放射治疗来选择肽类药物。这一测定将通过定量体内药代动力学研究和剂量学计算，利用microPET/CT和裸鼠淋巴瘤移植瘤的生物分布研究，以及自发性犬淋巴瘤的PET/CT研究，计算不同的模拟肽低聚物作为放射性结合物。3)将选定的多肽模拟物作为放射性偶联低聚物在荷人异种移植模型小鼠的治疗方案中进行评估，并将MTD和疗效与计算的剂量学进行比较。4)通过对患有自发性淋巴瘤的较大动物(狗)的微转移进行PET成像，将评估64Cu模拟肽低聚物提供体内靶向信号的能力，从而导致灵敏的肿瘤检测。这些药物在PET定量成像中的药代动力学的进一步研究将被用来确定选定的模拟肽低聚物的TL和计算剂量学，从而预测并在这些动物身上进行安全的90Y-拟肽低聚物MTD治疗。5)将选择64Cu和/或111Ln/90Y-模拟肽低聚物(S)，其特征可能显著增强T/NT和/或TL，以用于未来的人类方案试验。在小鼠体内的初步microPET成像显示，最初的64Cu肽模拟物具有明显的肿瘤靶向性。这项计划被认为有很高的成功可能性。

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.