Examining the integrity of the blood-brain barrier (BBB) and the use of lysophosphatidic acid (LPA) to modulate the barrier properties

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dc.contributor.supervisor Miller, Donald (Pharmacology & Therapeutics) en_US
dc.contributor.author On, Ngoc H.
dc.date.accessioned 2012-08-23T15:51:36Z
dc.date.available 2012-08-23T15:51:36Z
dc.date.issued 2011-03 en_US
dc.identifier.citation On, N. H., F. Chen, M. Hinton, and D. W. Miller. 2011. Assessment of P-glycoprotein activity in the blood-brain barrier (BBB) using near infrared fluorescence (NIRF) imaging techniques. Pharmaceutical Research (May 20) en_US
dc.identifier.uri http://hdl.handle.net/1993/8460
dc.description.abstract INTRODUCTION: The blood brain barrier (BBB), formed by the brain capillary endothelial cells separating the blood from the brain. Furthermore, the brain endothelial cells also express numerous transporter systems which help regulate and maintain the brain microenvironment. The protective function of the BBB and their transporter systems under pathological disease states, including brain tumor, can be an obstacle for the entry of therapeutic agents to the brain. OBJECTIVES: The current study set out to characterize brain tumor-induced alterations of the BBB of a mouse brain tumor model. Studies were performed to address changes in BBB permeability to P-gp dependent solutes using Rhodamine (R800). Furthermore, the use of lysophosphatidic acid (LPA) to modulate BBB permeability was also examined in healthy mice and tumor-bearing mice. METHODS: Tumors were induced by injecting Lewis Lung carcinoma (3LL) cells into the right hemisphere of female Balb/c mice. Changes in BBB permeability were assessed at various stages of tumor development, using both gadolinium contrast-enhanced agent (Gad) and 3H-mannitol. Functional activity of P-gp in the BBB was examined in adult mice following i.v. injection of R800 in the presence and absence of GF120918 (a P-gp inhibitor). Alterations in BBB permeability were characterized in healthy and tumor-bearing mice using a small (Gad) and large (IRdye800cw PEG) vascular permeability agent as well as R800 (changes in P-gp mediated permeability). RESULTS: Median mouse survival following 3LL injection was 17 days. The BBB was largely intact during tumor development with disruptions observed at the later stages of tumor development as indicated by Gad permeability. By inhibiting the function of P-gp with GF120918, the distribution of R800 in the brain increased by 4-fold. The enhancement effect of LPA on BBB permeability occurs within 3-6 minutes of injection with the barrier being restored back to its normal function within 20 minutes. Furthermore, an increased in brain penetration of IRdye800ce PEG and R800 were observed following LPA injection in both healthy and tumo-bearing mice. CONCLUSION: These studies provide the initial proof of concept for the use of BBB modulators including LPA and GF120918 to enhance drug delivery to the brain and the tumor sites. en_US
dc.publisher Springer en_US
dc.rights info:eu-repo/semantics/openAccess
dc.subject Blood-brain barrier en_US
dc.subject P-glycoprotein en_US
dc.subject Chemotherapeutic agents en_US
dc.subject Brain tumors en_US
dc.subject Lysophosphatidic acid en_US
dc.subject Permeability en_US
dc.title Examining the integrity of the blood-brain barrier (BBB) and the use of lysophosphatidic acid (LPA) to modulate the barrier properties en_US
dc.type info:eu-repo/semantics/doctoralThesis
dc.type doctoral thesis en_US
dc.degree.discipline Pharmacology and Therapeutics en_US
dc.contributor.examiningcommittee Parkinson, Fiona (Pharmacology & Therapeutics) Peeling, James (Pharmacology & Therapeutics) Eisenstat David (Biochemistry & Medical Genetics) Smith, Quentin (Texas Tech University Health Sciences Center) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note October 2012 en_US

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