SCIENCE@home

Delivery of immunoglobulin G antibodies to the rat nervous system following intranasal administration: Distribution, dose‐response, and mechanisms of delivery

Niyanta N. Kumar,Jeffrey J. Lochhead,Michelle E. Pizzo,Geetika Nehra,Sam Boroumand,G. Greene,R. Thorne

Published 2018 in Journal of Controlled Release

ABSTRACT

ABSTRACT 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 &mgr;g) 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. Graphical abstract Figure. No caption available. HighlightsDelivery of antibody‐based therapeutics to the CNS is challenging due to the BBB.Intranasal delivery can achieve therapeutically relevant levels of IgG in the CNS.Intranasally applied IgG reaches the CNS via perineural and perivascular pathways.Intranasal IgG delivery to the CNS has a favorable dose‐response.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-83 of 83 references · Page 1 of 1

CITED BY

Showing 1-88 of 88 citing papers · Page 1 of 1