Factors Impacting the Efficacy of Cell-mediated Drug Delivery to the Brain via the Blood Brain Barrier
Open Access
- Author:
- Selvi, Erhan Yavuz
- Graduate Program:
- Bioengineering
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- April 08, 2016
- Committee Members:
- Cheng Dong, Thesis Advisor/Co-Advisor
- Keywords:
- cell-mediated drug delivery
blood brain barrier
VE-cadherin
VCAM-1
ICAM-1
VLA-4
LFA-1
transendothelial migration - Abstract:
- Glioblastoma is the most prevalent primary malignant tumor of the brain and has a very poor prognosis of death usually occurring within 2 years at the most (Stupp et al., 2005). Cell-mediated drug delivery to the brain is a new field of treatment and the blood-brain barrier plays a vital role in delivery of drugs to the brain. The binding of vascular cadherin’s (VE-cadherin) cytosolic domain with intracellular catenins was shown to be an important aspect in the cell’s ability to limit permeability and maintaining its junctional strength (Navarro et al., 1995). Previous studies have shown VCAM-1/VLA-4 binding to induce VE-cadherin breakdown (Khanna et al., 2010). Gap formation in the endothelium with respect to time and the presence of immune cells or cytokines was examined in this study, as well as the compatibility of the immune cells for a model of cell-mediated drug delivery with a chemotaxis study. Gap formation due to co-culture with Jurkat cells was significant but not with THP-1 cells. Additionally, gap formation was not time dependent. VE-cadherin breakdown due to endothelium stimulation from tumor necrosis factor alpha (TNFα) for 24 hours resulted in increased gap formation when cultured with Jurkat cells, but not THP-1 cells. Cell adhesion molecules were most not expressed on the endothelium after 24 hours of TNFα exposure then 24 hours with no exposure. White blood cells (WBCs) isolated from human blood did not result in significant gap formation with the endothelium as well. Chemotaxis studies showed Jurkat cells to be the better candidate for cell-mediated drug delivery since it migrated more effectively through 8µm pores. Overall, Jurkat cells prove to be a better candidate for drug delivery in terms of gap formation and migration.