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Title:Development of intranasal therapeutic nanoparticles for the treatment of neurological disorders
Author(s):Joachim, Elizabeth Grace
Director of Research:Kim, Kevin K
Doctoral Committee Chair(s):Kim, Kevin K
Doctoral Committee Member(s):Choi, Hyungsoo; Liang, Zhi-Pei; Bashir, Rashid
Department / Program:Bioengineering
Discipline:Bioengineering
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):neuroprotection
stroke
estrogen
intranasal delivery
Abstract:Globally, ischemic stroke is a leading cause of both death and adult disability. Current therapeutics emphasize reperfusion without further mechanisms to reduce infarct volume or promote healing and are most effective within 3 h of symptom onset: a window in which less than 30% of stroke victims receive medical attention. Numerous neuroprotective agents, such as peptides, hormones, and siRNA, have been shown to confer neuroprotection following ischemic stroke in animal models. Clinically, treatment of ischemic stroke is hindered by the relative isolation of the central nervous system from the systemic circulation by the blood brain barrier (BBB). Though cannula and intracranial injections are practical methods to circumvent the BBB in laboratory conditions, such procedures are contraindicated in clinical settings. As such, we are interested in leveraging the intranasal (IN) pathway to bridge the gap between animal studies and clinical application. However, the advantages of the IN pathway are tempered by low efficiency, and, therefore, we have applied our gelatin nanoparticle (GNP) technology to aid drug delivery to the brain following IN administration. GNPs are a biodegradable, biocompatible, and cost-effective drug delivery platform. As we have previously demonstrated, GNPs can not only pass into the brain parenchyma following intranasal administration, but also extend and enhance the neuroprotective effects of peptide and siRNA model drugs when administered up to 6 h after middle cerebral artery occlusion (MCAO) in a rat model. The specific properties of intranasal GNPs that confer these beneficial effects are poorly understood. Therefore, we sought to support the development of GNPs as a drug delivery platform for the IN treatment of ischemic stroke and, potentially, other neurological disorders by studying their distribution and degradation. Finally, to further investigate the versatility and therapeutic potential of IN GNPs, we have applied our technology to the delivery of estrogen post-ischemia. The use of estrogens in stroke is a classic example of the disparity between animal and human studies; estrogen replacement therapy has repeatedly failed to show clinical benefit in the prevention of cerebrovascular disease despite extensive preclinical data demonstrating benefits. Therefore, the problem of estrogen in stroke is a particularly poignant test case for our hypothesis that IN GNPs can address disparities between preclinical and clinical studies by providing a patient-friendly drug administration method.
Issue Date:2018-12-05
Type:Thesis
URI:http://hdl.handle.net/2142/102930
Rights Information:Copyright 2018 Elizabeth Joachim
Date Available in IDEALS:2019-02-08
Date Deposited:2018-12


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