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Synthesis of Folate-Targeted Poly(Ethylene Glycol)-Based Conjugates And Their Precursors

Mulay, Prajakatta
http://orcid.org/0000-0001-6314-1175
http://rave.ohiolink.edu/etdc/view?acc_num=akron1574442562023675

Abstract Details

2019, Doctor of Philosophy, University of Akron, 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 intermediate products. Two-functional folate-targeted PEG-based fluorescein-labeled conjugates (FA-FL-PEG-FL-FA) with tetraethylene glycol, PEG with Mn = 1000 g/mol and 2050 g/mol, and discreet PEG (MW = 898 g/mol, Ð = 1) as the hydrophilic linkers were successfully synthesized using the second strategy. The enzyme-catalyzed Michael addition of thiol-functionalized PEGs to Sefose and the synthesis of cyclic polydisulfide polymers made using Reversible Redox Ring Polymerization (R3P) was also investigated and is discussed in this dissertation. In addition, my NSF-sponsored internship report is also presented in the appendices.
Lingyun Liu (Advisor)
Jie Zheng (Committee Member)
Rebecca Kuntz Willits (Committee Member)
Chrys Wesdemiotis (Committee Member)
Mark Soucek (Committee Member)
222 p.
Chemical Engineering; Chemistry; Molecules; Organic Chemistry; Polymer Chemistry; Polymers
poly ethylene glycol; Candida antarctica Lipase B; polymer functionalization; enzyme catalysis; gamma conjugated folic acid; PEG thiol; PEG amine; PEG bromide; folate targeted conjugates; transesterification; Michael addition; Sefose; cyclic polydisulfide

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Citations

  • Mulay, P. (2019). Synthesis of Folate-Targeted Poly(Ethylene Glycol)-Based Conjugates And Their Precursors [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1574442562023675

    APA Style (7th edition)

  • Mulay, Prajakatta. Synthesis of Folate-Targeted Poly(Ethylene Glycol)-Based Conjugates And Their Precursors. 2019. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1574442562023675.

    MLA Style (8th edition)

  • Mulay, Prajakatta. "Synthesis of Folate-Targeted Poly(Ethylene Glycol)-Based Conjugates And Their Precursors." Doctoral dissertation, University of Akron, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1574442562023675

    Chicago Manual of Style (17th edition)

akron1574442562023675
905
© 2019, all rights reserved.
This open access ETD is published by University of Akron and OhioLINK.