TY - JOUR
T1 - Delivery of immunoglobulin G antibodies to the rat nervous system following intranasal administration
T2 - Distribution, dose-response, and mechanisms of delivery
AU - Kumar, Niyanta N.
AU - Lochhead, Jeffrey J.
AU - Pizzo, Michelle E.
AU - Nehra, Geetika
AU - Boroumand, Sam
AU - Greene, Gretchen
AU - Thorne, Robert G.
N1 - Funding Information:
This work was generously supported by the Michael J. Fox Foundation for Parkinson's Research (UW Reference # MSN189990 ), the Clinical and Translational Science Award program administered through the NIH National Center for Advancing Translational Sciences ( NIH UL1TR000427 and KL2TE000428 ), the Wisconsin Alumni Research Foundation Accelerator Program , the University of Wisconsin-Madison School of Pharmacy , the Graduate School at the University of Wisconsin-Madison , fellowships through the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1256259 (MEP), NIH fellowships ( NRSA T32 EBO11434 – MEP), Parkinson's Foundation-American Parkinson's Disease Association Summer Student Fellowship ( PF-APDA-SFW-1730 – SB), the Hilldale Undergraduate Research Fellowship from the University of Wisconsin-Madison (SB), and the Howard Hughes Medical Institute Precollege and Undergraduate Science Education Program grant to Macalester College (GG). Laser scanning confocal microscopy was performed with training and guidance from Dr. Michael Taylor (Nikon A1R) and Dr. Arash Bashirullah (Olympus FV1000) at the University of Wisconsin-Madison School of Pharmacy.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/9/28
Y1 - 2018/9/28
N2 - The intranasal route has been hypothesized to circumvent the blood-brain and blood-cerebrospinal fluid barriers, allowing entry into the brain via extracellular pathways along olfactory and trigeminal nerves and the perivascular spaces (PVS) of cerebral blood vessels. We investigated the potential of the intranasal route to non-invasively deliver antibodies to the brain 30 min following administration by characterizing distribution, dose-response, and mechanisms of antibody transport to and within the brain after administering non-targeted radiolabeled or fluorescently-labeled full length immunoglobulin G (IgG) to normal adult female rats. Intranasal [125I]-IgG consistently yielded highest concentrations in the olfactory bulbs, trigeminal nerves, and leptomeningeal blood vessels with their associated PVS. Intranasal delivery also resulted in significantly higher [125I]-IgG concentrations in the CNS than systemic (intra-arterial) delivery for doses producing similar endpoint blood concentrations. Importantly, CNS targeting significantly increased with increasing dose only with intranasal administration, yielding brain concentrations that ranged from the low-to-mid picomolar range with tracer dosing (50 μg) up to the low nanomolar range at higher doses (1 mg and 2.5 mg). Finally, intranasal pre-treatment with a previously identified nasal permeation enhancer, matrix metalloproteinase-9, significantly improved intranasal [125I]-IgG delivery to multiple brain regions and further allowed us to elucidate IgG transport pathways extending from the nasal epithelia into the brain using fluorescence microscopy. The results show that it may be feasible to achieve therapeutic levels of IgG in the CNS, particularly at higher intranasal doses, and clarify the likely cranial nerve and perivascular distribution pathways taken by antibodies to reach the brain from the nasal mucosae.
AB - The intranasal route has been hypothesized to circumvent the blood-brain and blood-cerebrospinal fluid barriers, allowing entry into the brain via extracellular pathways along olfactory and trigeminal nerves and the perivascular spaces (PVS) of cerebral blood vessels. We investigated the potential of the intranasal route to non-invasively deliver antibodies to the brain 30 min following administration by characterizing distribution, dose-response, and mechanisms of antibody transport to and within the brain after administering non-targeted radiolabeled or fluorescently-labeled full length immunoglobulin G (IgG) to normal adult female rats. Intranasal [125I]-IgG consistently yielded highest concentrations in the olfactory bulbs, trigeminal nerves, and leptomeningeal blood vessels with their associated PVS. Intranasal delivery also resulted in significantly higher [125I]-IgG concentrations in the CNS than systemic (intra-arterial) delivery for doses producing similar endpoint blood concentrations. Importantly, CNS targeting significantly increased with increasing dose only with intranasal administration, yielding brain concentrations that ranged from the low-to-mid picomolar range with tracer dosing (50 μg) up to the low nanomolar range at higher doses (1 mg and 2.5 mg). Finally, intranasal pre-treatment with a previously identified nasal permeation enhancer, matrix metalloproteinase-9, significantly improved intranasal [125I]-IgG delivery to multiple brain regions and further allowed us to elucidate IgG transport pathways extending from the nasal epithelia into the brain using fluorescence microscopy. The results show that it may be feasible to achieve therapeutic levels of IgG in the CNS, particularly at higher intranasal doses, and clarify the likely cranial nerve and perivascular distribution pathways taken by antibodies to reach the brain from the nasal mucosae.
KW - Antibodies
KW - Brain
KW - Intranasal
KW - Olfactory
KW - Perivascular
KW - Trigeminal
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UR - http://www.scopus.com/inward/citedby.url?scp=85052134768&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2018.08.006
DO - 10.1016/j.jconrel.2018.08.006
M3 - Article
C2 - 30081144
AN - SCOPUS:85052134768
VL - 286
SP - 467
EP - 484
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -