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A new approach to chitosan-mediated gene delivery based on easily dissociated chitosan polyplexes of highly defined chitosan oligomers
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
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In: Gene TherapyArticle in journal (Refereed) Submitted
Identifiers
URN: urn:nbn:se:uu:diva-91057OAI: oai:DiVA.org:uu-91057DiVA: diva2:163640
Available from: 2003-11-18 Created: 2003-11-18Bibliographically approved
In thesis
1. Chitosan Polyplexes as Non-Viral Gene Delivery Systems: Structure-Property Relationships and In Vivo Efficiency
Open this publication in new window or tab >>Chitosan Polyplexes as Non-Viral Gene Delivery Systems: Structure-Property Relationships and In Vivo Efficiency
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The subject of this thesis was to develop and optimize delivery systems for plasmid DNA (pDNA) based on biocompatible polymers, in particular chitosan, suitable for non-viral gene therapy. At the onset of this thesis, studies had reported conflicting results on the efficiency of chitosan-based gene delivery systems. Therefore, structure-property relationships of chitosans as non-viral gene delivery systems in vitro and after lung administration in vivo were established for the first time.

Polymer-pDNA complexes (polyplexes) based on conventional high molecular weight chitosans transfected cells in vitro and after lung administration in vivo. The chitosan polyplexes were, in contrast to polyplexes formed with the "golden standard" polymer polyethylenimine (PEI), essentially non-toxic at escalating doses. However, a very high physical stability of the chitosan-pDNA complexes together with a low buffering capacity of chitosan at the slightly acidic endo/lysosomal pH resulted in a slow onset of the gene expression and also in a lower efficiency of gene expression compared to PEI polyplexes. A slow and biodegradation-dependent release of pDNA from the chitosan polyplexes was concluded to be a rate limiting step for the efficiency of high molecular weight chitosan. The optimized polyplexes of high molecular weight chitosan (around 1,000 monomer units) showed aggregated shapes and gave increased viscosity at concentrations used for in vivo gene delivery. To improve the pharmaceutical properties and the delivery properties of chitosan polyplexes, low molecular weight chitosans were studied. Chitosans of around 18 monomer units retained the ability to protect pDNA against DNase degradation, but were more easily dissociated than those of higher molecular weight and had an efficiency comparable to that of PEI in vitro and in vivo. The pharmaceutical advantages of low molecular weight chitosan polyplexes compared to higher molecular weights are that there is less aggregation and no increased viscosity at the concentrations used for in vivo gene delivery. Coupling of an oligosaccharide targeting ligand to chitosan further increased the efficiency of some oligomer polyplexes. In conclusion, biocompatible chitosan is an interesting alternative to other non-viral gene delivery systems such as PEI.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 58 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 301
Keyword
Pharmaceutics, gene therapy, gene delivery, non-viral, polyplex, chitosan, chitosan oligomers, polyethylenimine, plasmid DNA, lung, Galenisk farmaci
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-3771 (URN)91-554-5801-7 (ISBN)
Public defence
2003-12-11, B21, BMC, Husargatan 3, 751 23 Uppsala, 10:15
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Supervisors
Available from: 2003-11-18 Created: 2003-11-18Bibliographically approved

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