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Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Polymer Science and Engineering

Year Degree Awarded

2018

Month Degree Awarded

May

First Advisor

Gregory N. Tew

Subject Categories

Biological Engineering | Biomaterials | Immunoprophylaxis and Therapy | Polymer Chemistry

Abstract

The plasma membrane is a major obstacle in the development and use of biomacromolecules for intracellular applications. Consequently, proteins with intracellular targets represent an enormous, yet under studied avenue for therapeutics. Extended research has aimed at facilitating intracellular delivery of exogenous proteins using protein transduction domains (PTDs), which allow transport of bioactive molecules into cells. Synthetic polymers, inspired by PTDs, provide a well-controlled platform to vary molecular architecture for structure activity relationship studies. Specifically, this thesis focuses on the use of ring-opening metathesis, a facile and efficient polymerization technique, through which we can vary structural parameters to optimize delivery of non-covalently encapsulated proteins. The aim was to characterize, optimize, and utilize PTD mimics (PTDMs) for functional protein delivery. Fluorescently labeled cargo were used to elucidate the predominant cellular entry mechanism for the PTDMs and were compared to their ability to deliver protein into cells. A series of polymers was designed around the most membrane active polymers to explore the incorporation of guanidine and hydrophobic moieties, yielding a PTDM capable of high protein delivery into a variety of cell types. The PTDM was then explored for use as a vaccine delivery reagent into immune cells. The ability to have a specific response with the cargo of interest verifies cytosolic delivery using the PTDMs and provides valuable insight into their use to affect intracellular pathways.

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