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Author ORCID Identifier

https://orcid.org/0000-0001-5899-3357

AccessType

Open Access Dissertation

Document Type

dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Chemistry

Year Degree Awarded

2021

Month Degree Awarded

May

First Advisor

Jeanne Hardy

Second Advisor

S. Thayumanavan

Subject Categories

Biochemistry, Biophysics, and Structural Biology | Cell and Developmental Biology | Chemistry

Abstract

Cysteine aspartate proteases (caspases) act as the molecular scissors of cell death, disintegrating diverse cellular components necessary for survival and growth via proteolysis. Caspases are tightly regulated through a myriad of mechanisms including proteolytic processing, structural changes, post-translational modifications and metal binding. Correspondingly, cancers have evolved numerous resistance and desensitization mechanisms upstream or within the caspase pathway to avoid death signals. These mechanisms are extremely diverse and are not fully understood however, the field overwhelming suggests caspase activity and caspase inhibition antagonism to be critical for efficacious cancer therapies. Accordingly, exploiting the role of caspases in apoptosis has become an increasingly prevalent strategy for cancer intervention. As state-of-the-art nanoparticles continue to be developed, recombinant caspases themselves can be utilized to shift cancer equilibriums to be susceptible to death signals. Nevertheless, caspases are a particularly challenging therapeutic subset, requiring careful delivery vehicle design and compatibility for caspase introduction into cancer cells with sufficient proteolytic activity and native structural characteristics. In this dissertation we performed different mechanistic investigations to improve intracellular caspase delivery via polymeric nanogels that can not only be utilized therapeutically, but also can innovatively contribute to the comprehensive knowledge of caspase function.

DOI

https://doi.org/10.7275/22271546.0

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