Characterization of iron oxide nanoparticles (IONPs) for brain targeted delivery
| dc.contributor.author | Sun, Zhizhi | |
| dc.contributor.examiningcommittee | Parkinson, Fiona (Pharmacology & Therapeutics) Smyth, Donald (Pharmacology & Therapeutics) Hegmann, Torsten (Chemistry) Kabanov, Alexander (University of North Carolina) | en_US |
| dc.contributor.supervisor | Miller, Donald (Pharmacology and Therapeutics) | en_US |
| dc.date.accessioned | 2016-05-09T20:50:28Z | |
| dc.date.available | 2016-05-09T20:50:28Z | |
| dc.date.issued | 2016 | |
| dc.degree.discipline | Pharmacology and Therapeutics | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | The restrictive nature of the brain endothelial cells that form the blood-brain barrier (BBB) limits both the paracellular and transcellular passage of many molecules into the brain. Therefore, effective treatment of brain disorders requires a focus on improving drug permeability across the BBB. This thesis focuses on characterization and optimization of iron oxide nanoparticles (IONPs) as a potential platform for drug delivery to the brain. Given concerns with metal toxicity in the brain, we first examined the biocompatibility and cellular uptake profile of positively and negatively charged IONPs in brain endothelial cells, astrocytes, and neurons. These in vitro studies showed both IONP formulations were well tolerated at concentrations less than 100ug/mL, and that positively charged IONPs have a greater uptake profile than negatively charged IONPs across all cell types examined. It is hypothesized that transient disruption of the BBB combined with the application of a magnetic field, a process we have termed “Magnetic Field Enhanced Covective Diffusion” (MFECD), could be used to enhance IONPs penetration of the BBB. Using the cell culture model of the BBB, disruption of tight junctions with a hyperosmotic mannitol solution resulted in significant increases in permeability for the negatively charged IONP. Even further enhancement of negatively charged IONP permeability was observed when an external magnetic field was applied. Positively charged IONPs showed no significant change in permeability to osmotic disruption or magnetic field. Encouraged by the in vitro permeability studies, the pharmacokinetic properties of negatively charged IONPs was examined in healthy mice under control conditions or following transient BBB disruption using lysophosphatidic acid (LPA). Under normal conditions, IONPs had half-life of 6 minutes and liver and spleen were the major organs of IONP deposition, with limited distribution to the brain. Treatment with LPA significantly enhanced the brain accumulation of IONPs. In addition, examination of microglia and astrocyte activation showed transient BBB disruption and enhanced IONP accumulation in the brain did not lead to inflammation or toxicity. Together, our findings suggest transient disruption of the BBB, alone or coupled with MFECD, may be a safe and effective method for increasing IONP delivery to the brain. | en_US |
| dc.description.note | October 2016 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/31279 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | iron oxide nanoparticles | en_US |
| dc.subject | pharmacokinetics | en_US |
| dc.subject | drug delivery | en_US |
| dc.subject | blood-brain barrier | en_US |
| dc.title | Characterization of iron oxide nanoparticles (IONPs) for brain targeted delivery | en_US |
| dc.type | doctoral thesis | en_US |