Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Jered C. Garrison

Abstract

The Gastrin-Releasing Peptide Receptor (BB2r) has been intensively investigated as a cancer target over the years. Numerous diagnostic and therapeutic BB2r-targeted agents have been developed for various solid tumors, including prostate cancers, due to the high expression level of BB2r on neoplastic relative to normal tissues. The development of those targeted agents have mainly utilized the modified c-terminal of bombesin(BBN), a peptide that has nanomolar binding affinity to human BB2r. However, a major issue that hinders the clinical translational potential of low-molecular weight, receptor-targted agents, is their short residence time at tumor tissues due to the intrinsically high diffusion and clearance rates.

Detailed in this dissertation is a comparison study investigating important biological differences between two mouse models of prostate cancer and how these factors impact the delivery of BB2r-targeted agents. Specifically, we have evaluated the impact of differences in tumor vassculatur density, hypoxia burden and perfusion efficacy on BB2r-targeted agent uptake and distribution. Furthermore, herein, we proposed two different approaches to increase the tumor residualization of BB2r-targeted radiopharmaceutical agents, by developing chemical approaches to “trap” BB2r-targeted agents in prostate cancer cells through adduct formation with macromolecules. First proposed, BB2r-targted agents incorporating hydrophilic cysteine cathepsin (CC) inhibitors was developed. Due to the high concentration of CCs found in endolysosomal compartments, our agents have the ability to irreversibly bind to CCs after endocytosis. Two analogs, based on BB2r-targeted agonist and antagonist separately, demonstrated enhanced tumor retention and optimal tumor-to-non-target ratios compared to the matching controls. The second approach focused on the hypoxic nature of prostate cancer, which is due to the distorted architecture leading to the insuffucient delivery of oxygen, and was examined as a mechanism to increase retention of BB2r-targeted agents. Specifically, we explored the hypoxic-selectivity of a 2-nitroimidazole phosphoramide nitrogen mustard (2-NIPAM), a potential tumor trapping agent which is able to irreversibly bind to intracellular nucleophiles in hypoxic tissues.

Overall, we seek to determine the most suitable mouse model in evaluating the BB2r-targeted agents. We are also exploring strategies to elongate the retention time of BB2r-targeted agents in the prostate tumor tissues, thereby increasing the clinical translational potential of these agents. Future works include: 1) synthesis and evaluation of 2-NIPAM incorporated BB2r-targeted peptides in vitro and in vivo; 2) synthesis and assessment of hydrophilic CC inhibitors integrated into other receptor-targeted analogs. Further work is needed to demonstrate the feasibility and wide applicability of our strategies in different receptor-targeted systems.

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