Gelatin nanoparticles for improved neuroprotection of intranasally delivered osteopontin in ischemic stroke

Delivery of therapeutic agents to the brain is significantly hampered by the blood- brain barrier (BBB). Typically, only small, lipophilic molecules can freely enter the brain parenchyma following systemic administration. During the initial development phases, many drug candidates for neurological disorders are administered directly to target regions through use of cannula or intracranial injection. These administration routes are not practical clinically, and, as a result, many promising experimental drug candidates fail to enter clinical use due to an inability to effectively cross the BBB. The intranasal (IN) route is a promising pathway currently under investigation to bypass the BBB for rapid, non-invasive delivery of therapeutics to the brain. The advantages of the IN pathway are tempered by typically low efficiency, and, therefore, nanocarriers have been proposed to aid drug delivery to the brain following IN administration. Herein, we show the development of GNPs as a biodegradable, biocompatible, and cost-effective drug delivery platform using intranasal delivery of a peptide fragment to treat ischemic stroke in a rat model as proof-of-concept. Ischemic stroke is a leading cause of adult disability and 4th leading cause of death worldwide. The major impediments to functional recovery following stroke are short therapeutic windows and a lack of neuroprotective treatments. 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. Osteopontin (OPN), a ubiquitous protein with roles in cell migration, inflammation, and apoptosis, has been shown to confer neuroprotection following ischemic stroke in animal models. In this work, we not only successfully fabricated GNPs with a uniform shape, but also demonstrated the ability of these GNPs to pass into the brain parenchyma following intranasal administration. Critically, the use of GNPs as a carrier allowed for a 71.57% reduction in mean infarct volume and extended the therapeutic window of intranasally administered OPN peptide to at least 6 h post-middle cerebral artery occlusion (MCAO). Our findings support the development of GNPs as a promising drug delivery platform for the intranasal treatment of ischemic stroke and, potentially, other neurologic disorders.

Name thesis:degree_name

M.S.

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Bioengineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Joachim, Elizabeth

Contributors dc:contributor

• Kim, Kyekyoon

• Intranasal drug delivery
• Gelatin nanoparticles
• Neuroprotection
• Ischemic stroke
• Osteopontin

Statement dc:rights

• Copyright 2015 Elizabeth Joachim

Handle dc:identifier

http://hdl.handle.net/2142/78300

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/78300