Central nervous system pharmacologic effect in conscious rats after intravenous injection of a biotinylated vasoactive intestinal peptide analog coupled to a blood-brain barrier drug delivery system.
Previous studies showed that intracarotid artery perfusion of biotinylated vasoactive intestinal peptide analog (bio-VIPa) coupled to a blood-brain barrier (BBB) drug delivery vector, OX26/avidin, causes an increase in brain blood flow by 65% in N2O-anesthetized rats. OX26 is a murine monoclonal antibody to the rat transferrin receptor and undergoes receptor-mediated transport through the BBB in vivo. The present investigation examined the central nervous system effects of bio-VIPa after conventional i.v. injection to conscious rats. The VIPa was monobiotinylated (bio) with an-XX-noncleavable (amide) linker, and the bio-XX-VIPa conjugated to OX26/streptavidin (SA) maintained affinity for the VIP receptor in radioreceptor assays. Brain uptake of the bio-XX-VIPa coupled to the OX26/SA vector after i.v. injection was at least 10-fold higher than that of the free bio-XX-VIPa, because of both an increased plasma area under the concentration curve and BBB permeability-surface area product. Administration of the free bio-XX-VIPa increased salivary gland blood flow by 350%, but had no effect on brain blood flow. By contrast, bio-XX-VIPa/OX26-SA conjugate at equal doses (20 micrograms/kg) after i.v. injection increased brain blood flow by 60% in conscious rats, but had no effect on salivary gland blood flow. In summary, the use of the BBB peptide drug delivery system targeted the drug to the central nervous system, and optimized the therapeutic index of the VIPa by enhancing cerebral blood flow and by attenuating side effects in peripheral organs such as salivary gland.
Wu
D
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Department of Medicine, UCLA School of Medicine, USA.
Pardridge
W M
WM
D000818:Animals; D001710:Biotin / Q000008:administration & dosage; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D016503:Drug Delivery Systems; D004355:Drug Stability; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D014660:Vasoactive Intestinal Peptide; D001710:Biotin