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dc.contributor.advisorFranklin, Craigeng
dc.contributor.advisorSmith, Charles J.eng
dc.contributor.authorStott Reynolds, Tamilaeng
dc.date.issued2017eng
dc.date.submitted2017 Falleng
dc.descriptionAbstract from public.pdfeng
dc.description.abstract[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Introduction: Despite decades of research, prostate cancer remains an important disease, with 1 out of 7 men diagnosed within his lifetime. In 2017, 161,360 diagnoses are expected, representing 9.6% of all new cancer cases, falling behind breast and lung cancers in all people, and second only to skin cancer in American men. Prostate cancer continues to fall behind only lung and colorectal cancer with regard to cancer-related mortality in males, with nearly 27,000 directly attributable deaths estimated for 2017 (4.4% of all cancer deaths). Although direct mortality (1 in every 39 men) from prostate cancer is relatively low, the grave prognosis, excruciating pain, and increasing costs of palliative therapy associated with chronic, metastatic stages motivate the pursuit of innovative and more effective methods for earlier and accurate detection and therapy, as well as approaches for differentiating indolent from aggressive forms of the disease. The search for improved diagnostics and treatments with minimal toxicity and side effects continues, and investigations of one particular subset of these is the focus of this dissertation: Peptidebased, prostate biomarker-targeting radiopharmaceuticals. The work described in this disseration involves the metallation, characterization, in vivo and in vitro evaluations of dual-targeting, peptide-based radiopharmaceuticals with utility for imaging and potentially treating prostate tumors by virtue of their ability to target the ?V?3 integrin or the gastrin releasing peptide receptor (GRPr). Methods: [RGD-Glu-6Ahx- RM2] (RGD: Arg-Gly-Asp; Glu: glutamic acid; 6-Ahx: 6-amino hexanoic acid; RM2: (D-Phe-Gln-Trp-Ala-Val- Gly-His-Sta-Leu-NH2)) was conjugated to a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) bifunctional chelator (BFCA), purified via reversed-phase high-performance liquid chromatography (RP-HPLC), characterized by electrospray ionization-mass spectrometry (ESI-MS), and radiolabeled with 111In, 177Lu, 90Y or 86Y. Natural-metallated compounds were assessed for binding affinity for the ?V?3 integrin or GRPr in human glioblastoma U87-MG and prostate PC-3 cell lines and stability prior to in vivo evaluation in normal CF-1 mice and SCID mice xenografted with PC-3 cells. Results: Competitive displacement binding assays with PC-3 and U87-MG cells revealed high to moderate binding affinity for the GRPr or the ?V?3 integrin. Biodistribution studies indicated high tumor uptake in PC-3 tumor-bearing mice at 1h post-intravenous injection) and prolonged retention of tracer at 24h post-intravenous injection). Blocking assays corroborated the specificity of radioconjugates for each target. Micro-single photon emission computed tomography (microSPECT) and/or positron emission tomography (PET) confirmed favorable radiouptake profiles in xenografted mice. Conclusions: [RGD-Glu-[111In-DO3A]-6-Ahx- RM2],[RGD-Glu-[177Lu-DO3A]-6-Ahx-RM2],[RGD-Glu-[90Y-DO3A]-6-Ahx-RM2] and [RGD-Glu-[86Y-DO3A]-6-Ahx-RM2]show favorable pharmacokinetic and/or radiouptake profiles, meriting continued evaluation for molecular imaging in murine U87-MG/PC-3 xenograft models, patientderived xenografted murine models, or perhaps canine models. Advances in Knowledge and Implications for Patient Care: These heterovalent, peptide-targeting ligands perform comparably with many mono- and multivalent conjugates with the potential benefit of increased sensitivity for detecting cancer cells exhibiting differential expression of target receptors.eng
dc.description.bibrefIncludes biblographical referenceseng
dc.format.extentxvi, 159 pages : illustrationeng
dc.identifier.urihttps://hdl.handle.net/10355/63589
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartofcollectionUniversity of Missouri--Columbia. Graduate School. Theses and Dissertationseng
dc.rightsAccess to files is limited to the University of Missouri--Columbia.eng
dc.titleBivalent peptide-based radioconjugates for prostate cancer imaging and potential therapyeng
dc.typeThesiseng
thesis.degree.disciplinePathobiology area program (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


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