화학적 및 유전공학적으로 제조한 뇌송달 벡터의 뇌수송량 비교

Abstract

Drug delivery to the brain may be achieved by producing chimeric peptide, attaching the drug to protein "vectors" which are transported into the brain from the blood by a receptor-mediated transcytosis through the blood-brain barrier (BBB). Since the BBB expresses high concentrations of transferrin receptor, and it was reported that anti-transferrin receptor mouse monoclonal antibody (OX26) undergoes transcytosis through the BBB, it is logical to assume that a drug delivery system via transferrin receptor-mediated transcytosis is a promising strategy. In the present study, therefore, we tested feasibility of several OX26 based vectors for the brain delivery of a model drug. Avidin-based delivery vectors such as OX26-streptavidin (OX26-SA), OX26-neutralite avidin (OX26-NLA) were chemically synthesized vectors and OX26 immunoglobulin G 3 type C_H3 fusion avidin (OX26 IgG3C_H3-AV) was genetically engineered. To improve the efficiency of producing chimeric peptide, we used avidin-biotin technology. Pharmacokinetics of [³H]biotin bound to OX26-SA, OX26-NLA and OX26 IgG3C_H3-AV was determined by intravenous injection technique, and their stabilities in plasma were analyzed using HPLC. The brain delivery of [³H]biotin bound to OX26-SA, OX26-NLA and OX26 IgG3C_H3-AV (expressed as %ID/g brain) was 0.22±0.01, 0.18±0.01 and 0.25±0.09, respectively. The areas under the plasma concentration versus time curve (AUC) for OX26-SA, OX26-NLA, OX26 IgG3C_H3-AV from time zero to 60 min were 209±10, 195±9, 134±29 %ID·min/㎖, respectively and their total clearances (CL_(tot)) were 1.00±0.09, 1.08±0.07 and 1.54±0.29 ㎖/min/㎏, espectively. These results showed that these vectors possess preferable pharmaceutical (e.g., resonable stability) and pharmacokinetics (e.g., significant brain uptake and enhanced AUC) for brain delivery. Therefore, these vectors may be broadly useful in the brain delivery of drugs that are not transported into the brain to a significant extent.