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Author ORCID Identifier

https://orcid.org/0000-0001-5448-802X

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Polymer Science and Engineering

Year Degree Awarded

2022

Month Degree Awarded

February

First Advisor

Todd Emrick

Subject Categories

Polymer Chemistry

Abstract

This dissertation describes the synthesis, characterization, and application of novel polymer zwitterion-drug conjugates intended for treating glioblastoma, with a particular focus on phosphorylcholine (PC) and temozolomide (TMZ). Using versatile TMZ-containing monomers, injectable polymer prodrugs and implantable polymeric hydrogels were prepared over a broad range of drug incorporations with tunable properties, making them ideally suited for further in vivo and clinical evaluations. The work presented here greatly expands the knowledge base of TMZ formulations and gives rise to several routes which circumvent the challenges associated with its use. Chapter 2 describes the incorporation of a novel TMZ-methacrylate monomer into random and block copolymers by controlled free radical polymerizations. The solution properties of these polyMPC-TMZ copolymers was investigated, and it was demonstrated that TMZ conjugation to the polymer backbone significantly enhanced drug stability in physiological conditions. The antitumor activity of polyMPC-TMZ copolymers was demonstrated in chemosensitive (U87MG) and chemoresistant (T98G) human glioblastoma cell lines. Additionally, the impact of a redox-responsive drug-to-polymer linker on drug release and cytotoxicity was investigated. Chapter 3 augments the polyMPC-TMZ conjugate platform through the incorporation of additional co-monomers, including disulfiram (DSF) and gemcitabine (GEM), to overcome chemoresistance in glioblastoma cells. These polymers—envisioned as staggered release materials—employ various methods of covalent conjugation chemistries and demonstrated drug release and stability properties dependent on the pH and reducing potential of the buffer environment. Finally, Chapter 4 details the preparation of polymeric hydrogels based on MPC, poly(ethylene glycol) (PEG), and the polyMPC-TMZ conjugates described in Chapter 2. Physical encapsulation of the prodrugs into UV-crosslinked hydrogels gave rise to pellets with tunable drug release, enhanced shelf-stability in ambient conditions, and robust swelling and mechanical properties. Additionally, preliminary examinations of these pellets in healthy (HEK293A) and glioblastoma (U87MG) cell lines were conducted, providing insight for the development of additional routes of hydrogel preparation and drug incorporation.

DOI

https://doi.org/10.7275/27072199.0

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