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Tumor-Targeting Fluorinated Phthalocyanines for Theranostic Applications Erik Nathaniel Carrión Seton Hall University, [email protected]

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Tumor-Targeting Fluorinated Phthalocyanines for Theranostic Applications Erik Nathaniel Carrión Seton Hall University, Erik.Carrion@Student.Shu.Edu Seton Hall University eRepository @ Seton Hall Seton Hall University Dissertations and Theses Seton Hall University Dissertations and Theses (ETDs) Spring 5-19-2018 Tumor-Targeting Fluorinated Phthalocyanines for Theranostic Applications Erik Nathaniel Carrión Seton Hall University, [email protected] Follow this and additional works at: https://scholarship.shu.edu/dissertations Part of the Inorganic Chemistry Commons, Materials Chemistry Commons, Medicinal- Pharmaceutical Chemistry Commons, and the Organic Chemistry Commons Recommended Citation Carrión, Erik Nathaniel, "Tumor-Targeting Fluorinated Phthalocyanines for Theranostic Applications" (2018). Seton Hall University Dissertations and Theses (ETDs). 2524. https://scholarship.shu.edu/dissertations/2524 TUMOR-TARGETING FLUORINATED PHTHALOCYANINES FOR THERANOSTIC APPLICATIONS A Dissertation submitted to Seton Hall University in partial fulfillment of the requirements for the degree of Doctorate of Philosophy By Erik Nathaniel Carrión May 2018 Department of Chemistry and Biochemistry Seton Hall University South Orange, NJ, USA Copyright © 2018 by Erik Nathaniel Carrión ALL RIGHTS RESERVED 2 ABSTRACT TUMOR-TARGETING FLUORINATED PHTHALOCYANINES FOR THERANOSTIC APPLICATIONS 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). F48H7CONHPcZn-AHX-Pep42 F48H7CONHPcZn-R’-Pep42-R9 (R’ = AHX/PEG6) Scheme 1. Schematic representation of GRP78 -targeting fluorinated PcZn bioconjugates. AHX = aminohexanoate; PEG = polyethylene glycol. 1 F48H7COOHPcCu is also reported and capable of generating singlet oxygen ( O2). 1 F48H7CONHPcZn-AHX-Pep42, like the unconjugated PcZn, still performed O2-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 1 unrelated to O2 production. The work herein highlights the development of catalytic, fluorine- based anti-cancer drugs that may be useful as potential theranostic agents. 4 Dedicated to my beloved parents, Daniel and Lupe Carrión and brother, Daniel G. Carrión. 5 ACKNOWLEDGEMENTS My journey as a PhD graduate student is one that I will never forget nor the people who were a part of it. First and foremost, I would like to thank my mentor, Dr. Sergiu M. Gorun for introducing me to phthalocyanines and their properties. He taught me some of the fundamentals of X-ray crystallography wherein I grew beautiful crystals, even though the majority of them diffracted poorly or not at all! I will always appreciate the time he spent with me, showing me the significant amount of information that can be extracted at the atomic level. With every experiment, analyses need to be done with a grain of salt and every scientific claim I made needed to be supported with hard, scientific data as per one of his many famous mantras, “In God we trust, everyone else...bring data”. Secondly, I would also like to thank my research co-mentor, Dr. David Sabatino, for welcoming me into his lab and introducing me to peptide chemistry. His expertise with solid-phase organic synthesis was vital in this work in developing drugs for cancer therapy and diagnostic, or simply theranostic (our new favorite word now) applications. I will always remember his inspiring speeches which always motivated us in our work and the importance of meeting deadlines in a timely manner. It was a privilege working with both of my mentors. Their constant support, encouragement, and guidance were equally helpful towards the completion of this thesis work. I would also like to thank Dr. Murphy and his group for not only introducing me to fluorescence spectroscopy but also for allowing me to have an office area in his lab before joining my current research groups. Dr. Lalancette and Dr. Roman Brukh are gratefully acknowledged for their help in acquiring and interpreting X-ray diffraction and mass spectrometry data, respectively. Along these lines, I would also like to acknowledge Dr. Daniel Paley (Columbia University) and Dr. Michelle Neary (Hunter College) for also acquiring X-ray diffraction data and 6 performing structure solutions. I was also fortunate enough to work in collaboration with Dr. Tina Chu in exploring the potential antimicrobial activity of our materials. Dr. Yuri Kazakevich is acknowledged for his generous donation of reverse-phase columns and offering his expertise with any HPLC-related questions we had. Dr. Graça Vicente, Zehua Zhou, Dr. Eddie Merino, and Dr. Allan Blake are thanked for their collaborative work with biology. I would also like to thank Maureen Grutt for her help with my graduate school paperwork. Dr. Cecilia Marzabadi and Dr. Nicholas Snow are acknowledged for their support to attend ACS national conferences. Dr. Cosimo Antonacci is acknowledged for his help in running the undergraduate teaching labs. Rafael Rivera is also acknowledged for his help in ordering the chemicals needed for my work. Jimmy is also acknowledged for helping me with maintenance work in the lab. My former colleague in the Gorun group, Dr. Hemantbhai Patel, is gratefully acknowledged for training me in phthalocyanine synthesis, purification, and characterization as well as Dimitry Kalantarov for his help with the photo-oxidation equipment. In addition, I would also like to thank past and current graduate group members in both Gorun’s and Sabatino’s group I would also like to acknowledge Jenyffer Santiago for her support and patience with me during my studies, especially during the days when I needed to work later than anticipated. She was there for me during the good days and the bad and for that I cannot thank her enough. Last, but not least, I would like to express my sincerest gratitude towards my family, my parents, Daniel and Lupe Carrión, and my brother, Daniel G. Carrión for everything. Words cannot describe how truly grateful I am for the sacrifices they have made to help me receive the education I have now. Everything I am now is because of their love, support, and guidance. I love you all very much and I hope I made you proud. 7 TABLE OF CONTENTS Chapter Page 1. INTRODUCTION TO FLUORINATED METAL PHTHALOCYANINES ..............27 1.1. General Introduction to Phthalocyanines ......................................................28 1 1.2. Photosensitized Production of Singlet Oxygen, O2. ....................................33 1.2.1. Absorption and Emission Mechanism (Jablonski Diagram) 33 1 1.2.2. Electronic Structure of O2. 35 1.3. Application to Photodynamic Therapy ..........................................................37 1.3.1. Porphyrins as Photosensitizers 38 1.3.2. Phthalocyanines as Near-Infrared Photosensitizers for PDT. 39 1.4. Generation of Functional Fluorine-based Phthalocyanines ...........................40 1.5. Project Goals .................................................................................................44 References ........................................................................................................................46 2. CARBOXYL-FUNCTIONALIZED FLUOROALKYL ZINC AND COPPER PHTHALOCYANINES ...................................................................................................55 2.1. Introduction ...................................................................................................56 2.2. Objectives ......................................................................................................61 2.3. Experimental Section ....................................................................................61 2.3.1. Materials and Methods 61 2.3.2. Synthesis 62 2.3.3. Glove Box Techniques 63 2.3.4. Microwave Synthesis 63 2.3.5. UV-Vis Aggregation Study 63 2.3.6. NMR Spectroscopy 63 2.3.7. High-resolution Mass Spectrometry 64 2.3.8. X-ray Crystallography 64 2.3.9. Singlet Oxygen Production 65 2.3.10. Spectrofluorimetry Measurements 66 2.4. Results and Discussion ..................................................................................67 2.4.1. Synthesis 67 2.4.2. Single Crystal X-ray Diffraction studies 68
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