Date of Award
Doctor of Philosophy
Paul M. Dalhaimer
Steven M. Abel, Eric E. Boder, Sherry Cox
Nanoparticles have been of interest to the pharmaceutical industry since the 1980s. The first FDA approved nanoparticle-based therapies included liposomal anesthesia agents. Since then, the amount of FDA-approved nanoparticle therapies remains low. This is because nanoparticle-patient interactions can be very complex and are not well understood. Complicating factors also include increasing obesity rates among the patient population and many small animal pre-clinical trials are completed with healthy, lean animals. The biochemical differences between lean and obese patients prevents early studies from accurately predicting nanoparticle clinical behaviors. Many nanoparticles fail in trails. In this thesis, I aimed to uncover how nanoparticles interact with cells in an obesity-like environment.
I focused mainly on nanoparticles made from PEO-PBD di-block polymers (synthesized by Jimmy Mays’s group in chemistry). The di-block polymers form into long, flexible cylinders (“filomicelles” or more generally, cylindrical nanoparticles (CNPs)). CNPs have been previously shown to have favorable circulation times compared to spherical nanoparticles, but I wanted to know how CNP enter cells. Surprisingly, this mechanism is not well-known for any nanoparticle. I focused on the potential interaction between CNPs and the major HDL receptor SR-BI. This was done with in vitro experiments involving the small molecule inhibition and binding site competition of SR-BI. In vivo experiments were also conducted with SR-BI deficient mice and co-injection of CNPs and HDL.
I then wanted to study the effects obesity would have on the pharmokinetics profile and biodistribution of CNPs and liposomal nanoparticles (LNPs). LNPs are the most used NPs in the clinic, so they provide a good control to evaluate the possibility of using CNPs in the clinic. I used a combination of controlled diet and leptin deficiency in mice to conduct this study. Interestingly, obesity caused CNPs to localize to the liver faster than lean controls. LNPs had the opposite effect. Further experimentation suggested this was due to different destination cell types within the liver for CNP vs LNP. In the third study, I developed a nucleic acid therapy that can trigger the lipolysis (breakdown) of neutral lipids in mammalian cells using a split-intein technology that I learned as an undergraduate.
Raith, Mitchell, "Interactions Between Soft Nanoparticles and Mammalian Cells. " PhD diss., University of Tennessee, 2022.