Defense Date
2024
Document Type
Thesis
Degree Name
Doctor of Philosophy
Department
Chemistry
First Advisor
Xuewei Wang
Abstract
Nitric oxide (NO) plays an essential role in various physiological functions, including cardiovascular regulation, immunity, and neurotransmission. The challenge of harnessing NO's therapeutic potential lies in the controlled delivery of this gaseous molecule. S-nitrosothiols (RSNOs), which can spontaneously and catalytically release NO, offer a promising method for its exogenous delivery. However, their application is hindered by the unpredictable kinetics of NO release across different conditions. This research tackles these challenges by presenting three interconnected projects that aim to achieve safe, effective, and sustained NO release from RSNO formulations, specifically using two representative RSNOs: S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP), making them suitable for a wide range of biomedical applications.
Chapter 1 provides an overview of NO generation and function in vivo, elucidating the chemical reactions involved. It also summarizes current FDA-approved NO-related therapies and lists the most commonly studied NO-releasing compounds, highlighting their pros and cons. The chapter also reviews the developments in NO-releasing materials and solutions, identifying the challenges within this field. Additionally, it offers an overview of the dissertation study.
Chapter 2 introduces a one-step 3D printing strategy to fabricate NO-releasing silicone medical devices, featuring an RSNO-loaded bulk with a drug-free coating. The embedded RSNO crystals within the polymeric matrix enable sustained NO release, thereby endowing the device with antibacterial properties. This additive manufacturing platform, which avoids the need for drug dissolution and eliminates thermal or UV curing steps, offers unique opportunities for producing customized drug-eluting silicone devices.
Chapter 3 explores a series of aqueous GSNO formulations with the potential to serve as lock solutions for catheters, aimed at preventing catheter-associated infections. This chapter highlights the critical role of buffer in pH-sensitive NO donor formulations and discusses the significant stabilization effect of alpha-cyclodextrin on GSNO. This stabilization extends the NO release duration from days to weeks, showcasing the potential for long-term infection control in clinical settings.
Chapter 4 describes the development of a simple, light-controlled NO generator that operates without the need for a NO2 filter or an elaborate feedback control system, simply by limiting photon incidence. This innovative design promises to lower the costs associated with NO inhalation therapy, making it particularly beneficial for settings with limited resources.
Chapter 5 provides comprehensive summaries of the dissertation study. This chapter identifies the remaining challenges that need to be addressed and outlines directions for future research.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-16-2024
Included in
Biochemistry Commons, Other Chemicals and Drugs Commons, Pharmaceutical Preparations Commons, Polymer and Organic Materials Commons