The in vivo use of chloroquine to promote non‐viral gene delivery to the liver via the portal vein and bile duct
Identifieur interne : 002054 ( Main/Exploration ); précédent : 002053; suivant : 002055The in vivo use of chloroquine to promote non‐viral gene delivery to the liver via the portal vein and bile duct
Auteurs : Xiaohong Zhang [Royaume-Uni] ; Greta J. Sawyer [Royaume-Uni] ; Xuebin Dong [Royaume-Uni] ; Ying Qiu [Royaume-Uni] ; Louise Collins [Royaume-Uni] ; John W. Fabre [Royaume-Uni]Source :
- The Journal of Gene Medicine [ 1099-498X ] ; 2003-03.
English descriptors
- Teeft :
- Amino, Bile, Bile duct, Bile duct ligation, Chloroquine, Chloroquine administration, Chloroquine levels, Clinical practice, Copyright, Daily doses, Dextrose, Dos, Dosing, Duct, Electrostatic binding, Endocytic, Endocytic vesicles, Fabre, Gene, Gene delivery, Gene expression, Gene transfer, Hepatic artery, Hepatocytes, Intraperitoneal, John wiley sons, Liquid nitrogen, Liver lobule, Lobe, Local chloroquine, Luciferase, Luciferase activity, Luciferase reporter gene expression, Optimal gene delivery, Oral chloroquine, Peptide, Perfused, Perfused lobes, Pgl3, Pgl3 plasmid, Plasmid, Portal, Portal vein, Pressure shocks, Proc natl acad, Serum chloroquine concentration, Serum chloroquine concentrations, Serum chloroquine levels, Serum levels, Single intraperitoneal dose, Single intraperitoneal injection, Systemic toxicity, Tissue extracts, Toxicity, Vector system, Vivo, Vivo gene delivery, Zhang.
Abstract
Background: Assistance with exit from endocytic vesicles is a key factor for non‐viral gene delivery, and is a particular challenge in vivo. We have evaluated the in vivo use of chloroquine administered systemically, orally and/or locally for gene delivery to the liver. Methods: The DNA vector (polylysine‐molossin) is a 31 amino acid bifunctional synthetic peptide, incorporating an amino terminal chain of 16 lysines for electrostatic binding of DNA. Gene delivery was to the right lateral lobes of the liver by branches of the bile duct or portal vein. Results: Single intraperitoneal injections of 8, 25 and 75 mg/kg of chloroquine (the maximum tolerated single intraperitoneal dose) resulted in increasing levels of luciferase reporter gene expression, following gene delivery via the bile duct. 100 mg/kg of chloroquine orally was equivalent to 25 mg intraperitoneally. A 3‐day course of intraperitoneal and oral chloroquine gave ∼10–30‐fold higher gene expression than an optimal single dose, and resulted in a scattering of positive hepatocytes in the lobule. Gene delivery via the bile duct was much more effective than via the portal vein. Serum chloroquine levels at the time of gene delivery showed a highly significant correlation with gene expression, but the maximum achievable levels in vivo (∼1–2 µM) were much lower than those required for optimal in vitro gene delivery. Chloroquine (0.2–5 mM) was also given locally in the bile duct with vector/DNA complexes. Maximum gene expression was obtained with 0.5 mM local chloroquine, but the level of gene expression was only equivalent to the 25 mg intraperitoneal dose. Conclusions: The in vivo use of chloroquine is effective for promoting gene delivery to the liver, but requires multiple dosing and is limited by systemic toxicity. Copyright © 2002 John Wiley & Sons, Ltd.
Url:
DOI: 10.1002/jgm.340
Affiliations:
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Sawyer</name></author><author><name sortKey="Dong, Xuebin" sort="Dong, Xuebin" uniqKey="Dong X" first="Xuebin" last="Dong">Xuebin Dong</name></author><author><name sortKey="Qiu, Ying" sort="Qiu, Ying" uniqKey="Qiu Y" first="Ying" last="Qiu">Ying Qiu</name></author><author><name sortKey="Collins, Louise" sort="Collins, Louise" uniqKey="Collins L" first="Louise" last="Collins">Louise Collins</name></author><author><name sortKey="Fabre, John W" sort="Fabre, John W" uniqKey="Fabre J" first="John W." last="Fabre">John W. 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Fabre</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Sciences, Institute of Liver Studies, Guy's, King's and St Thomas' School of Medicine, King's College Hospital, London SE5 9PJ</wicri:regionArea><wicri:noRegion>London SE5 9PJ</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation><affiliation wicri:level="1"><country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country><wicri:regionArea>Correspondence address: Department of Clinical Sciences, Institute of Liver Studies, King's College Hospital, London SE5 9PJ</wicri:regionArea><wicri:noRegion>London SE5 9PJ</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The Journal of Gene Medicine</title><title level="j" type="alt">JOURNAL OF GENE MEDICINE, THE</title><idno type="ISSN">1099-498X</idno><idno type="eISSN">1521-2254</idno><imprint><biblScope unit="vol">5</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="209">209</biblScope><biblScope unit="page" to="218">218</biblScope><biblScope unit="page-count">10</biblScope><publisher>John Wiley & Sons, Ltd.</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2003-03">2003-03</date></imprint><idno type="ISSN">1099-498X</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1099-498X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Amino</term><term>Bile</term><term>Bile duct</term><term>Bile duct ligation</term><term>Chloroquine</term><term>Chloroquine administration</term><term>Chloroquine levels</term><term>Clinical practice</term><term>Copyright</term><term>Daily doses</term><term>Dextrose</term><term>Dos</term><term>Dosing</term><term>Duct</term><term>Electrostatic binding</term><term>Endocytic</term><term>Endocytic vesicles</term><term>Fabre</term><term>Gene</term><term>Gene delivery</term><term>Gene expression</term><term>Gene transfer</term><term>Hepatic artery</term><term>Hepatocytes</term><term>Intraperitoneal</term><term>John wiley sons</term><term>Liquid nitrogen</term><term>Liver lobule</term><term>Lobe</term><term>Local chloroquine</term><term>Luciferase</term><term>Luciferase activity</term><term>Luciferase reporter gene expression</term><term>Optimal gene delivery</term><term>Oral chloroquine</term><term>Peptide</term><term>Perfused</term><term>Perfused lobes</term><term>Pgl3</term><term>Pgl3 plasmid</term><term>Plasmid</term><term>Portal</term><term>Portal vein</term><term>Pressure shocks</term><term>Proc natl acad</term><term>Serum chloroquine concentration</term><term>Serum chloroquine concentrations</term><term>Serum chloroquine levels</term><term>Serum levels</term><term>Single intraperitoneal dose</term><term>Single intraperitoneal injection</term><term>Systemic toxicity</term><term>Tissue extracts</term><term>Toxicity</term><term>Vector system</term><term>Vivo</term><term>Vivo gene delivery</term><term>Zhang</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: Assistance with exit from endocytic vesicles is a key factor for non‐viral gene delivery, and is a particular challenge in vivo. We have evaluated the in vivo use of chloroquine administered systemically, orally and/or locally for gene delivery to the liver. Methods: The DNA vector (polylysine‐molossin) is a 31 amino acid bifunctional synthetic peptide, incorporating an amino terminal chain of 16 lysines for electrostatic binding of DNA. Gene delivery was to the right lateral lobes of the liver by branches of the bile duct or portal vein. Results: Single intraperitoneal injections of 8, 25 and 75 mg/kg of chloroquine (the maximum tolerated single intraperitoneal dose) resulted in increasing levels of luciferase reporter gene expression, following gene delivery via the bile duct. 100 mg/kg of chloroquine orally was equivalent to 25 mg intraperitoneally. A 3‐day course of intraperitoneal and oral chloroquine gave ∼10–30‐fold higher gene expression than an optimal single dose, and resulted in a scattering of positive hepatocytes in the lobule. Gene delivery via the bile duct was much more effective than via the portal vein. Serum chloroquine levels at the time of gene delivery showed a highly significant correlation with gene expression, but the maximum achievable levels in vivo (∼1–2 µM) were much lower than those required for optimal in vitro gene delivery. Chloroquine (0.2–5 mM) was also given locally in the bile duct with vector/DNA complexes. Maximum gene expression was obtained with 0.5 mM local chloroquine, but the level of gene expression was only equivalent to the 25 mg intraperitoneal dose. Conclusions: The in vivo use of chloroquine is effective for promoting gene delivery to the liver, but requires multiple dosing and is limited by systemic toxicity. Copyright © 2002 John Wiley & Sons, Ltd.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Zhang, Xiaohong" sort="Zhang, Xiaohong" uniqKey="Zhang X" first="Xiaohong" last="Zhang">Xiaohong Zhang</name></noRegion><name sortKey="Collins, Louise" sort="Collins, Louise" uniqKey="Collins L" first="Louise" last="Collins">Louise Collins</name><name sortKey="Dong, Xuebin" sort="Dong, Xuebin" uniqKey="Dong X" first="Xuebin" last="Dong">Xuebin Dong</name><name sortKey="Fabre, John W" sort="Fabre, John W" uniqKey="Fabre J" first="John W." last="Fabre">John W. Fabre</name><name sortKey="Fabre, John W" sort="Fabre, John W" uniqKey="Fabre J" first="John W." last="Fabre">John W. Fabre</name><name sortKey="Fabre, John W" sort="Fabre, John W" uniqKey="Fabre J" first="John W." last="Fabre">John W. Fabre</name><name sortKey="Qiu, Ying" sort="Qiu, Ying" uniqKey="Qiu Y" first="Ying" last="Qiu">Ying Qiu</name><name sortKey="Sawyer, Greta J" sort="Sawyer, Greta J" uniqKey="Sawyer G" first="Greta J." last="Sawyer">Greta J. Sawyer</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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