Date of Award

Spring 5-19-2018

Degree Type

Dissertation

Degree Name

PhD. Chemistry

Department

Chemistry and Biochemistry

Advisor

Sergiu M. Gorun, Ph.D.

Committee Member

David Sabatino, Ph.D.

Committee Member

Wyatt R. Murphy, Ph.D.

Committee Member

Cecilia Marzabadi, Ph.D.

Keywords

Fluorinated phthalocyanines, theranostic, photodynamic therapy (PDT), fluorescence, singlet oxygen, Glucose Regulated Protein 78 (GRP78)

Abstract

Hydrocarbon-based therapeutics and imaging agents are prone to chemical oxidation and degradation resulting in loss of activity and limited functional utility. Thus, more material is required to achieve long-lasting therapeutic effects. Phthalocyanines (Pcs) and their metal complexes (PcMs) can be utilized as prodrugs requiring only renewable energy resources namely, air and light, for cancer therapy and diagnostic (theranostic) applications related to photodynamic therapy (PDT). Replacement of labile C-H bonds in the Pc scaffold with a combination of fluoro and perfluoroisopropyl groups has resulted in a stable yet reactive oxidation catalyst of biological significance and importance. For example, F64PcZn, lacks tumor-cell specificity and may attach non-covalently to a tumor-targeting biovector via van der Waals interactions or via the metal-center. However, the former may leach and the latter may alter the Pc’s photo-physical and photo-chemical properties. Thus, the need for functionalized Pcs is desirable for covalent conjugation while retaining its function and reactivity. We report the bioconjugation of F48H7COOHPcZn to a peptidic ligand, Pep42, with oncoprotein recognition towards Gluocse Regulated Protein of 78 kDa (GRP78) in order to generate a small library of tumor-targeting fluorinated phthalocyanine bioconjugates (Scheme 1).

F48H7COOHPcCu is also reported and capable of generating singlet oxygen (1O2). F48H7CONHPcZn-AHX-Pep42, like the unconjugated PcZn, still performed 1O2-mediated substrate oxidation and showed fluorescence after peptide attachment. Pc labeling did not affect the cargo delivery capabilities of Pep42 towards Hep2 cells. F48H7CONHPcZn-AHX-Pep42-R9 and F48H7CONHPcZn-PEG6-Pep42-R9 were biocompatible towards Hep2 cells under dark and light conditions while F48H7CONHPcZn-AHX-Pep42 showed moderate cytotoxicity in both cases unrelated to 1O2 production. The work herein highlights the development of catalytic, fluorine- based anti-cancer drugs that may be useful as potential theranostic agents.

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