Forrest, LairdMoulder, Kenneth Ryan2019-12-102019-12-102019-08-312019http://dissertations.umi.com/ku:16765https://hdl.handle.net/1808/29847The inherent properties of protein therapeutics (e.g. high molecular weight, charged, conformationally dependent) has historically limited their administration to parenteral routes which presents new challenges to their controlled delivery. Hydrogel and nanoparticle drug delivery systems can parenterally deliver a wide variety of drugs in a controlled manner while sustaining their therapeutic efficacy. Nanogels, formed from amphiphilic polymers, combine the unique and tunable properties of hydrogels and nanoparticles into one drug delivery system and have the potential to drastically improve the clinical applicability of protein therapeutics delivered subcutaneously. Hyaluronic acid, a ubiquitous polysaccharide of the extracellular matrix often used in drug delivery applications, was hydrophobically functionalized by the addition of glycine-modified vitamin E (-tocopherol) to form a self-assembling nanogel (HAtoco). The characterization of HAtoco was further developed by modifying its molecular weight and tocopherol substitution towards an optimum 33 kDa backbone with a 10mol% substitution. Physical and chemical characterization of the optimum HAtoco demonstrated its polydisperse effective size, stable colloidal and chemical stability and continued biodegradability by the endogenous enzyme hyaluronidase. In addition, HAtoco has shown the ability to double the in vitro release half-life of three model proteins (BSA, RNase, Lysozyme) and the in vivo release half-life of the clinical protein therapeutic Coversin when delivered subcutaneously to mice. Structural studies of HAtoco bound Coversin demonstrated destabilization of the protein upon adsorption, but released Coversin from the HAtoco nanogel demonstrated complement inhibition for at least 73 hours in vitro. Overall, HAtoco has demonstrated the ability to bind protein therapeutics in a reversible manner capable of prolonging their release in a therapeutically efficacious state.180 pagesenCopyright held by the author.Pharmaceutical sciencesCoversinHyaluronic acidNanogelVitamin EDissertationopenAccess