Delivery of peptides and proteins through the blood-brain barrier.
Peptide and protein therapeutics are generally excluded from transport from blood to brain, owing to the negligible permeability of these drugs to the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo. However, peptides or protein therapeutics may be delivered to the brain with the use of the chimeric peptide strategy for peptide drug delivery. Chimeric peptides are formed when a non-transportable peptide therapeutic is coupled to a BBB drug transport vector. Transport vectors are proteins such as cationized albumin, or the OX26 monoclonal antibody to the transferrin receptor; these proteins undergo absorptive-mediated and receptor-mediated transcytosis through the BBB, respectively. In addition to vector development, another important element of the chimeric peptide strategy is the design of strategies for coupling drugs to the vector that give high efficiency coupling and result in the liberation of biologically active peptides following cleavage of the bond linking the therapeutic and the transport vector. The avidin/biotin system has been recently shown to be advantageous in fulfilling these criteria for successful linker strategies. The use of the OX26 monoclonal antibody, the use of the avidin/biotin system as a linker strategy, and the design of a vasoactive intestinal peptide (VIP) analogue that is suitable for monobiotinylation and retention of biologic activity following cleavage, allowed for the recent demonstration of in vivo pharmacologic effects in brain following the systemic administration of relatively low doses (12 microg/kg) of neuropeptide.
Bickel
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Department of Medicine, UCLA School of Medicine, Research Laboratory, Los Angeles, CA 90095-1682, , USA. wpardrid@med1.medsch.ucla.edu
Yoshikawa
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Pardridge
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D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D016503:Drug Delivery Systems; D006801:Humans; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D011506:Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*
D010455:Peptides; D011506:Proteins