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

Morris, Christopher J., Smith, Mathew W., Griffiths, Peter C., 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.

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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 of excess synthetic free LTP-1 peptide. The specific nature of the target receptor or mechanism involved in LTP-1 lung transport remains unclear although the enhanced transport is enabled through a mechanism that is non-disruptive with respect to the pulmonary transport of hydrophilic permeability probes. This study shows proof-of principle that array technologies can be effectively exploited to identify peptides mediating enhanced transmucosal delivery of macromolecule therapeutics across an intact organ.

Item Type: Article
Additional Information: Received 13 August 2010
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Rachel Smith
Date Deposited: 17 Mar 2011 11:00
Last Modified: 23 Aug 2020 23:28
URI: https://ueaeprints.uea.ac.uk/id/eprint/26469
DOI: 10.1016/j.jconrel.2010.12.003

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