Undergraduate Honors Theses

Thesis Defended

Spring 2012

Document Type

Thesis

Department

Biochemistry

First Advisor

Dr, Tad H. Koch

Abstract

Described are studies focused on prodrug delivery of a doxorubicin-formaldehyde conjugate, doxazolidine (Doxaz). Designed for targeted activation by the serine protease plasmin, Protease-Activated Doxazolidine (PAD) embodies a new approach to selective cancer treatment. Following a model developed by the Koch laboratory, the PAD prodrug consists of a peptide tag attached to Doxaz via a self-eliminating spacer. Enzymatic cleavage of the peptide and subsequent spacer elimination results in release of active Doxaz into the tumor environment from the otherwise inactive prodrug. Problems in the current synthesis of PAD are addressed in steps taken towards a new synthetic pathway. Additionally, this study addresses preliminary biological evaluation of PAD activation and treatment feasibility through multiple enzyme and cancer cell assays. Finally, this work addresses the specific role of the plasmin system in PAD activation through RNA interference. Using short hairpin RNA to knockdown key components of the plasmin activation pathway, a more accurate portrayal of the plasmin system’s role in PAD activation can be attained. Results suggest PAD is a feasible drug candidate and offer encouragement for advanced evaluation as a novel therapeutic.

Share

COinS