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Title:
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Formulations of Lazaroid-U74389G for Organ Targeting and Potential Chemotherapy |
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Author:
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Chow, Diana S. |
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Description:
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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 . |
Citation
Formulations of Lazaroid-U74389G for Organ Targeting and Potential Chemotherapy.
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