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Cytosolic delivery of antisense oligonucleotides by listeriolysin O-containing liposomes

Antisense oligodeoxynucleotides (ODNs) possess great potential as sequence-specific therapeutic agents. Sufficient concentrations of intact ODN must bypass membrane barriers and access the cytosol and nucleus, for ODNs to be therapeutically effective. A cytosolic delivery strategy was designed to im... Full description

Journal Title: Gene therapy July 2003, Vol.10(13), pp.1105-15
Main Author: Mathew, E
Other Authors: Hardee, G E , Bennett, C F , Lee, K-D
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0969-7128 ; PMID: 12808441 Version:1
Link: http://pubmed.gov/12808441
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recordid: medline12808441
title: Cytosolic delivery of antisense oligonucleotides by listeriolysin O-containing liposomes
format: Article
creator:
  • Mathew, E
  • Hardee, G E
  • Bennett, C F
  • Lee, K-D
subjects:
  • Bacterial Toxins
  • Bone Marrow Cells -- Metabolism
  • Cytosol -- Metabolism
  • Genetic Therapy -- Methods
  • Intercellular Adhesion Molecule-1 -- Genetics
  • Oligonucleotides, Antisense -- Administration & Dosage
ispartof: Gene therapy, July 2003, Vol.10(13), pp.1105-15
description: Antisense oligodeoxynucleotides (ODNs) possess great potential as sequence-specific therapeutic agents. Sufficient concentrations of intact ODN must bypass membrane barriers and access the cytosol and nucleus, for ODNs to be therapeutically effective. A cytosolic delivery strategy was designed to improve the efficiency of ODN delivery in bone-marrow-derived macrophages. This liposome-based formulation utilizes listeriolysin O (LLO), the endosomolytic hemolysin from Listeria monocytogenes, to mediate the escape of ODN from endocytic compartments into the cytosol. To monitor the cytosolic delivery of ODN, subcellular trafficking of fluorescently labeled ODNs was visualized using epifluorescence microscopy. The expression of target protein and mRNA after delivery was measured using flow cytometry and Northern blot analysis, respectively. ODN specific for murine intercellular adhesion molecule-1 (ICAM-1) encapsulated in LLO-liposomes was released to the cytosol and trafficked to the nucleus, efficiently and specifically suppressing activation-induced expression of ICAM-1 at both protein and mRNA levels. Delivery without LLO resulted in sequestration of ODN in vesicular compartments leading to little inhibition of ICAM-1 expression, which supports the requirement of LLO for efficient cytosolic delivery using this system. The data clearly demonstrate that LLO-mediated escape of ODN from intracellular vesicles is an effective approach to achieve full therapeutic antisense activity in cultured macrophages.
language: eng
source:
identifier: ISSN: 0969-7128 ; PMID: 12808441 Version:1
fulltext: fulltext
issn:
  • 09697128
  • 0969-7128
url: Link


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titleCytosolic delivery of antisense oligonucleotides by listeriolysin O-containing liposomes
creatorMathew, E ; Hardee, G E ; Bennett, C F ; Lee, K-D
ispartofGene therapy, July 2003, Vol.10(13), pp.1105-15
identifierISSN: 0969-7128 ; PMID: 12808441 Version:1
subjectBacterial Toxins ; Bone Marrow Cells -- Metabolism ; Cytosol -- Metabolism ; Genetic Therapy -- Methods ; Intercellular Adhesion Molecule-1 -- Genetics ; Oligonucleotides, Antisense -- Administration & Dosage
descriptionAntisense oligodeoxynucleotides (ODNs) possess great potential as sequence-specific therapeutic agents. Sufficient concentrations of intact ODN must bypass membrane barriers and access the cytosol and nucleus, for ODNs to be therapeutically effective. A cytosolic delivery strategy was designed to improve the efficiency of ODN delivery in bone-marrow-derived macrophages. This liposome-based formulation utilizes listeriolysin O (LLO), the endosomolytic hemolysin from Listeria monocytogenes, to mediate the escape of ODN from endocytic compartments into the cytosol. To monitor the cytosolic delivery of ODN, subcellular trafficking of fluorescently labeled ODNs was visualized using epifluorescence microscopy. The expression of target protein and mRNA after delivery was measured using flow cytometry and Northern blot analysis, respectively. ODN specific for murine intercellular adhesion molecule-1 (ICAM-1) encapsulated in LLO-liposomes was released to the cytosol and trafficked to the nucleus, efficiently and specifically suppressing activation-induced expression of ICAM-1 at both protein and mRNA levels. Delivery without LLO resulted in sequestration of ODN in vesicular compartments leading to little inhibition of ICAM-1 expression, which supports the requirement of LLO for efficient cytosolic delivery using this system. The data clearly demonstrate that LLO-mediated escape of ODN from intracellular vesicles is an effective approach to achieve full therapeutic antisense activity in cultured macrophages.
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abstractAntisense oligodeoxynucleotides (ODNs) possess great potential as sequence-specific therapeutic agents. Sufficient concentrations of intact ODN must bypass membrane barriers and access the cytosol and nucleus, for ODNs to be therapeutically effective. A cytosolic delivery strategy was designed to improve the efficiency of ODN delivery in bone-marrow-derived macrophages. This liposome-based formulation utilizes listeriolysin O (LLO), the endosomolytic hemolysin from Listeria monocytogenes, to mediate the escape of ODN from endocytic compartments into the cytosol. To monitor the cytosolic delivery of ODN, subcellular trafficking of fluorescently labeled ODNs was visualized using epifluorescence microscopy. The expression of target protein and mRNA after delivery was measured using flow cytometry and Northern blot analysis, respectively. ODN specific for murine intercellular adhesion molecule-1 (ICAM-1) encapsulated in LLO-liposomes was released to the cytosol and trafficked to the nucleus, efficiently and specifically suppressing activation-induced expression of ICAM-1 at both protein and mRNA levels. Delivery without LLO resulted in sequestration of ODN in vesicular compartments leading to little inhibition of ICAM-1 expression, which supports the requirement of LLO for efficient cytosolic delivery using this system. The data clearly demonstrate that LLO-mediated escape of ODN from intracellular vesicles is an effective approach to achieve full therapeutic antisense activity in cultured macrophages.
pmid12808441
doi10.1038/sj.gt.3301966
eissn14765462
oafree_for_read
date2003-07