Title:
Local and sustained delivery of hydrophobic drugs to the spinal cord with polyketal microparticles

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dc.contributor.advisor Murthy, Niren
dc.contributor.author Kao, Chen-Yu en_US
dc.contributor.committeeMember Jonathan D. Glass
dc.contributor.committeeMember Michael E. Davis
dc.contributor.committeeMember Thomas H. Barker
dc.contributor.committeeMember Valeria T. Milam
dc.contributor.department Biomedical Engineering en_US
dc.date.accessioned 2011-03-04T21:18:19Z
dc.date.available 2011-03-04T21:18:19Z
dc.date.issued 2009-07-30 en_US
dc.description.abstract Amyotrophic lateral sclerosis (ALS) is a devastating disease. Currently, there is no cure for this disease, and effective treatment strategies are greatly needed. Calpain activation plays a major role in the motor neuron degeneration that causes ALS. Therefore, therapeutic strategies can inhibit calpain activity in the central nervous system (CNS) have great clinical potential. The calpain inhibitors AK295 and MDL-28170 have been demonstrated to be neuroprotective in animal models of neurological injury, and should have great potential to treat ALS; however delivery problems have hindered their clinical success. Therefore, development of a new strategy that can locally deliver the calpain inhibitors to the central nervous system could significantly improve the treatment of ALS. The objectives of my thesis research were (1) to develop high molecular weight polyketals that provide sustained release properties for hydrophobic molecules, (2) to formulate calpain inhibitor-encapsulated polyketal microparticles which have a release half life of one month in vitro, (3) and to evaluate the performance of polyketal microparticles for delivering calpain inhibitors to the spinal cord in vivo. In completing these specific aims, we have developed biodegradable polymeric microparticles for the delivery of calpain inhibitors, AK295 and MDL-28170 to treat ALS. The results of calpain assays showed that both AK-PKMs and MDL-PKMs maintained most of their inhibitory activities even after the robust emulsion process. The in vitro release profile of MDL-28170 in MDL-PKMs showed that 50 % of the drug was released in the first 30 days. Experiments using dye-encapsulated microparticles showed that polyketal microparticles (1-2 ìm) are not easily cleared in the neutral physiological environment and can have potential to continuously release drug from the injection sites in the spinal cord. The efficacy of calpain inhibitor-encapsulated PKMs were studied by evaluation the behavior and survival of SOD1G93A rats, a genetic rat model for ALS. We observed the trend toward improvements in grip strength and rotarod performance in the first two months from the AK-PKMs treated group, however, further improvements are needed to enhance their in vivo efficacy. en_US
dc.description.degree Ph.D. en_US
dc.identifier.uri http://hdl.handle.net/1853/37304
dc.publisher Georgia Institute of Technology en_US
dc.subject Microparticle en_US
dc.subject Polyketal en_US
dc.subject Sustained release en_US
dc.subject Amyotrophic lateral sclerosis en_US
dc.subject Intrapinal cord injection en_US
dc.subject Drug delivery en_US
dc.subject Hydrophobic en_US
dc.subject Calpain inhibitors en_US
dc.subject.lcsh Calpain
dc.subject.lcsh Polymeric drug delivery systems
dc.subject.lcsh Polymers in medicine
dc.subject.lcsh Biomedical materials
dc.title Local and sustained delivery of hydrophobic drugs to the spinal cord with polyketal microparticles en_US
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.corporatename Wallace H. Coulter Department of Biomedical Engineering
local.contributor.corporatename College of Engineering
relation.isOrgUnitOfPublication da59be3c-3d0a-41da-91b9-ebe2ecc83b66
relation.isOrgUnitOfPublication 7c022d60-21d5-497c-b552-95e489a06569
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