Drug targeting to the brain using avidin-biotin technology in the mouse; (blood-brain barrier, monoclonal antibody, transferrin receptor, Alzheimer's disease).
A beta1-40 peptide radiopharmaceuticals could be used to image A beta brain amyloid in transgenic mouse models of Alzheimer's disease should the A beta peptide radiopharmaceutical be made transportable through the blood-brain barrier (BBB) in vivo. The present studies used the RI7-217 rat monoclonal antibody to the mouse transferrin receptor as a BBB drug targeting vector for the delivery to brain of A beta1-40 radiolabeled with either 125-Iodine or 111-Indium. The A beta peptide radiopharmaceutical is conjugated to the RI7 MAb using avidin biotin technology, wherein the A beta1-40 peptide radiopharmaceutical is monobiotinylated (bio) and bound to a conjugate of the RI7 MAb and streptavidin (SA). The [125 I]-bio-A beta1-40 or the [111 In]-bio-A beta1-40 either free or bound to the RI7/SA conjugate was injected intravenously into anesthetized adult mice and plasma pharmacokinetics and organ uptake were measured over the next 60 minutes. The A beta1-40 peptide radiopharmaceutical radiolabeled with 111-Indium was the preferred formulation, compared to peptide labeled with 125-Iodine, because there was a greater metabolic stability and reduced artifactual organ uptake of metabolites associated with the use of the 111-Indium nuclide. However, biotinylated A beta1-40 peptide radiopharmaceuticals conjugated to the RI7/SA brain drug targeting system were metabolically unstable in mice in vivo owing to active biotinidase activity. Future work involving brain drug targeting in mice that utilizes avidin biotin technology will need to incorporate biotin analogues that are resistant to biotinidase.
Jeong Lee
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Department of Medicine UCLA School of Medicine Los Angeles, CA 90095-1682, USA.
Pardridge
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WM
D000581:Amidohydrolases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics; D001360:Avidin / Q000097:blood / Q000493:pharmacokinetics*; D001710:Biotin / Q000097:blood / Q000493:pharmacokinetics*; D043523:Biotinidase; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002213:Capsid / Q000097:blood / Q000493:pharmacokinetics; D036022:Capsid Proteins; D016503:Drug Delivery Systems / Q000379:methods*; D007202:Indicators and Reagents / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000097:blood / Q000493:pharmacokinetics*; D016601:RNA-Binding Proteins / Q000097:blood / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011990:Receptors, Transferrin / Q000276:immunology / Q000378:metabolism; D019809:Streptavidin / Q000097:blood / Q000493:pharmacokinetics
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D036022:Capsid Proteins; D007202:Indicators and Reagents; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D019275:Radiopharmaceuticals; D011990:Receptors, Transferrin; C078592:amyloid beta-protein (1-40); D001360:Avidin; D001710:Biotin; D019809:Streptavidin; D000581:Amidohydrolases; D043523:Biotinidase