Graduation Date

Spring 5-9-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Aaron Mohs, PhD

Second Advisor

Tatiana Bronich, PhD

Third Advisor

Yuri Lyubchenko, D. Sc.

Fourth Advisor

Joeseph Vetro, PhD

Abstract

Cancer, one of the most challenging maladies facing modern medicine, is a complex family of diseases that requires a multifaceted treatment regime. In recent years, increased research effort has been placed on the development of nanoscale formulations as a potential method to improve therapeutic efficacy and offer better treatment. Both drug formulation and biomedical imaging has benefitted from the development of new, nanoscale agents. Hyaluronic Acid (HA), a naturally occurring glycosaminoglycan, is a promising platform for the development of new drug delivery systems. Furthermore, hyaluronic acid is the principal ligand for the cell surface receptor CD44, which is overexpressed on many different cancer cells. For these reasons, HA is often used as a component in novel formulations of anticancer therapies or biomedical imaging agents. This work is divided into two sections: the first detailing the use of hyaluronic acid-derived contrast agents for integrated preoperative and intraoperative imaging, and the second part investigating the effects of hydrophobic modification on the dynamics of HA. These two parts coalesce in the exploration of HA as a backbone of nanoformulations and strive to improve the ability to use HA as a foundation of better formulations. In the first part of this dissertation, a mixed micelle formulation comprised of both fluorescent and paramagnetic labeled HA is used to provide higher contrast in a murine model of breast cancer. The ratio of fluorescent and paramagnetic HA is optimized to 3 provide contrast in fluorescence and magnetic resonance imaging. In the second part of this dissertation, theoretical approaches using molecular dynamics simulation are employed to better elucidate the behavior of hydrophobically modified HA. The unifying theme of this dissertation is the enhanced understanding of HA-based nanoformulations. Beginning with direct, experimental application, limitations are discovered in the development of a multimodality imaging agent formulation using HA as the backbone. Instigated by this limitation, theoretical approaches are employed to better define and describe the foundational principals of nanoformulation using HA. Ultimately, the work presented herein serves to further the ability to design, characterize, and apply HA-based nanomedicines.

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