ORCID

http://orcid.org/0000-0001-6423-6715

Date of Award

Spring 5-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Chemistry

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Radiometals play a crucial role in nuclear medicine for the diagnosis and therapy of various diseases including cancer and neurological disorders. In fact, there is a broad range of radiometals that are currently in use for imaging and therapy such as 99mTc, 89Zr, 68Ga, 177Lu, and 64/67Cu. Radiometal use in nuclear medicine has been stimulated by advances in radionuclide production that allow for fast, reliable, and cost-efficient production and an extensive understanding of molecular targets and tumor biomarkers. In recent years, there has been a growing interest in theranostics - the combination of imaging and therapy related to the same specific molecular targets. This union is believed to result in safer and more targeted treatments for patients as treatment plans are guided by the same or a similar diagnostic counterpart. In this work, we explored the potential of biomolecules labeled with radiometals in the application of cancer imaging/therapy and amyloid β imaging. In the context of cancer, we examined integrin avB6 and gastrin-releasing peptide receptor (GRPR) as molecular targets that are over-expressed in a variety of different cancer types. Different bifunctional chelators (DOTA, PCTA) conjugated to a peptide targeting integrin avB6 were assessed in vitro and in vivo, which showed that both chelates were suitable for complexing 64Cu and imaging avB6. However, similar to other peptides, these constructs had rapid blood clearance which precludes delivery of high radiation doses to tumors for therapeutic purposes. Therefore, an albumin-binding entity was added to increase blood circulation and enhance tumor uptake. The pseudo matched pair of 68Ga/177Lu was employed to investigate the theranostic potential of the peptide. PET imaging with the non-albumin peptide radiolabeled with 68Ga revealed specific tumor uptake. 177Lu therapy studies with albumin binding peptides in tumor-bearing mice showed favorable results with regards to tumor inhibition.In recent years, there has been a renewed interest in the true matched pair of 64Cu/67Cu instead of the more traditional 68Ga/177Lu pair. Here, we investigated the potential of a 64/67Cu-labeled bombesin peptide as a theranostic for prostate cancer. The peptide targets gastrin-releasing peptide receptor (GRPR) which is an attractive biomarker for imaging and therapy of various types of cancers, including prostate cancer. In fact, [64Cu]Cu-SAR-BBN is in clinical development for PET imaging (ACTRN12619001383156). The aim of this research was to evaluate [67Cu]Cu-SAR-BBN for its preclinical therapeutic efficacy to determine its potential for clinical translation. A 67Cu therapy study showed that tumor-bearing mice receiving 6 x 24 MBq demonstrated excellent tumor inhibition and increased survival time.In addition to cancer, we looked at the potential of small molecules radiolabeled with 68Ga for the imaging of amyloid β in cerebral amyloid angiopathy (CAA). The investigated 1,4,7-triazacyclononane compounds conjugated to a benzothiazole moiety as an amyloid β binding motif and radiolabeled with 68Ga proved to have excellent specific binding to amyloid plaques in mouse brain sections and limited blood-brain barrier penetration, thus indicating their potential for the imaging of amyloid plaques in the blood vessels of the brain.

Language

English (en)

Chair and Committee

Buck Rogers

Committee Members

Liviu Mirica

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