Delivery of Targeted Nanoparticles Across the Blood-Brain Barrier Using a Detachable Targeting Ligand

Chronic diseases of the central nervous system are poorly treated due to the inability of most therapeutics to cross the blood-brain barrier. The blood-brain barrier is an anatomical and physiological barrier that severely restricts solute influx, including most drugs, from the blood to the brain. One promising method to overcome this obstacle is to use endogenous solute influx systems at the blood-brain barrier to transport drugs. Therapeutics designed to enter the brain through transcytosis by binding the transferrin receptor, however, are restricted within endothelial cells. The focus of this work was to develop a method to increase uptake of transferrin-containing nanoparticles into the brain by overcoming these restrictive processes.

To accomplish this goal, nanoparticles were prepared with surface transferrin molecules bound through various liable chemical bonds. These nanoparticles were designed to shed the targeting molecule during transcytosis to allow increased accumulation of nanoparticles within the brain.

Transferrin was added to the surface of nanoparticles through either redox or pH sensitive chemistry. First, nanoparticles with transferrin bound through disulfide bonds were prepared. These nanoparticles showed decreased avidity for the transferrin receptor after exposure to reducing agents and increased ability to enter the brain in vivo compared to those lacking the disulfide link.

Next, transferrin was attached through a chemical bond that cleaves at mildly acidic pH. Nanoparticles containing a cleavable link between transferrin and gold nanoparticle cores were found to both cross an in vitro model of the blood-brain barrier and accumulate within the brain in significantly higher numbers than similar nanoparticles lacking the cleavable bond. Also, this increased accumulation was not seen when using this same strategy with an antibody to transferrin receptor, indicating that behavior of nanoparticles at the blood-brain barrier varies depending on what type of targeting ligand is used.

Finally, polymeric nanoparticles loaded with dopamine and utilizing a superior acid-cleavable targeting chemistry were investigated as a potential treatment for Parkinson’s disease. These nanoparticles were capable of increasing dopamine quantities in the brains of healthy mice, highlighting the therapeutic potential of this design. Overall, this work describes a novel method to increase targeted nanoparticle accumulation in the brain.

Tectonics of Central and Eastern California, Late Cretaceous to Modern

The Late Cretaceous to Modern tectonic evolution of central and eastern California has been studied for many decades, with published work generally focusing on specific geographic areas and time periods. The resulting literature leaves the reader, whether graduate student, faculty member, or layperson, wondering what a coherently integrated tectonic evolution might look like, or if it would be at all possible to undertake such a task. This question is the common thread weaving together the four studies presented in this work. Each of the individual chapters is targeted at a specific location and time period which I have identified as a critical yet missing link in piecing together a coherent regional tectonic story. In the first chapter, we re-discover a set of major west down normal faults running along the western slope of the southern Sierra, the western Sierra fault system (WSFS). We show that one of these faults was offset by roughly a kilometer in Eocene time, and that this activity directly resulted in the incision of much of the relief present in modern Kings Canyon. The second chapter is a basement landscape and thermochronometric study of the hanging wall of the WSFS. New data from this study area provide a significant westward expansion of basement thermochronometric data from the southern Sierra Nevada batholith. Thermal modeling results of these data provide critical new constraints on the early exhumation of the Sierra Nevada batholith, and in the context of the results from Chapter I, allow us to piece together a coherent chronology of tectonic forcings and landscape evolution for the southern Sierra Nevada. In the third chapter, I present a study of the surface rupture of the 1999 Hector Mine earthquake, a dextral strike slip event on a fault in the Eastern California Shear Zone (ECSZ). New constraints on the active tectonics in ECSZ will help future studies better resolve the enigmatic mismatch between geologic slip rates and geodetically determined regional rates. Chapter IV is a magnetostratigraphic pilot study of the Paleocene Goler Formation. This study provides strong evidence that continued investigation will yield new constraints on the depositional age of the only fossil-bearing Paleocene terrestrial deposit on the west coast of North America. Each of these studies aims to provide important new data at critical missing links in the tectonic evolution of central and eastern California.