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.
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