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Enhanced pulmonary absorption of a macromolecule through coupling to a sequence-specific phage display-derived peptide

Morris, Christopher John, Smith, Mathew W., Griffiths, Peter Charles, McKeown, Neil B. and Gumbleton, Mark 2011. Enhanced pulmonary absorption of a macromolecule through coupling to a sequence-specific phage display-derived peptide. Journal of Controlled Release 151 (1) , pp. 83-94. 10.1016/j.jconrel.2010.12.003

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Abstract

With the aim of identifying a peptide sequence that promotes pulmonary epithelial transport of macromolecule cargo we used a stringent peptide-phage display library screening protocol against rat lung alveolar epithelial primary cell cultures. We identified a peptide-phage clone (LTP-1) displaying the disulphide-constrained 7-mer peptide sequence, C-TSGTHPR-C, that showed significant pulmonary epithelial translocation across highly restrictive polarised cell monolayers. Cell biological data supported a differential alveolar epithelial cell interaction of the LTP-1 peptide-phage clone and the corresponding free synthetic LTP-1 peptide. Delivering select phage-clones to the intact pulmonary barrier of an isolated perfused rat lung (IPRL) resulted in 8.7% of lung deposited LTP-1 peptide-phage clone transported from the IPRL airways to the vasculature compared (p < 0.05) to the cumulative transport of less than 0.004% for control phage-clone groups. To characterise phage-independent activity of LTP-1 peptide, the LTP-1 peptide was conjugated to a 53 kDa anionic PAMAM dendrimer. Compared to respective peptide-dendrimer control conjugates, the LTP-1–PAMAM conjugate displayed a two-fold (bioavailability up to 31%) greater extent of absorption in the IPRL. The LTP-1 peptide-mediated enhancement of transport, when LTP-1 was either attached to the phage clone or conjugated to dendrimer, was sequence-dependent and could be competitively inhibited by co-instillation

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Pharmacy
Subjects: Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Phage-display ; Peptide ; Dendrimer ; Lung ; Absorption ; Isolated perfused lung
Publisher: Elsevier
ISSN: 0168-3659
Funders: EPSRC
Last Modified: 03 Apr 2018 20:36
URI: http://orca.cf.ac.uk/id/eprint/9744

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