| Triggered intracellular activation of disulfide crosslinked polyelectrolyte gene delivery complexes with extended systemic circulation in vivo. | |
| | |
MedLine Citation:
|
PMID: 11406766 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
We have developed polyelectrolyte gene delivery vectors that display good extracellular stability and are activated intracellularly to permit transgene expression. The strategy comprises covalent crosslinking of primary amines in poly-L-lysine/DNA complexes with a crosslinking agent that can later be cleaved by reduction. Crosslinked complexes maintained the same size and surface charge but showed increased stability against polyelectrolyte exchange with poly-L-aspartic acid. Surface modification with polyethyleneglycol improved solubility and masked their positive surface charge. Crosslinked complexes showed 10-fold increased plasma circulation following intravenous administration to Balb/c mice. In the absence of chloroquine, the levels of transgene expression in B16F10 murine melanoma cells were similar for crosslinked and non-crosslinked complexes, however, chloroquine selectively potentiated transgene expression by the non-crosslinked complexes. Cellular uptake of the complexes was the same, irrespective of crosslinking. Following microinjection into the cytoplasm of Xenopus oocytes, or the cytoplasm or nucleus of Rat-1 fibroblasts, crosslinked complexes mediated the same transgene expression as non-crosslinked complexes, indicating crosslinked complexes are rapidly reduced and activated intracellularly. We therefore hypothesize that the lower in vitro transfection activity of crosslinked complexes in the presence of chloroquine is due to reduced transfer from endosome to cytoplasm, mainly due to increased stability against destabilization by chloroquine. The extended systemic circulation together with triggered intracellular activation makes these complexes a promising system for targeted gene delivery in vivo. |
| | |
Authors:
|
D Oupický; R C Carlisle; L W Seymour |
Related Documents
:
|
9857346 - Liver-directed gene transfer: a linear polyethlenimine derivative mediates highly effic... 10330036 - Effect of immune response on gene transfer to the lung via systemic administration of c... 16305446 - Toxicogenomics of cationic lipid-based vectors for gene therapy: impact of microarray t... 12604036 - A new colloidal lipidic system for gene therapy. 18405356 - The human abc transporter pseudogene family: evidence for transcription and gene-pseudo... 9486796 - Her, a gene required for sexual differentiation in drosophila, encodes a zinc finger pr... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: Gene therapy Volume: 8 ISSN: 0969-7128 ISO Abbreviation: Gene Ther. Publication Date: 2001 May |
Date Detail:
|
Created Date: 2001-06-14 Completed Date: 2001-08-02 Revised Date: 2006-11-15 |
Medline Journal Info:
|
Nlm Unique ID: 9421525 Medline TA: Gene Ther Country: England |
Other Details:
|
Languages: eng Pagination: 713-24 Citation Subset: IM |
Affiliation:
|
CRC Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TA, UK. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Cross-Linking Reagents DNA / pharmacokinetics Disulfides / pharmacokinetics* Electrolytes Female Gene Transfer Techniques* Genetic Vectors / pharmacokinetics* Liver / metabolism Mice Mice, Inbred BALB C Microinjections Polyethylene Glycols / pharmacology Polylysine / pharmacokinetics Sodium Chloride / pharmacology Solubility Tissue Distribution Transcription, Genetic Xenopus |
| Chemical | |
Reg. No./Substance:
|
0/Cross-Linking Reagents; 0/Disulfides; 0/Electrolytes; 0/Polyethylene Glycols; 25104-18-1/Polylysine; 7647-14-5/Sodium Chloride; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Recombinant adenovirus expressing adeno-associated virus cap and rep proteins supports production of...
Next Document: A synthetic leucine zipper-based dimerization system for combining multiple promoter specificities.