Delivery of interferon-beta to the monkey nervous system following intranasal administration.
We determined the nervous system targeting of interferon-beta1b (IFN-beta1b), a 20 kDa protein used to treat the relapsing-remitting form of multiple sclerosis, following intranasal administration in anesthetized, adult cynomolgus monkeys. Five animals received an intranasal bolus of [(125)I]-labeled IFN-beta1b, applied bilaterally to the upper nasal passages. Serial blood samples were collected for 45 min, after which the animals were euthanized by transcardial perfusion-fixation. High resolution phosphor imaging of tissue sections and gamma counting of microdissected tissue were used to obtain the distribution and concentration profiles of [(125)I]-IFN-beta1b in central and peripheral tissues. Intranasal administration resulted in rapid, widespread targeting of nervous tissue. The olfactory bulbs and trigeminal nerve exhibited [(125)I]-IFN-beta1b levels significantly greater than in peripheral organs and at least one order of magnitude higher than any other nervous tissue area sampled. The basal ganglia exhibited highest [(125)I]-IFN-beta1b levels among CNS regions other than the olfactory bulbs. Preferential IFN-beta1b distribution to the primate basal ganglia is a new finding of possible clinical importance. Our study suggests both IFN-beta and IFN-alpha, which share the same receptor, may be bound with relatively high affinity in these structures, possibly offering new insight into a neurovegetative syndrome induced by IFN-alpha therapy and suspected to involve altered dopamine neurotransmission in the basal ganglia. Most importantly, our results suggest intranasally applied macromolecules may bypass the blood-brain barrier and rapidly enter the primate CNS along olfactory- and trigeminal-associated extracellular pathways, as shown previously in the rat. This is the first study to finely detail the central distribution of a labeled protein after intranasal administration in non-human primates.
Thorne
R G
RG
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
Hanson
L R
LR
Ross
T M
TM
Tung
D
D
Frey
W H
WH
D000281:Administration, Intranasal; D000818:Animals; D001345:Autoradiography; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001931:Brain Mapping; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007155:Immunologic Factors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D016899:Interferon-beta / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008251:Macaca; D008297:Male; D009420:Nervous System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011863:Radioimmunoassay; D017471:Receptors, Interferon / Q000187:drug effects / Q000378:metabolism; D014276:Trigeminal Nerve / Q000187:drug effects / Q000378:metabolism
D007155:Immunologic Factors; D007457:Iodine Radioisotopes; D017471:Receptors, Interferon; D016899:Interferon-beta