Doctor of Philosophy, University of Akron, 2019, Chemical Engineering

Breast Cancer is the most common cancer among women and nearly 1 in every 8 American women suffer from it. Triple negative breast cancer, a type of breast cancer that can be only treated using chemotherapy, affects nearly 20% of the breast cancer diagnosed women. Early detection of breast cancer increases survival rates among patients. This dissertation discusses the development of a new two-functional folate-targeted poly(ethylene glycol)-based fluorescein-labeled conjugate (FA-FL-PEG-FL-FA) for potential applications in selective diagnosis of triple negative breast cancer. Since folate, or vitamin B9, receptors (FRs) are overexpressed in breast cancer cells, the diagnosis of these cells is targeted by using a γ-thiolated folic acid (FA-γ-SH) as the targeting precursor. α-carboxyl group present on folate is necessary for binding with the FRs, therefore, exclusive γ-thiolation was achieved by using n-butyllithium that selectively forms the lithium salt (FA-γ-Li) at the γ-carboxyl position due to its higher pKa. The subsequent thiolation was achieved by reducing FA-γ-S-S-γ-FA, which was prepared by reacting a dibrominated disulphide compound (Br-S-S-Br, synthesized via enzyme-catalyzed transesterification) with FA-γ-Li. To increase the retention time in the body and improve the solubility of the agent in water, functionalized PEGs were used as the hydrophilic linkers. Diamine, dithiol, and dibromide functionalization of PEGs were achieved using novel enzyme (Candida antartica Lipase B)-catalyzed esterifications and transesterifications. Specifically, three strategies to synthesize FA-FL-PEG-FL-FA were investigated for their synthetic convenience and feasibility. Strategy 1 used diamine-functionalized PEG (H2N-PEG-NH2), Strategy 2 used dithiol-functionalized PEG (HS-PEG-SH), and Strategy 3 used dibromide-functionalized PEG (Br-PEG-Br) as the precursors. The first strategy and the third strategy were not successful owing to not quantitatively yielding the interm (open full item for complete abstract)

Committee: Lingyun Liu (Advisor); Jie Zheng (Committee Member); Rebecca Kuntz Willits (Committee Member); Chrys Wesdemiotis (Committee Member); Mark Soucek (Committee Member) Subjects: Chemical Engineering; Chemistry; Molecules; Organic Chemistry; Polymer Chemistry; Polymers

Doctor of Philosophy, University of Akron, 2019, Chemical Engineering

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, Ð=1.00, Mn =1160 g/mol, Ð=1.14 and Mn =2200 g/mol, Ð=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°C. Reaction between FL-A and HS-PEG-SH without CALB catalysis did not go to completion even after 18 hours at 52°C but completed in 2 minutes when C (open full item for complete abstract)

Committee: Jie Zheng PhD (Advisor); Ge Zhang PhD (Committee Member); Chrys Wesdemiotis PhD (Committee Member); Bi-min Zhang Newby PhD (Committee Member); Mark Soucek PhD (Committee Member) Subjects: Biomedical Engineering; Chemical Engineering; Chemistry; Materials Science; Polymer Chemistry; Polymers

PhD, University of Cincinnati, 2001, Arts and Sciences : Chemistry

PAMAM dendrimers have been synthesized using two separate acrylamide monomer compounds, (2-acryloylamino-ethyl)-carbamic acid tert-butyl ester (1) and N-cyanomethyl-acrylamide (18). These monomer units allow for facile synthesis of PAMAM dendrimers with decreased opportunity of defects. Zero and first generations dendrimers have been synthesized with compound 1 and zero through second generation dendrimers have been synthesized with compound 18. Various amine-terminated compounds were used as initiator cores from which the dendrimers were grown. Dendrimers were also grown using 3-[(2-tert-butoxycarbonylamino-ethyl)-(2-methoxycarbonyl-ethyl)-amino]-propionic acid methyl ester (9). After selective deprotection of this compound, normal amino acid coupling procedures were used to produce the next higher half-generation dendrimer.

Committee: Prof. Allan Pinhas (Advisor); Prof. William Heineman (Other); Prof. H. Halsall (Other); Prof. R. Wilson (Other) Subjects: Chemistry, Organic

Master of Science, University of Akron, 2012, Polymer Science

Two of the most commonly employed bioadhesives used for wound closure applications today are fibrin-based and cyanoacrylate-based bioadhesives, both of which have adverse effects. Fibrin-based bioadhesives allow for the possible transmission of viral blood-borne pathogens, while cyanoacrylate-based bioadhesives have toxicity concerns due to their degradation into formaldehyde. To address these drawbacks and many others, it is proposed that a polyisobutylene-based bioadhesive be employed, since polyisobutylene has a long, successful history as a bio-friendly material. Potential polyisobutylene-based bioadhesives first were prepared by the difunctionalization of α-ω-dihydroxy polyisobutylenes with vinyl methacrylate through “green” enzyme catalyzed Candida antarctica lipase B (CALB) transesterification reactions at 50¿¿¿¿¿¿¿ within 24 hours with high yields. Four different compounded crosslinking solution formulations consisting of synthesized α-ω-dimethacrylate polyisobutylenes, 10% or 20% of the trifunctional crosslinker 2-ethyl-2-hydroxymethyl-1-,3-propanediol trimethacrylate (TMP-TMA) and a 20% solution of the ultra-violet (UV) reactive photoinitiator 2,2-dimethoxy-2-phenylacetophenone effectively demonstrated the ability to crosslink terminally functionalized linear polyisobutylenes into continuous film networks under ambient conditions quickly (< 5 min.) by the use of UV light. Various techniques were used to characterize their crosslinking and physical properties, as well as to determine that the molecular weight of α-ω-dimethacrylate polyisobutylenes had a greater effect on the characterizable attributes than the amount of TMP-TMA employed. Techniques used to characterize the continuous polyisobutylene film networks included: the evaluation of polyisobutylene film discontinuities; the measurement and calculation of their physical dimensions; aesthetic evaluation; solvent extraction and swelling assessments; FTIR; TGA; and DSC. These methods characterized th (open full item for complete abstract)

Committee: Judit E. Puskas Dr. (Advisor); Chrys Wesdemiotis Dr. (Committee Member) Subjects: Polymer Chemistry; Polymers

Doctor of Philosophy, University of Akron, 2009, Polymer Science

The objective of this research was to investigate the enzyme-catalyzed functionalization of polymers. For this purpose, first, model small molecules were employed in Candida antarctica lipase B (CALB)-catalyzed transesterification and Michael addition reactions. CALB-catalyzed transesterification of ethyl acetate and vinyl acetate with 2-phenyl-1-propanol (2PPOH), the model compound for primary hydroxyl-functionalized polyisobutylene (PIB) prepared from the α-methylstyrene epoxide (α-MSE)/TiCl4 initiator system, indicated that the latter was a more effective acyl donor as it formed unstable vinyl alcohol which instantly tautomerized to acetaldehyde and thus rendered the reaction irreversible. The comparison of the catalytic activity of CALB with that of a commercially available transesterification catalyst, bis[dibutylchlorotin(IV)] oxide, revealed that in the transesterification of vinyl acetate with 2PPOH, CALB was the more reactive catalyst. Ethylene glycol (EG) was reacted with vinyl methacrylate (VMA) in the presence of CALB as a model reaction for the methacrylation of poly(ethylene glycol) (PEG) and it was observed that the reaction proceeded in a consecutive fashion first yielding the monosubstituted product followed by disubstituted ester. Thymine was reacted with both vinyl acrylate (VA) and VMA through Michael addition in the presence of CALB as a model reaction for the addition of thymine to (meth)acrylated polymers. Quantitative conversion was observed in the case of VA whereas VMA gave 63% conversion. The resulting vinyl esters of thymine were then reacted with EG through transesterification using CALB as the model reaction for the addition of thymine to hydroxyl-functionalized polymers. It was observed that the majority of the product was the monosubstituted EG. These synthetic procedures were then applied to polymer functionalization.The primary hydroxyl-functionalized PIB prepared from α-MSE/TiCl4 was not reactive towards CALB. On the other hand, PI (open full item for complete abstract)

Committee: Judit E. Puskas PhD (Advisor) Subjects: Polymers