Synthesis and characterization of dendrimer-based nitric oxide delivery systems

Nitric oxide (NO) has garnered much attention as a therapeutic due to its multifaceted role in human physiology. However, NO is a highly reactive radical, making its chemical storage and controlled release extremely challenging. Although several small molecule NO donors have been reported in the literature, the limited NO storage and the inability to target NO to a specific site of action have seriously hindered the clinical utility of NO donors. To address these limitations, my research has focused on the synthesis of macromolecular NO-releasing dendrimers that store large quantities of NO (1–5 μmol NO/mg). Herein, the synthesis and characterization of two systems are presented employing the two most common small molecule NO donors: N-bound diazeniumdiolates and S-nitrosothiols. Decomposition of the diazeniumdiolate NO donor was proton initiated under aqueous conditions with the NO release being highly influenced by the local dendritic environment. S-nitrosothiol dendrimer conjugates were subject to decomposition by various triggers of NO release (e.g., copper and light) and also shown to directly transfer NO to proteins via transnitrosation. The systems described in this thesis represent two of the highest NO-releasing nanoparticle NO donors reported to date. Additionally, studies investigating the cytotoxicity of multifunctional dendrimer conjugates and the physiological activity of dendrimer derived nitric oxide are presented.