Graduation Date

Fall 12-18-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dr. Jered Garrison

Abstract

The main objective of this body of work is to develop polymeric drug delivery systems for cancer radiotherapy and the decorporation of radiological materials. The polymeric systems for radiotherapy were evaluated in vitro and in vivo (in normal, prostate, and ovarian cancer mice models). The polymeric system for radionuclide decorporation was also evaluated in vitro and in a normal mouse model. Due to its attractive properties, the N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymer was utilized as the main carrier for the developed systems.

Chapter 1 provides an overview of prostate and ovarian cancer, targeted radiopharmaceuticals, nanomedicine-based drug delivery for cancer, HPMA copolymers, and decorporation agents of radiological materials.

In chapter 2, we aimed to develop targeted HPMA copolymers to improve prostate cancer treatment. HPMA copolymers were modified with bombesin (BBN) peptide analogs to target the gastrin-releasing peptide receptor (GRPR) that is overexpressed in several tumors, including prostate cancer. Based on varying the content and charge, a total of ten BBN-HPMA copolymers were synthesized and evaluated in GRPR-overexpressing prostate cancer cell line (PC-3), and the biodistribution profile of the optimized copolymers was evaluated in a normal CF-1 mouse model. The in vitro results showed enhanced internalization via GRPR targeting was charge- and BBN density-dependent. While the negative and zwitterionic conjugates showed low PC-3 uptake values, the positively-charged BBN-polymeric conjugates revealed a direct relationship between the extent of cellular internalization and BBN-incorporation density. In vivo studies of the positively-charged copolymers resulted in rapid blood clearance by the mononuclear phagocyte system (MPS)-associated tissues. Further optimization to avoid rapid MPS recognition is needed in the future.

In chapter 3, we aimed to improve the radiotherapy of ovarian cancer by developing a polymeric delivery system, using HPMA copolymer as a carrier, that overcomes the current drawbacks of radiolabeled nanomedicine (e.g., retention in MPS-associated tissues and long circulation times needed for tumor targeting). The new system (MP-90-TCO-C) combines two strategies in one system. The first strategy is to enhance the clearance of retained large polymers in the MPS-associated tissues via biodegradation, by cathepsin S enzyme (Cat S) that is abundantly expressed in these tissues, into small and easily cleared fragments from the body. The second strategy is based on employing bioorthogonal in vivo chemistry between a trans-cyclooctene- (TCO) modified polymer (MP-90-TCO-C) and a tetrazine- (TZ) based radiotracer. Kinetic and in vitro Cat S studies were evaluated. In vivo studies were performed using two ovarian cancer and a normal CF-1 mouse models. The kinetic studies revealed ultra-fast reactions between MP-90-TCO-C, and the TZ-radiotracer while MP-90-TCO-C was also found to be cleaved in vitro by Cat S. The in vivo studies showed biodegradation of the copolymer in the CF-1 mouse model with excellent in vivo TCO/TZ reactivity in ovarian cancer models with improved tumor to non-target ratios observed. These results show the feasibility of this approach to enhance the treatment of ovarian cancer.

In chapter 4, we aimed to design a polymeric system that can be suitable for prophylactic applications to reduce the exposure to radioactive actinides, which can occur in case of accidental internal contamination. DTPA is approved for actinide decorporation after exposure, but due to its short half-life, DTPA is not ideal for prophylactic applications. To overcome this drawback, we developed a DTPA-based polymeric system (P-DTPA) based on an HPMA copolymer. We evaluated its decorporation efficacy using an actinide model in vitro and in a normal CF-1 mouse model under prophylactic settings. The in vitro results showed the tolerability of P-DTPA and the ability to chelate the actinide model in the presence of competing biological metals. The in vivo results showed the superiority of P-DTPA over DTPA in enhancing the excretion of the radioactive material. This enhanced decorporation effect is mainly attributed to the longer circulation time of P-DTPA compared to DTPA.

In chapter 5, all results from the three projects will be summarized, and future research directions will be provided.

Available for download on Tuesday, December 06, 2022

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