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Stabilized plasmid-lipid particles for systemic gene therapy

The structure of 'stabilized plasmid-lipid particles' (SPLP) and their properties as systemic gene therapy vectors has been investigated. We show that SPLP can be visualized employing cryo-electron microscopy to be homogeneous particles of diameter 72 +/- 5 nm consisting of a lipid bilayer surroundi... Full description

Journal Title: Gene Therapy Nov 2000, Vol.7(21), pp.1867-74
Main Author: Tam, P
Other Authors: Monck, M , Lee, D , Ludkovski, O , Leng, E , Clow, K , Stark, H , Scherrer, P , Graham, R , Cullis, P
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 09697128 ; DOI: 10.1038/sj.gt.3301308
Link: http://search.proquest.com/docview/218707118/?pq-origsite=primo
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title: Stabilized plasmid-lipid particles for systemic gene therapy
format: Article
creator:
  • Tam, P
  • Monck, M
  • Lee, D
  • Ludkovski, O
  • Leng, E
  • Clow, K
  • Stark, H
  • Scherrer, P
  • Graham, R
  • Cullis, P
subjects:
  • Animals–Methods
  • Cryoelectron Microscopy–Genetics
  • Female–Therapy
  • Gene Expression–Therapy
  • Genetic Therapy–Therapy
  • Genetic Vectors–Therapy
  • Injections, Intravenous–Therapy
  • Lipids–Therapy
  • Luciferases–Therapy
  • Lung Neoplasms–Therapy
  • Mice–Therapy
  • Mice, Inbred C57bl–Therapy
  • Neoplasms, Experimental–Therapy
  • Plasmids–Therapy
  • Lipids
  • Luciferases
ispartof: Gene Therapy, Nov 2000, Vol.7(21), pp.1867-74
description: The structure of 'stabilized plasmid-lipid particles' (SPLP) and their properties as systemic gene therapy vectors has been investigated. We show that SPLP can be visualized employing cryo-electron microscopy to be homogeneous particles of diameter 72 +/- 5 nm consisting of a lipid bilayer surrounding a core of plasmid DNA. It is also shown that SPLP exhibit long circulation lifetimes (circulation half-life >6 h) following intravenous (i.v.) injection in a murine tumor model resulting in accumulation of up to 3% of the total injected dose and concomitant reporter gene expression at a distal (hind flank) tumor site. In contrast, i v. injection of naked plasmid DNA or plasmid DNA-cationic liposome complexes did not result in significant plasmid delivery to the tumor site or gene expression at that site. Furthermore, it is shown that high doses of SPLP corresponding to 175 microg plasmid per mouse are nontoxic as assayed by monitoring serum enzyme levels, whereas i.v. injection of complexes give rise to significant toxicity at dose levels above 20 microg plasmid per mouse. It is concluded that SPLP exhibit properties consistent with potential utility as a nontoxic systemic gene therapy vector.
language: eng
source:
identifier: ISSN: 09697128 ; DOI: 10.1038/sj.gt.3301308
fulltext: fulltext
issn:
  • 09697128
  • 0969-7128
url: Link


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titleStabilized plasmid-lipid particles for systemic gene therapy
creatorTam, P ; Monck, M ; Lee, D ; Ludkovski, O ; Leng, E ; Clow, K ; Stark, H ; Scherrer, P ; Graham, R ; Cullis, P
ispartofGene Therapy, Nov 2000, Vol.7(21), pp.1867-74
identifierISSN: 09697128 ; DOI: 10.1038/sj.gt.3301308
subjectAnimals–Methods ; Cryoelectron Microscopy–Genetics ; Female–Therapy ; Gene Expression–Therapy ; Genetic Therapy–Therapy ; Genetic Vectors–Therapy ; Injections, Intravenous–Therapy ; Lipids–Therapy ; Luciferases–Therapy ; Lung Neoplasms–Therapy ; Mice–Therapy ; Mice, Inbred C57bl–Therapy ; Neoplasms, Experimental–Therapy ; Plasmids–Therapy ; Lipids ; Luciferases
descriptionThe structure of 'stabilized plasmid-lipid particles' (SPLP) and their properties as systemic gene therapy vectors has been investigated. We show that SPLP can be visualized employing cryo-electron microscopy to be homogeneous particles of diameter 72 +/- 5 nm consisting of a lipid bilayer surrounding a core of plasmid DNA. It is also shown that SPLP exhibit long circulation lifetimes (circulation half-life >6 h) following intravenous (i.v.) injection in a murine tumor model resulting in accumulation of up to 3% of the total injected dose and concomitant reporter gene expression at a distal (hind flank) tumor site. In contrast, i v. injection of naked plasmid DNA or plasmid DNA-cationic liposome complexes did not result in significant plasmid delivery to the tumor site or gene expression at that site. Furthermore, it is shown that high doses of SPLP corresponding to 175 microg plasmid per mouse are nontoxic as assayed by monitoring serum enzyme levels, whereas i.v. injection of complexes give rise to significant toxicity at dose levels above 20 microg plasmid per mouse. It is concluded that SPLP exhibit properties consistent with potential utility as a nontoxic systemic gene therapy vector.
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titleStabilized plasmid-lipid particles for systemic gene therapy
descriptionThe structure of 'stabilized plasmid-lipid particles' (SPLP) and their properties as systemic gene therapy vectors has been investigated. We show that SPLP can be visualized employing cryo-electron microscopy to be homogeneous particles of diameter 72 +/- 5 nm consisting of a lipid bilayer surrounding a core of plasmid DNA. It is also shown that SPLP exhibit long circulation lifetimes (circulation half-life >6 h) following intravenous (i.v.) injection in a murine tumor model resulting in accumulation of up to 3% of the total injected dose and concomitant reporter gene expression at a distal (hind flank) tumor site. In contrast, i v. injection of naked plasmid DNA or plasmid DNA-cationic liposome complexes did not result in significant plasmid delivery to the tumor site or gene expression at that site. Furthermore, it is shown that high doses of SPLP corresponding to 175 microg plasmid per mouse are nontoxic as assayed by monitoring serum enzyme levels, whereas i.v. injection of complexes give rise to significant toxicity at dose levels above 20 microg plasmid per mouse. It is concluded that SPLP exhibit properties consistent with potential utility as a nontoxic systemic gene therapy vector.
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titleStabilized plasmid-lipid particles for systemic gene therapy
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abstractThe structure of 'stabilized plasmid-lipid particles' (SPLP) and their properties as systemic gene therapy vectors has been investigated. We show that SPLP can be visualized employing cryo-electron microscopy to be homogeneous particles of diameter 72 +/- 5 nm consisting of a lipid bilayer surrounding a core of plasmid DNA. It is also shown that SPLP exhibit long circulation lifetimes (circulation half-life >6 h) following intravenous (i.v.) injection in a murine tumor model resulting in accumulation of up to 3% of the total injected dose and concomitant reporter gene expression at a distal (hind flank) tumor site. In contrast, i v. injection of naked plasmid DNA or plasmid DNA-cationic liposome complexes did not result in significant plasmid delivery to the tumor site or gene expression at that site. Furthermore, it is shown that high doses of SPLP corresponding to 175 microg plasmid per mouse are nontoxic as assayed by monitoring serum enzyme levels, whereas i.v. injection of complexes give rise to significant toxicity at dose levels above 20 microg plasmid per mouse. It is concluded that SPLP exhibit properties consistent with potential utility as a nontoxic systemic gene therapy vector.
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pubNature Publishing Group
doi10.1038/sj.gt.3301308
urlhttp://search.proquest.com/docview/218707118/
eissn14765462
date2000-11-01