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dc.contributor.advisor Chow, Diana S.
dc.creator Ibrahim, Fady
dc.date.accessioned 2012-02-07T20:00:02Z
dc.date.accessioned 2012-02-07T20:00:09Z
dc.date.available 2012-02-07T20:00:02Z
dc.date.available 2012-02-07T20:00:09Z
dc.date.created 2011-05
dc.date.issued 2012-02-07
dc.date.submitted May 2011
dc.identifier.uri http://hdl.handle.net/10657/216
dc.description.abstract Radiotherapy is an important tool in the treatment of brain tumors. However, radiotherapy‘s success is limited by its toxic lipid peroxidation effects on the surrounding tissues. Lazaroid U74389G (LAZ) is a 21-aminosteroid that has a potent inhibitory effect on iron-dependent lipid peroxidation. It acts as an antioxidant and a membrane stabilizer. It prevents the damage in the brain after radiation by a selective distribution to vascular endothelium and its anti-oxidant activity. LAZ suffers from high liver uptake and short half life after an IV administration. We propose to circumvent this problem by using intravenous administration of nanosuspension or liposomal formulations or intracranial implantation of sustained release formulation. The nanosuspensions can provide a dramatic change in the biodistribution of the drug especially targeting RES organs. The nanosuspensions were prepared by wet milling techniques to produce nanosuspensions of 250 and 125 nm. The surface potential of the particles were modified in a later stage by adding ionic surfactants to produce neutral, anionic and cationic nanosuspensions. The anionic nanosuspension accumulated in the lungs 3-8 folds of that from the solution demonstrating a promising formulation for targeting lung cancers. The microspheres were formulated using the biodegradable polymer PLGA with various molecular weights and densities. The microspheres sustained the release of 90% of LAZ over 21 days using the lowest molecular weight PLGA 0.43 g/dL and only 40% of LAZ load was released from the highest density PLGA 0.65 g/dL over the same period of time. By using a mixture of microspheres formulated from various PLGA polymers, the release profile can be potentially tailored to match the therapy protocol of different patients. LAZ was formulated in conventional (Lipo B) and PEGylated (Lipo G) liposomes. The formulations were characterized for the size, zeta potential and release in PBS and plasma. Healthy nude mice received 1 mg/kg IV doses of the solution or liposomes to characterize the plasma pharmacokinetics and organ biodistribution. Lipo G increased the brain exposure of LAZ 13 folds of that from the solution, and was further used in a brain Glioblastoma bearing model expressing luciferase enzyme as a reporter gene. The animals received no treatment or were treated with radiation together with Lipo G or Lipo G alone at a dose of 5mg/kg IP. The tumor size was monitored by bioluminescence imaging and malondialdehyde level was used as a surrogate for lipid peroxidation in the brain tissue. Lipo G showed higher stability in plasma compared Lipo B. In healthy mice, Lipo G yielded a higher AUC in plasma and prolonged t1/2 compared to those from the solution and Lipo B. Brain exposure from Lipo G was 4 and13 times those from LipoB and solution, respectively. Both tumor size and lipid peroxidation were significantly reduced in Lipo G treated group compared to the no-treatment control. PEGylated LAZ liposomes demonstrated cytotoxic effects against Glioblastoma and protection against radiation induced necrosis.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.subject Lazaroi U-74389G, Liposomes, Nanosuspensions, Microspheres, Radiotherapy, Radioprotective, Chemotherapy, Glioblastoma, Brain, Pharmacokinetics, Organ Distribution
dc.title Formulations of Lazaroid-U74389G for Organ Targeting and Potential Chemotherapy
dc.date.updated 2012-02-07T20:00:09Z
dc.type.material text *
dc.type.genre thesis *
thesis.degree.name Pharmaceutics
thesis.degree.level Doctoral
thesis.degree.discipline Pharmacy
thesis.degree.grantor University of Houston
thesis.degree.department Pharmacological and Pharmaceutical Sciences
dc.contributor.committeeMember Bates, Theodore R.
dc.contributor.committeeMember Li, Chun
dc.contributor.committeeMember New, Pamela
dc.contributor.committeeMember Tam, Vincent H.

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