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

36 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

Fingerprint

Gene transfer
Shielding
Tumors
Lipids
Peptides
Transfection
Genes
Neoplasms
Luciferases
Neuroblastoma
Integrins
Nanoparticles
Nucleic Acids
Furin
Cathepsin B
Glycols
Esterases
Liposomes
Buffers
Salts

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

Cite this

Grosse, Stephanie M ; Tagalakis, Aristides D ; Mustapa, M Firouz Mohd ; Elbs, Martin ; Meng, Qing-Hai ; Mohammadi, Atefeh ; Tabor, Alethea B ; Hailes, Helen C ; Hart, Stephen L. / Tumor-specific gene transfer with receptor-mediated nanocomplexes modified by polyethylene glycol shielding and endosomally cleavable lipid and peptide linkers. In: FASEB Journal. 2010 ; Vol. 24, No. 7. pp. 2301-13.
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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-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.",
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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, Stephanie M; Tagalakis, Aristides D; Mustapa, M Firouz Mohd; Elbs, Martin; Meng, Qing-Hai; Mohammadi, Atefeh; Tabor, Alethea B; Hailes, Helen C; Hart, Stephen L.

In: FASEB Journal, Vol. 24, No. 7, 04.03.2010, p. 2301-13.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tumor-specific gene transfer with receptor-mediated nanocomplexes modified by polyethylene glycol shielding and endosomally cleavable lipid and peptide linkers

AU - Grosse, Stephanie M

AU - Tagalakis, Aristides D

AU - Mustapa, M Firouz Mohd

AU - Elbs, Martin

AU - Meng, Qing-Hai

AU - Mohammadi, Atefeh

AU - Tabor, Alethea B

AU - Hailes, Helen C

AU - Hart, Stephen L

PY - 2010/3/4

Y1 - 2010/3/4

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents/administration & dosage

KW - Cell Line, Tumor

KW - Cells, Cultured

KW - Drug Delivery Systems/methods

KW - Endosomes/metabolism

KW - Gene Transfer Techniques

KW - Hydrolysis

KW - Lipids

KW - Mice

KW - Nanoparticles/chemistry

KW - Neuroblastoma/pathology

KW - Peptides

KW - Polyethylene Glycols

KW - Prodrugs

KW - Swine

U2 - 10.1096/fj.09-144220

DO - 10.1096/fj.09-144220

M3 - Article

C2 - 20203088

VL - 24

SP - 2301

EP - 2313

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 7

ER -