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Low Charge Density Cationic Polymers for Gene Delivery: Exploring the Influence of Structural Elements on In Vitro Transfection
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
2012 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 12, no 6, 840-848 p.Article in journal (Refereed) Published
Abstract [en]

A series of end-functionalized poly(trimethylene carbonate) DNA carriers, characterized by low cationic charge density and pronounced hydrophobicity, was used to study structural effects on in vitro gene delivery. As the DNA-binding moieties were identical in all polymer structures, the differences observed between the different polymers were directly related to the functionality and length of the polymer backbone. The transfection efficiency and cytotoxicity of the polymer/DNA complexes were thus found to be dependent on a combination of polymer charge density and functionality, highlighting the importance of such structural considerations in the development of materials for efficient gene delivery.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2012. Vol. 12, no 6, 840-848 p.
Keyword [en]
amphiphiles, biodegradable, biological applications of polymers, gene delivery, transfection
National Category
Polymer Chemistry Biochemistry and Molecular Biology
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-169673DOI: 10.1002/mabi.201100480ISI: 000304711200014OAI: oai:DiVA.org:uu-169673DiVA: diva2:507536
Available from: 2012-03-05 Created: 2012-03-05 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Functional Cyclic Carbonate Monomers and Polycarbonates: Synthesis and Biomaterials Applications
Open this publication in new window or tab >>Functional Cyclic Carbonate Monomers and Polycarbonates: Synthesis and Biomaterials Applications
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The present work describes a selection of strategies for the synthesis of functional aliphatic polycarbonates. Using an end-group functionalization strategy, a series of DNA-binding cationic poly(trimethylene carbonate)s was synthesized for application as vectors for non-viral gene delivery. As the end-group functionality was identical in all polymers, the differences observed in DNA binding and in vitro transfection studies were directly related to the length of the hydrophobic poly(trimethylene carbonate) backbone and the number of functional end-groups. This enabled the use of this polymer system to explore the effects of structural elements on the gene delivery ability of cationic polymers, revealing striking differences between different materials, related to functionality and cationic charge density.

In an effort to achieve more flexibility in the synthesis of functional polymers, polycarbonates were synthesized in which the functionalities were distributed along the polymer backbone. Through polymerization of a series of alkyl halide-functional six-membered cyclic carbonates, semicrystalline chloro- and bromo-functional homopolycarbonates were obtained. The tendency of the materials to form crystallites was related to the presence of alkyl as well as halide functionalities and ranged from polymers that crystallized from the melt to materials that only crystallized on precipitation from a solution. Semicrystallinity was also observed for random 1:1 copolymers of some of the monomers with trimethylene carbonate, suggesting a remarkable ability of repeating units originating from these monomers to form crystallites.

For the further synthesis of functional monomers and polymers, azide-functional cyclic carbonates were synthesized from the bromo-functional monomers. These were used as starting materials for the click synthesis of triazole-functional cyclic carbonate monomers through Cu(I)-catalyzed azide–alkyne cycloaddition. The click chemistry strategy proved to be a viable route to obtain structurally diverse monomers starting from a few azide-functional precursors. This paves the way for facile synthesis of a wide range of novel functional cyclic carbonate monomers and polycarbonates, limited only by the availability of suitable functional alkynes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 911
Keyword
DNA condensation, gene delivery, ionomers, polyplexes, self-assembly, amphiphiles, biodegradable, biological applications of polymers, transfection, cyclic carbonate monomers, polycarbonates, semicrystalline polymers, click chemistry, triazoles, cycloaddition
National Category
Organic Chemistry Polymer Chemistry Biochemistry and Molecular Biology
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-169677 (URN)978-91-554-8310-4 (ISBN)
Public defence
2012-05-04, Häggsalen, Ångströmlaboratoriet, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2012-04-13 Created: 2012-03-05 Last updated: 2012-04-19Bibliographically approved

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