Intranasal delivery for peptide and siRNA to the brain using lipid-based nanocarriers for the treatment of neuroinflammation.
Degree: PhD, School of Pharmacy, 2015, Northeastern University
Neurodegenerative diseases are the most prevalent brain diseases affecting more than 5.5 million people worldwide. If left unconstrained, 30 years from now, more than 12 million Americans will suffer from these diseases. neuro-inflammation has been one of the common denominator in broad spectrum of neurodegenerative diseases, such as Alzheimer's, Parkinson's, Sclerosis, and age-related macular degeneration diseases. Prevention and cure of these brain diseases has been facing outstanding challenge due the limited delivery of pharmacological therapeutics to the brain primarily due to presence of blood-brain barrier (BBB), blood-CSF barrier and expression of efflux transporters.; The objective of this thesis project is to develop and characterize a nanoemulsion delivery system to explore the potential of intranasal delivery of cyclosporine peptide and TNF-alpha gene silencing siRNA-based drugs to block the activity of cytokines in LPS-induced animal model of neuro-inflammation. Targeting brain regions by exploiting transport of anti-inflammatory drugs through the olfactory pathways, thus bypassing the BBB, while avoiding peripheral distribution of the drugs and blocking proinflammatory cytokines seems to be a rational approach for the treatment of neuro-inflammation.; We prepared and characterized nanoemulsion formulations for both of the therapeutic drugs: cyclosporine and TNF-alpha silencing siRNA. Multiple cell culture models were screened to mimic the structural and functional aspects of nasal epithelial. RPMI2650 cells demonstrated an enhanced permeability and intracellular uptake of nanoemulsion formulations. With the use of in vivo magnetic resonance imaging (MRI) we qualitatively showed better and higher distribution of nanoemulsion formulations via intranasal dosing. LPS induced neuro-inflammation based model was established and the anti-inflammatory therapeutic effect and safety of both CSA and TNF-alpha silencing siRNA was proven based on intranasal delivery of nanoemulsion formulation.; We demonstrate that intranasal drug delivery using nanoemulsion systems not only enhances the uptake and distribution in brain but also shows anti-inflammatory therapeutic effects as evidence by reduction in the proinflammatory cytokines in LPS induced neuro-inflammation model. Overall, this study reveals utility of intranasal delivery of nanoemulsion as a non-invasive means to bypass BBB and provides preliminary evidence for a safe and effective drug delivery strategy for targeting brain. These findings open up an opportunity to target at variety of diseases underpinned by inflammation within the nervous system, where exposure of drugs is a major limitation.
Subjects/Keywords: neurodegenerative diseases; intranasal drug delivery; Intranasal medication; Small interfering RNA; Therapeutic use; Peptides; Therapeutic use; Nervous system; Degeneration; Animal models; Nanomedicine; Drug delivery systems; Blood-brain barrier
to Zotero / EndNote / Reference
APA (6th Edition):
Yadav, S. (2015). Intranasal delivery for peptide and siRNA to the brain using lipid-based nanocarriers for the treatment of neuroinflammation. (Doctoral Dissertation). Northeastern University. Retrieved from http://hdl.handle.net/2047/D20198907
Chicago Manual of Style (16th Edition):
Yadav, Sunita. “Intranasal delivery for peptide and siRNA to the brain using lipid-based nanocarriers for the treatment of neuroinflammation.” 2015. Doctoral Dissertation, Northeastern University. Accessed July 17, 2019.
MLA Handbook (7th Edition):
Yadav, Sunita. “Intranasal delivery for peptide and siRNA to the brain using lipid-based nanocarriers for the treatment of neuroinflammation.” 2015. Web. 17 Jul 2019.
Yadav S. Intranasal delivery for peptide and siRNA to the brain using lipid-based nanocarriers for the treatment of neuroinflammation. [Internet] [Doctoral dissertation]. Northeastern University; 2015. [cited 2019 Jul 17].
Available from: http://hdl.handle.net/2047/D20198907.
Council of Science Editors:
Yadav S. Intranasal delivery for peptide and siRNA to the brain using lipid-based nanocarriers for the treatment of neuroinflammation. [Doctoral Dissertation]. Northeastern University; 2015. Available from: http://hdl.handle.net/2047/D20198907