CENTRAL-NERVOUS-SYSTEM PHARMACOLOGICAL EFFECT IN CONSCIOUS RATS AFTERINTRAVENOUS-INJECTION OF A BIOTINYLATED VASOACTIVE-INTESTINAL-PEPTIDEANALOG COUPLED TO A BLOOD-BRAIN-BARRIER DRUG-DELIVERY SYSTEM

Previous studies showed that intracarotid artery perfusion of biotinyl ated vasoactive intestinal peptide analog (bio-VIPa) coupled to a bloo d-brain barrier (BBB) drug delivery vector, OX26/avidin, causes an inc rease in brain blood flow by 65% in N2O-anesthetized rats. OX26 is a m urine monoclonal antibody to the rat transferrin receptor and undergoe s receptor-mediated transport through the BBB in vivo. The present inv estigation examined the central nervous system effects of bio-VIPa aft er conventional i.v. injection to conscious rats. The VIPa was monobio tinylated (bio) with an -XX- noncleavable (amide) linker, and the bio- XX-VIPa conjugated to OX26/streptavidin (SA) maintained affinity for t he VIP receptor in radioreceptor assays. Brain uptake of the bio-XX-VI Pa 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 incr eased plasma area under the concentration curve and BBB permeability-s urface area product. Administration of the free bio-XX-VIPa increased salivary gland blood flow by 350%, but had no effect on brain blood fl ow. By contrast, bio-XX-VIPa/OX26-SA conjugate at equal doses (20 mu g /kg) after i.v. injection increased brain blood flow by 60% in conscio us rats, but had no effect on salivary gland blood flow. In summary, t he use of the BBB peptide drug delivery system targeted the drug to th e central nervous system, and optimized the therapeutic index of the V IPa by enhancing cerebral blood flow and by attenuating side effects i n peripheral organs such as salivary gland.