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Peptide sequences mediating tropism to intact blood-brain barrier: An in vivo biodistribution study using phage display

Smith, Mathew W., Aljayyoussi, Ghaith and Gumbleton, Mark 2012. Peptide sequences mediating tropism to intact blood-brain barrier: An in vivo biodistribution study using phage display. Peptides 38 (1) , pp. 172-180. 10.1016/j.peptides.2012.06.019

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Abstract

Peptide motifs that demonstrate tropism for the blood brain barrier (BBB) are of real translational value in developing innovative delivery strategies for biological brain targeted therapies. In vivo peptide-phage display affords peptide selection against the full complement of biological markers within the correct cellular macro- and micro-environments. Here a stringent in vivo biopanning protocol was employed in the rat aimed at identifying cyclic 7-mer peptide motifs that mediate tropism to brain microvasculature. Five rounds of biopanning identified 349 unique peptide motifs in the brain tissue gray matter compartment (microvasculature and parenchyma). While in general no consensus was evident linking peptide physico-chemical properties and brain tropism, peptides bearing c-SxTSSTx-c or c-xxxSSTx-c motifs were found to be present in high abundance. Based on amino acid frequency distribution of the 349 unique peptides sequences a theoretical ‘idealized’ peptide pattern, c-PP(S/P)SSST-c, could be derived. For the most abundant experimental peptide sequence found in brain tissue, c-SYTSSTM-c, an in vivo pharmacokinetic and whole body tissue biodistribution study was performed. Based upon tissue exposure data (i.e. tissue AUC(0–infinity)) the sequence c-SYTSSTM-c efficiently retargeted phage virions to the brain providing an approximate 5-fold greater (P < 0.05) accumulation in brain over control phage; in all other organs no significant (P > 0.05) difference in tissue tropism between c-SYTSSTM-c and control phages were evident. This peptide and more generally the peptide motifs, -SxTSSTx- or -xxxSSTx-, warrant further investigation as agents mediating sequence-dependent tropism to brain microvasculature potentially able to deliver biologic cargo to the CNS.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Brain tropism; Blood–brain barrier; Phage display; Peptide; Biodistribution; Pharmacokinetics
Publisher: Elsevier
ISSN: 0196-9781
Last Modified: 04 Jun 2017 04:58
URI: http://orca.cf.ac.uk/id/eprint/47070

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