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Publication Date

2024-5

First Advisor

Maren E. Buck

Second Advisor

Sarah J. Moore

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Chemistry

Keywords

amphiphilic copolymers, post-polymerization modifications, bioconjugation, targeted therapeutics

Abstract

Targeted drug delivery systems like protein-polymer conjugates (PPCs) and protein-drug conjugates (PDCs) offer a promising alternative to traditional cancer treatments by decreasing off-target effects and lowering the dosage required for effective treatment. PPCs and PDCs are both robust systems that offer a variety of biological applications. PPCs are able to load multiple drugs per polymer chain, thus lowering the dosage required when compared to PDCs, which are limited in their loading. Small molecules have minimal effects on the conjugated protein if the conjugation site is away from the binding interface, whereas polymers can either stabilize or destabilize the protein, vary pharmacological and chemical properties of the PPC, or it could block binding of the protein to cell receptors. In this thesis, we proposed to develop a combinatorial approach to synthesize a library of amine-reactive amphiphilic copolymers and probe the influence of polymer chemistry and reactivity on the preparation and function of PPCs in a biological context. Further, we proposed to design and synthesize a cleavable disulfide linker for protein-drug conjugates that aims to expand the design space for protein-small molecule conjugates. We also investigated the release rates and kinetics of the cleavable linker. We will be targeting the integrin αvβ3 receptor present on solid tumor cells for targeted drug delivery via engineered Fn3 proteins with specific binding to integrin αvβ3. The Fn3 proteins will either be conjugated to polymers that can have stabilizing effects on the protein and/or carry cytotoxic payloads, or conjugated directly to cytotoxic payloads via a cleavable disulfide linker.

Rights

©2024 Thatcher Lee. Access limited to the Smith College community and other researchers while on campus. Smith College community members also may access from off-campus using a Smith College log-in. Other off-campus researchers may request a copy through Interlibrary Loan for personal use.

Language

English

Comments

209 pages: color illustrations, charts. Includes bibliographical references (pages 160-163).

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