Nanoformulation of Brain‐Derived Neurotrophic Factor with Target Receptor‐Triggered‐Release in the Central Nervous System |
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| Authors: | James M. Fay Chi‐Duen Poon Natasha Vinod Yuling Zhao Kristin Bullock Si Qin Xiang Yi William A. Banks Alexander V. Kabanov |
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| Affiliation: | 1. Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA;2. Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA;3. Research Computer Center, University of North Carolina, Chapel Hill, NC, USA;4. Joint UNC/NC State Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC, USA;5. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA;6. Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA;7. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA;8. Laboratory for Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia |
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| Abstract: | Brain‐derived neurotrophic factor (BDNF) is identified as a potent neuroprotective and neuroregenerative agent for many neurological diseases. Regrettably, its delivery to the brain is hampered by poor serum stability and rapid brain clearance. Here, a novel nanoformulation is reported composed of a biocompatible polymer, poly(ethylene glycol)‐b‐poly(l ‐glutamic acid) (PEG‐PLE), that hosts the BDNF molecule in a nanoscale complex, termed here Nano‐BDNF. Upon simple mixture, Nano‐BDNF spontaneously forms uniform spherical particles with a core–shell structure. Molecular dynamics simulations suggest that binding between BDNF and PEG‐PLE is mediated through electrostatic coupling as well as transient hydrogen bonding. The formation of Nano‐BDNF complex stabilizes BDNF and protects it from nonspecific binding with common proteins in the body fluid, while allowing it to associate with its receptors. Following intranasal administration, the nanoformulation improves BDNF delivery throughout the brain and displays a more preferable regional distribution pattern than the native protein. Furthermore, intranasally delivered Nano‐BDNF results in superior neuroprotective effects in the mouse brain with lipopolysaccharides‐induced inflammation, indicating promise for further evaluation of this agent for the therapy of neurologic diseases. |
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| Keywords: | central nervous system drug delivery intranasal delivery neurotrophic factors polyion complexes |
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