Tumor-specific gene transfer with receptor-mediated nanocomplexes modified by polyethylene glycol shielding and endosomally cleavable lipid and peptide linkers

Stephanie M Grosse, Aristides D Tagalakis, M Firouz Mohd Mustapa, Martin Elbs, Qing-Hai Meng, Atefeh Mohammadi, Alethea B Tabor, Helen C Hailes, Stephen L Hart

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Synthetic nanoparticle formulations have the potential for tumor-targeted gene delivery. Receptor-targeted nanocomplex (RTN) formulations comprise mixtures of cationic liposomes and targeting peptides that self-assemble on mixing with nucleic acids. RTN formulations were prepared containing different polyethylene glycol (PEG)ylated lipids with esterase-cleavable linkers (e.g., ME42) to promote intracellular PEG detachment and nanoparticle disassembly. In addition, integrin-targeting peptides (peptide ME27) were tested with endosomal furin- and cathepsin B-cleavable peptide linkers located between the integrin-binding ligand and the K(16) nucleic acid-binding domain to promote intracellular disengagement from the receptor. ME42/ME27 RTNs formed stable particles of <200 nm in isotonic salt buffers, compared with 4-microm particles formed by un-PEGylated RTNs. Transfection efficiency by PEG-modified, cleavable RTNs improved approximately 2-fold in 4 different cell lines, with 80% efficiency in murine neuroblastoma cells. In an in vivo model of neuroblastoma, ME42/ME27 RTNs delivering luciferase genes were tumor specific, with little expression in other organs tested. PEGylation of the RTNs enhanced luciferase transfection 5-fold over non-PEG formulations, whereas the cleavability of the peptide ME27 enhanced transfection 4-fold over that of RTNs with noncleavable peptides. Cleavability of the lipid for in vivo transfections had no effect. PEGylated, cleavable RTN formulations offer prospects for tumor-specific therapeutic gene transfer.

Original languageEnglish
Pages (from-to)2301-13
Number of pages13
JournalFASEB Journal
Volume24
Issue number7
DOIs
Publication statusPublished - 4 Mar 2010

Keywords

  • Animals
  • Antineoplastic Agents/administration & dosage
  • Cell Line, Tumor
  • Cells, Cultured
  • Drug Delivery Systems/methods
  • Endosomes/metabolism
  • Gene Transfer Techniques
  • Hydrolysis
  • Lipids
  • Mice
  • Nanoparticles/chemistry
  • Neuroblastoma/pathology
  • Peptides
  • Polyethylene Glycols
  • Prodrugs
  • Swine

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