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

Grosse, SM; Tagalakis, AD; Mustapa, MFM; Elbs, M; Meng, QH; Mohammadi, A; ... Hart, SL; + view all (2010) Tumor-specific gene transfer with receptor-mediated nanocomplexes modified by polyethylene glycol shielding and endosomally cleavable lipid and peptide linkers. FASEB J , 24 (7) 2301 - 2313. 10.1096/fj.09-144220.

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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-mu m particles formed by un-PEGylated RTNs. Transfection efficiency by PEG-modified, cleavable RTNs improved similar to 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.-Grosse, S. M., Tagalakis, A. D., Firouz Mohd Mustapa, M., Elbs, M., Meng, Q.-H., Mohammadi, A., Tabor, A. B., Hailes, H. C., Hart, S. L. Tumor-specific gene transfer with receptor-mediated nanocomplexes modified by polyethylene glycol shielding and endosomally cleavable lipid and peptide linkers. FASEB J. 24, 2301-2313 (2010). www.fasebj.org

Type:Article
Title:Tumor-specific gene transfer with receptor-mediated nanocomplexes modified by polyethylene glycol shielding and endosomally cleavable lipid and peptide linkers
DOI:10.1096/fj.09-144220
Keywords:integrin-targeting peptides, PEGylated lipids, cleavable linkers, systemic delivery, nonviral vectors, gene expression, SYNTHETIC VECTOR SYSTEM, AIRWAY EPITHELIAL-CELLS, DELIVERY VECTOR, VASCULAR CELLS, PHAGE DISPLAY, IN-VITRO, INTEGRIN, BINDING, PEG, DNA
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Infection and Immunity > ICH - Molecular Immunology Unit
UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry

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