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Functionalization and Synthesis Of © 2019 GAYATRI SHRIKHANDE ALL RIGHTS RESERVED FUNCTIONALIZATION AND SYNTHESIS OF DIFUNCTIONAL FOLATE-TARGETED POLYMERIC CONJUGATES FOR POTENTIAL DIAGNOSTIC APPLICATIONS A Dissertation Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Gayatri Shrikhande December, 2019 FUNCTIONALIZATION AND SYNTHESIS OF DIFUNCTIONAL FOLATE-TARGETED POLYMERIC CONJUGATES FOR POTENTIAL DIAGNOSTIC APPLICATIONS. Gayatri Shrikhande Dissertation Approved: Accepted: _______________________________ ______________________________ Advisor Department Chair Dr. Jie Zheng Dr. H Michael Cheung _______________________________ ______________________________ Committee Member Interim Dean of the College Dr. Bi-min Zhang Newby Dr. Craig Menzemer _______________________________ ______________________________ Committee Member Dean of the Graduate School Dr. Ge Zhang Dr. Chand Midha _______________________________ ______________________________ Committee Member Date Dr. Chrys Wesdemiotis _______________________________ Committee Member Dr. Mark Soucek ii ABSTRACT The aim of this research was to synthesize polymer-diagnostic agent conjugates with two folate functionalities for potential diagnostic applications. Conjugates with fluorescein (FL) as an imaging agent, poly(ethylene glycol) (PEG) as a hydrophilic linker and two folic acid (FA) as targeting agents were synthesized by chemo-enzymatic method using Candida antarctica lipase B (CALB) catalyst for the multivalent targeting of folate receptors (FRs) overexpressed on cancer cells. In this dissertation work, imaging agent FL was first acrylated using acryloyl chloride (AcrCl) in the presence of triethylamine (TEA) to precisely synthesize fluorescein o-acrylate (FL-A, yield: 52.49%) and fluorescein o,o’- diacrylate (FL-DA, yield: 63.9%). A kinetic study of FL-DA synthesis was conducted using a Nuclear Magnetic Resonance (NMR)-750 MHz spectrophotometer instrument which demonstrated the formation FL-DA in 13 seconds reaction time. Hence, our FL-DA synthesis was extremely fast and easy to purify using silica gel. Acrylate moieties of FL- DA and FL-A allow the CALB-catalyzed Michael addition of thiol and amine to develop the conjugates. First, FL-A with single acrylate moiety was reacted with PEG-diamine (H2N-PEG- NH2) by the CALB-catalyzed Michael addition. However, the nucleophilic secondary amine of FL-NH-PEG-NH-FL interfered with the acrylation of ‘OH’ of FL-A. Hence, a new synthetic strategy was developed where H2N-PEG-NH2 was replaced by dithiol- functionalized PEG (HS-PEG-SH, Mn =899 g/mol, Đ=1.00, Mn =1160 g/mol, Đ=1.14 and iii Mn =2200 g/mol, Đ=1.09) and tetraethylene glycol (HS-TEG-SH, FW= 370.48 g/mol) which were synthesized in Dr. Puskas’ lab to avoid the interference of the amine group in the acrylation reaction. Michael addition between FL-A and HS-TEG-SH, by CALB- catalysis was extremely fast and completed in 1 minute at 52℃. Reaction between FL-A and HS-PEG-SH without CALB catalysis did not go to completion even after 18 hours at 52℃ but completed in 2 minutes when CALB was added. CALB catalysis was found to be extremely useful to synthesize FL-TEG-FL and FL-PEG-FL compounds. Further acrylation of the ‘OH’ of FL-A, followed by the attachment of FA-SH by the Michael addition resulted in successful development of the difunctional FL-PEG conjugate with different molecular weights. PEGylation of FL using brominated PEG was also attempted by lithium chemistry to develop the FL-PEG-FL conjugate which can be further acrylated for the attachment of FA-SH. However, due to the presence of impurities during the PEGylation, no further reactions were performed. Next, tetrafunctional FL compounds were synthesized by the aza-Michael addition reaction between FL-DA and secondary amines by studying the effect of CALB-catalysis. These multifunctional FL compounds can be used as precursors to develop polymeric conjugates. The aza-Michael addition reactions of small molecules, such as diethanolamine (DEA) and diallylamine (DAA) to FL-DA were completed in 1 minute at room temperature without CALB-catalysis in dimethyl sulfoxide (DMSO), while the reactions were extremely slow in chloroform. CALB catalysis was found to be extremely useful with large sterically hindered molecules, such as diethyl iminodiacetate (DIDA) as the reaction time was three times less than the reaction without CALB catalysis. The aza-Michael addition product of DEA with FL-DA (tetrahydroxy-functionalized FL) was highly unstable, it iv hydrolyzed back to FL due to neighboring group (OH) participation. Hence to avoid the hydrolysis, new dihydroxy-functionalized secondary amines with longer alkyl chains were synthesized by ultraviolet (UV)-mediated thiol-ene click reaction between DAA and 4- mercapto-1-butanol and with 9-mercapto-1-nonanol. CALB-catalyzed Michael addition of these newly synthesized dihydroxy secondary amines to FL-DA resulted in successful synthesis of tetrahydroxy functionalized FL. Finally, a scale-up of FL-DA synthesis is discussed in this dissertation, where FL- DA was successfully scaled up in a 5-liter capacity jacketed reactor with overhead stirrer and a pure product with 54.32% yield was obtained. The cost to synthesize 1 g of FL-DA in the lab was 41.29 USD. The structures of all products were confirmed by Proton NMR (1H-NMR), Carbon- 13 NMR (13C-NMR) and Matrix-assisted Laser Desorption/Ionization Time of Flight (MALDI-ToF MS). v DEDICATION This dissertation is dedicated to my family: My mother, Swati Shrikhande; my father, Sanjay Shrikhande; my brother, Gaurang Shrikhande and my love, my husband, Abhishek Deshpande. This dissertation would not have been possible without their warm love, continued patience and endless support. vi ACKNOWLEDGEMENTS I am grateful to Dr. Judit Puskas for providing me this great research opportunity, valuable guidance and support during Ph.D. I am thankful to Dr. Jie Zheng for his continued help and suggestions throughout my Ph.D. I would also like to thank My Ph.D. committee Dr. Chrys Wesdemiotis, Dr. Ge (Christie) Zhang, Dr. Mark Soucek and Dr. Bi- min Zhang Newby for providing constructive feedback and motivation through the course of this research. I would like to express deep gratitude to Dr. Sanghamitra Sen for teaching me various chemistry skills and for her guidance. Her teaching helped me grow as a researcher. Financial support by the Breast Cancer Innovation Foundation, Akron is greatly appreciated. I am very delightful to work with my good friend Prajakatta Mulay with whom I had a great collaboration in research. I also would like to thank Dr. Aditya Jindal, Andrew McClain, Dr. Jozsef Kantor, Dr. Gabor Kaszas and Dr. Carin Helfer for their help. I acknowledge Dr. Wesdemiotis’ research group at The University of Akron and The Ohio State University Mass Spectrometry Facility for the mass spectrometry analysis of the samples. I would like to thank our collaborator Cleveland Clinic for the in vitro and in vivo studies. Dr. Venkat Dudipala’s guidance towards Nuclear Magnetic Resonance (NMR) technique is valuable. I am thankful to Dr. Richard Elliot for his help with the Molecular Orbital PACkage (MOPAC) simulation software during the scale-up experiment. Last but not the least I thank all past members of the Dr. Puskas’ group for their help and wonderful memories and all my friends, family for their love and support. vii TABLE OF CONTENTS Page LIST OF TABLES ............................................................................................................ xiii LIST OF FIGURES .......................................................................................................... xiv CHAPTER I. INTRODUCTION .................................................................................................. 1 II. BACKGROUND .................................................................................................... 5 2.1. Folate-targeted cancer diagnosis and treatment .......................................... 5 2.1.1. Cancer statistics .............................................................................. 5 2.1.2. Motivation for breast-cancer focus ................................................. 5 2.1.3. Folate-targeting ............................................................................... 6 2.1.3.1. FA-receptor mediated endocytosis (RME) ................... 10 2.1.3.2. Clinical trials ................................................................. 12 2.1.3.3. Multivalent targeting ..................................................... 14 2.2. Modular approach to FA-targeted diagnostic devices .............................. 17 2.2.1. Cleveland Clinic comparative trials .............................................. 19 2.2.2. New synthetic strategies ............................................................... 24 2.3. Components of the new strategies ............................................................ 28 2.3.1. Fluorescein (FL)............................................................................ 28 2.3.2. Poly(ethylene glycol) (PEG) linker .............................................. 32 2.3.2.1. PEG-diamine (H2N-PEG-NH2) ..................................... 33 viii 2.3.2.2. PEG-dithiol (HS-PEG-SH) ........................................... 35 2.3.3. Thiol-functionalized folic acid (FA-γ-SH) ................................... 37 2.4. Construction of the conjugates .................................................................. 39 2.4.1.
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