Synthesis and application of integrin targeting lipopeptides in targeted gene delivery

Research output: Contribution to journalArticle

  • External authors:
  • Jodie E. Waterhouse
  • Richard P. Harbottle
  • Michael Keller
  • Charles Coutelle
  • Michael R. Jorgensen
  • Andrew D. Miller

Abstract

One of the main problems facing gene therapy is the ability to target the delivery of DNA to specific cells of choice. Recently, we developed a synthetic nonviral vector platform system known as LMD (liposome:mu:DNA) that was designed for further modular upgrading with tool-kits of chemical components. First-generation LMD systems were prepared from DC-Chol/DOPE cationic liposomes (DC-Chol=3β-[N-(N′,N′-dimethylaminoethane)carbamoyl] cholesterol, DOPE=dioleoyl-L-α-phosphatidylethanolamine), μ peptide from the adenovirus core and plasmid DNA (pDNA). Here we report attempts to realise peptide-targeted gene delivery that build upon the LMD platform. Our strategy was to prepare novel lipopeptides with a lipid moiety designed to insert into the outer lipid bilayer of LMD particles whilst simultaneously presenting a peptide moiety for cell-surface receptor binding. One main functional peptide sequence was selected (PLAEIDGIELA; tenascin peptide sequence) known to target α9β1-integrin proteins predominant on upper-airway epithelial cells. This sequence was investigated along with a corresponding control sequence. The syntheses of two classes (A and B) of lipopeptides are reported; the syntheses of class A lipopeptides requires a modification of Mitsunobu chemistry that could be of general utility to facilitate Mitsunobu reactions in other diverse systems. "Targeted" LMD and LD transfections with class A or B lipopeptides exhibit nonspecific peptide enhancements (up to one order of magnitude) over non-lipopeptide control transfections but few specific effects. Specific targeting effects can be seen if the overall LMD or LD particle cationic charge is lowered, but nonspecific effects are never eliminated. Whilst promising, these data now highlight the need for in vivo data and even a new modular, aqueous chemistry for the controlled adaptation of LMD particles in buffer in order for successful peptide-targeted, synthetic, nonviral gene delivery to be realised. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA.

Bibliographical metadata

Original languageEnglish
Pages (from-to)1212-1223
Number of pages11
JournalChemBioChem: a European journal of chemical biology
Volume6
Issue number7
DOIs
Publication statusPublished - Jul 2005