title: Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.
abstract: Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.
authors: Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States of America. benjamin_bleier@meei.harvard.edu
authors: Benjamin S
authors: BS
authors: Bleier
authors: Richie E
authors: RE
authors: Kohman
authors: Rachel E
authors: RE
authors: Feldman
authors: Shreshtha
authors: S
authors: Ramanlal
authors: Xue
authors: X
authors: Han
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism; D004058:Diffusion; D051379:Mice; D008970:Molecular Weight; D009297:Nasal Mucosa / Q000378:metabolism* / Q000637:transplantation*; D010539:Permeability; D012235:Rhodamines / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors
chemical_list: D003911:Dextrans; D012235:Rhodamines
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