New Class of Polymers for the Delivery of Macromolecular Therapeutics
Identifieur interne : 002606 ( Main/Exploration ); précédent : 002605; suivant : 002607New Class of Polymers for the Delivery of Macromolecular Therapeutics
Auteurs : Hector Gonzalez [États-Unis] ; Sue Jean Hwang [États-Unis] ; M. E. Davis [États-Unis]Source :
- Bioconjugate Chemistry [ 1043-1802 ] ; 1999.
Abstract
Cationic polymers show promise for the in vitro and in vivo delivery of macromolecular therapeutics. Known cationic polymers, e.g., poly(L)lysine (PLL) and polyethylenimine (PEI), have been employed in native and modified forms for the delivery of plasmid DNA (pDNA) and reveal varying levels of toxicity. Here, we report the preparation of a new class of cationic polymers that are specifically designed to deliver macromolecular therapeutics. Linear, cationic, β-cyclodextrin (β-CD)-containing polymers (CD-polymers) are synthesized by copolymerizing difunctionalized β-CD monomers (AA) with other difunctionalized comonomers (BB) such that an AABBAABB product is formed. The β-CD polymers are able to bind ∼5 kbp pDNA above polymer to DNA (+/−) charge ratios of 1.5, compact the bound pDNA into particles of approximately 100−150 nm in size at charge ratios above 5+/−, and transfect cultured cells at charge ratios above 10+/−. In vitro transfections with the new β-CD-polymers are comparable to the best results obtained in our hands with PEI and Lipofectamine. Some cell line-dependent toxicities are observed for serum-free transfections; however, no toxicity is revealed at charge ratios as high as 70+/− in transfections conducted in 10% serum. Single IV and IP doses as high as 200 mg/kg in mice showed no mortalities.
Url:
DOI: 10.1021/bc990072j
Affiliations:
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Therapeutics</title><author><name sortKey="Gonzalez, Hector" sort="Gonzalez, Hector" uniqKey="Gonzalez H" first="Hector" last="Gonzalez">Hector Gonzalez</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Division of Chemistry and Chemical Engineering, California Institute of Technology,Pasadena</wicri:cityArea></affiliation><affiliation></affiliation></author><author><name sortKey="Hwang, Sue Jean" sort="Hwang, Sue Jean" uniqKey="Hwang S" first="Sue Jean" last="Hwang">Sue Jean Hwang</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Division of Chemistry and Chemical Engineering, California Institute of Technology,Pasadena</wicri:cityArea></affiliation><affiliation></affiliation></author><author><name sortKey="Davis, M E" sort="Davis, M E" uniqKey="Davis M" first="M. E." last="Davis">M. E. Davis</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Division of Chemistry and Chemical Engineering, California Institute of Technology,Pasadena</wicri:cityArea></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</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="1999-09-24">1999</date><date when="1999-11-15">1999</date><biblScope unit="vol">10</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="1068">1068</biblScope><biblScope unit="page" to="1074">1074</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">Cationic polymers show promise for the in vitro and in vivo delivery of macromolecular therapeutics. Known cationic polymers, e.g., poly(L)lysine (PLL) and polyethylenimine (PEI), have been employed in native and modified forms for the delivery of plasmid DNA (pDNA) and reveal varying levels of toxicity. Here, we report the preparation of a new class of cationic polymers that are specifically designed to deliver macromolecular therapeutics. Linear, cationic, β-cyclodextrin (β-CD)-containing polymers (CD-polymers) are synthesized by copolymerizing difunctionalized β-CD monomers (AA) with other difunctionalized comonomers (BB) such that an AABBAABB product is formed. The β-CD polymers are able to bind ∼5 kbp pDNA above polymer to DNA (+/−) charge ratios of 1.5, compact the bound pDNA into particles of approximately 100−150 nm in size at charge ratios above 5+/−, and transfect cultured cells at charge ratios above 10+/−. In vitro transfections with the new β-CD-polymers are comparable to the best results obtained in our hands with PEI and Lipofectamine. Some cell line-dependent toxicities are observed for serum-free transfections; however, no toxicity is revealed at charge ratios as high as 70+/− in transfections conducted in 10% serum. Single IV and IP doses as high as 200 mg/kg in mice showed no mortalities.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Gonzalez, Hector" sort="Gonzalez, Hector" uniqKey="Gonzalez H" first="Hector" last="Gonzalez">Hector Gonzalez</name></region><name sortKey="Davis, M E" sort="Davis, M E" uniqKey="Davis M" first="M. E." last="Davis">M. E. Davis</name><name sortKey="Davis, M E" sort="Davis, M E" uniqKey="Davis M" first="M. E." last="Davis">M. E. Davis</name><name sortKey="Hwang, Sue Jean" sort="Hwang, Sue Jean" uniqKey="Hwang S" first="Sue Jean" last="Hwang">Sue Jean Hwang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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