Preliminary Characterization of Novel Amino Acid Based Polymeric Vesicles as Gene and Drug Delivery Agents
Identifieur interne : 002443 ( Main/Exploration ); précédent : 002442; suivant : 002444Preliminary Characterization of Novel Amino Acid Based Polymeric Vesicles as Gene and Drug Delivery Agents
Auteurs : M. D. Brown [Royaume-Uni] ; A. Sch Tzlein [Royaume-Uni] ; A. Brownlie [Royaume-Uni] ; V. Jack [Royaume-Uni] ; W. Wang [Royaume-Uni] ; L. Tetley [Royaume-Uni] ; A. I. Gray [Royaume-Uni] ; I. F. Uchegbu [Royaume-Uni]Source :
- Bioconjugate Chemistry [ 1043-1802 ] ; 2000.
Abstract
The amino acid homopolymers, poly-l-lysine and poly-l-ornithine, have been modified by the covalent attachment of palmitoyl and methoxypoly(ethylene glycol) (mPEG) residues to produce a new class of amphiphilic polymersPLP and POP, respectively. These amphiphilic amino acid based polymers have been found to assemble into polymeric vesicles in the presence of cholesterol. Representatives of this new class of polymeric vesicles have been evaluated in vitro as nonviral gene delivery systems with a view to finding delivery systems that combine effective gene expression with low toxicity in vivo. In addition, the drug-carrying capacity of these polymeric vesicles was evaluated with the model drug doxorubicin. Chemical characterization of the modified polymers was carried out using 1H NMR spectroscopy and the trinitrobenzene sulfonic acid (TNBS) assay for amino groups. The amphiphilic polymers were found to have an unreacted amino acid, palmitoyl, mPEG ratio of 11:5:1, and polymeric vesicle formation was confirmed by freeze-fracture electron microscopy and drug encapsulation studies. The resulting polymeric vesicles, by virtue of the mPEG groups, bear a near neutral ζ-potential. In vitro biological testing revealed that POP and PLP vesicle−DNA complexes are about one to 2 orders of magnitude less cytotoxic than the parent polymer−DNA complexes although more haemolytic than the parent polymer−DNA complexes. The polymeric vesicles condense DNA at a polymer:DNA weight ratio of 5:1 or greater and the polymeric vesicle−DNA complexes improved gene transfer to human tumor cell lines in comparison to the parent homopolymers despite the absence of receptor specific ligands and lysosomotropic agents such as chloroquine.
Url:
DOI: 10.1021/bc000052d
Affiliations:
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Sch Tzlein</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Strathclyde, CRC Department of Medical Oncology,University of Glasgow, and Department of Infection and Immunity, University of Glasgow, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Brownlie, A" sort="Brownlie, A" uniqKey="Brownlie A" first="A." last="Brownlie">A. Brownlie</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Strathclyde, CRC Department of Medical Oncology,University of Glasgow, and Department of Infection and Immunity, University of Glasgow, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Jack, V" sort="Jack, V" uniqKey="Jack V" first="V." last="Jack">V. Jack</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Strathclyde, CRC Department of Medical Oncology,University of Glasgow, and Department of Infection and Immunity, University of Glasgow, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Wang, W" sort="Wang, W" uniqKey="Wang W" first="W." last="Wang">W. Wang</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Strathclyde, CRC Department of Medical Oncology,University of Glasgow, and Department of Infection and Immunity, University of Glasgow, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation></author><author><name sortKey="Tetley, L" sort="Tetley, L" uniqKey="Tetley L" first="L." last="Tetley">L. Tetley</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Strathclyde, CRC Department of Medical Oncology,University of Glasgow, and Department of Infection and Immunity, University of Glasgow, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Gray, A I" sort="Gray, A I" uniqKey="Gray A" first="A. I." last="Gray">A. I. Gray</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Strathclyde, CRC Department of Medical Oncology,University of Glasgow, and Department of Infection and Immunity, University of Glasgow, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Uchegbu, I F" sort="Uchegbu, I F" uniqKey="Uchegbu I" first="I. F." last="Uchegbu">I. F. Uchegbu</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pharmaceutical Sciences, University of Strathclyde, CRC Department of Medical Oncology,University of Glasgow, and Department of Infection and Immunity, University of Glasgow, Glasgow G4 0NR</wicri:regionArea><wicri:noRegion>Glasgow G4 0NR</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Bioconjugate Chemistry</title><title level="j" type="abbrev">Bioconjugate Chem.</title><idno type="ISSN">1043-1802</idno><idno type="eISSN">1520-4812</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published" when="2000-10-25">2000</date><date when="2000-11-20">2000</date><biblScope unit="vol">11</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="880">880</biblScope><biblScope unit="page" to="891">891</biblScope></imprint><idno type="ISSN">1043-1802</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1043-1802</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The amino acid homopolymers, poly-l-lysine and poly-l-ornithine, have been modified by the covalent attachment of palmitoyl and methoxypoly(ethylene glycol) (mPEG) residues to produce a new class of amphiphilic polymersPLP and POP, respectively. These amphiphilic amino acid based polymers have been found to assemble into polymeric vesicles in the presence of cholesterol. Representatives of this new class of polymeric vesicles have been evaluated in vitro as nonviral gene delivery systems with a view to finding delivery systems that combine effective gene expression with low toxicity in vivo. In addition, the drug-carrying capacity of these polymeric vesicles was evaluated with the model drug doxorubicin. Chemical characterization of the modified polymers was carried out using 1H NMR spectroscopy and the trinitrobenzene sulfonic acid (TNBS) assay for amino groups. The amphiphilic polymers were found to have an unreacted amino acid, palmitoyl, mPEG ratio of 11:5:1, and polymeric vesicle formation was confirmed by freeze-fracture electron microscopy and drug encapsulation studies. The resulting polymeric vesicles, by virtue of the mPEG groups, bear a near neutral ζ-potential. In vitro biological testing revealed that POP and PLP vesicle−DNA complexes are about one to 2 orders of magnitude less cytotoxic than the parent polymer−DNA complexes although more haemolytic than the parent polymer−DNA complexes. The polymeric vesicles condense DNA at a polymer:DNA weight ratio of 5:1 or greater and the polymeric vesicle−DNA complexes improved gene transfer to human tumor cell lines in comparison to the parent homopolymers despite the absence of receptor specific ligands and lysosomotropic agents such as chloroquine.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Brown, M D" sort="Brown, M D" uniqKey="Brown M" first="M. D." last="Brown">M. D. Brown</name></noRegion><name sortKey="Brownlie, A" sort="Brownlie, A" uniqKey="Brownlie A" first="A." last="Brownlie">A. Brownlie</name><name sortKey="Gray, A I" sort="Gray, A I" uniqKey="Gray A" first="A. I." last="Gray">A. I. Gray</name><name sortKey="Jack, V" sort="Jack, V" uniqKey="Jack V" first="V." last="Jack">V. Jack</name><name sortKey="Sch Tzlein, A" sort="Sch Tzlein, A" uniqKey="Sch Tzlein A" first="A." last="Sch Tzlein">A. Sch Tzlein</name><name sortKey="Tetley, L" sort="Tetley, L" uniqKey="Tetley L" first="L." last="Tetley">L. Tetley</name><name sortKey="Uchegbu, I F" sort="Uchegbu, I F" uniqKey="Uchegbu I" first="I. F." last="Uchegbu">I. F. Uchegbu</name><name sortKey="Uchegbu, I F" sort="Uchegbu, I F" uniqKey="Uchegbu I" first="I. F." last="Uchegbu">I. F. Uchegbu</name><name sortKey="Wang, W" sort="Wang, W" uniqKey="Wang W" first="W." last="Wang">W. Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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