The blood-brain barrier (BBB) represents a large obstacle for the treatment of central nervous system diseases. Targeting endogenous
nutrient transporters that transcytose the BBB is one promising approach to selectively and noninvasively deliver a drug payload
to the brain. The main limitations of the currently employed transcytosing receptors are their ubiquitous expression in the peripheral
vasculature and the inherent low levels of transcytosis mediated by such systems. In this review, approaches designed to increase the repertoire
of transcytosing receptors which can be targeted for the purpose of drug delivery are discussed. In particular, combinatorial protein
libraries can be screened on BBB cells in vitro or in vivo to isolate targeting peptides or antibodies that can trigger transcytosis. Once
these targeting reagents are discovered, the cognate BBB transcytosis system can be identified using techniques such as expression cloning
or immunoprecipitation coupled with mass spectrometry. Continued technological advances in BBB genomics and proteomics, membrane
protein manipulation, and in vitro BBB technology promise to further advance the capability to identify and optimize peptides and
antibodies capable of mediating drug transport across the BBB.
Keywords: Blood-brain barrier, receptor-mediated transport, brain drug delivery.
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