Cerebrovascular permeability to peptides: manipulations of transport systems at the blood-brain barrier.

The study of peptide transport across the blood-brain barrier (BBB) is a field fraught with conflicting interpretations. This review presents a fairly strong case that peptides can be differentially transported at the BBB. However, minimal transport of peptides could have important impact on central nervous system (CNS) functions since only small amounts are needed for physiologic pharmacologic and/or pathologic effects. Several BBB peptide transport mechanisms (i.e., receptor-mediated, absorptive-mediated, carrier-mediated and non-specific passive diffusion), as well as non-transport processes (i.e., endocytosis without transcytosis, absorption and metabolism) are discussed. It is emphasized that peptide transport systems at the BBB could be important targets for both therapeutic delivery of peptides and the development of certain brain pathologies. Strategies to manipulate peptide BBB transport processes have been discussed including lipidization, chemical modifications of the N-terminal end, coupling of transport with post-BBB metabolism and formation of potent neuroactive peptides, up-regulation of putative peptide transporters, use of chimeric peptides in which non-transportable peptide is chemically linked to a transportable peptide, use of monoclonal antibodies against peptide receptors, and binding of circulating peptides to apolipoproteins. It is suggested that future directions should be directed towards development of molecular strategies to up-regulate specific BBB peptide transporters to enhance brain delivery of peptide neuropharmaceuticals, or to down-regulate transport of peptides with potential role in cerebral pathogenesis.