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Targeted gene delivery with oligosaccharide-substituted chitosan oligomers in vitro and after lung administration in vivo
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
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2006 In: Journal of controlled release, Vol. 115, no 1, 103-112 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 115, no 1, 103-112 p.
Identifiers
URN: urn:nbn:se:uu:diva-95239OAI: oai:DiVA.org:uu-95239DiVA: diva2:169375
Available from: 2006-11-29 Created: 2006-11-29Bibliographically approved
In thesis
1. Linear and Branched Chitosan Oligomers as Delivery Systems for pDNA and siRNA In Vitro and In Vivo
Open this publication in new window or tab >>Linear and Branched Chitosan Oligomers as Delivery Systems for pDNA and siRNA In Vitro and In Vivo
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, chitosan, a biocompatible polysaccharide that has been approved as a food additive was selected as a platform for the development of safe, efficient non-viral gene delivery systems to mammalian cells. Previously, chitosan-based gene formulations had been generally associated with high molecular weight chitosans, which were poorly characterised in terms of molecular weight distribution and degree of acetylation. Therefore, in order to improve the properties of chitosan-based gene formulations, the research associated with this thesis focused on establishing the structure-property relationships of well-defined, low molecular weight chitosans (chitosan oligomers) as delivery systems for nucleic acids (pDNA and siRNA) in vitro and after lung administration in vivo. pDNA dissociated more easily from chitosan oligomers than from conventional high molecular weight chitosans, resulting in a faster onset and higher levels of in vivo gene expression, comparable to those mediated by polyethyleneimine (PEI), one of the most efficient non-viral delivery systems. Coupling of a trisaccharide branch to the chitosan oligomers so as to target extracellular lectins resulted in a significant improvement in transfection efficiency because of enhanced cellular uptake and colloidal stability. In contrast to pDNA, longer linear chitosan oligomers were required to form physically-stable nanoparticles with siRNA that mediated efficient, sustained gene silencing in vitro. Finally, the use of an optimised catheter device for the nebulisation of small volumes of pDNA formulations resulted in improved dose precision and lung distribution in vivo compared with conventional intratracheal instillation. In conclusion, chitosan oligomers are interesting and viable alternatives to other non-viral gene delivery systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 46
Keyword
Medical sciences, Chitosan oligomers, gene delivery, gene expression, pDNA, siRNA, MEDICIN OCH VÅRD
Identifiers
urn:nbn:se:uu:diva-7376 (URN)91-554-6747-4 (ISBN)
Public defence
2006-12-21, B41, BMC, Husargatan 3, Uppsala, 09:15
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Supervisors
Available from: 2006-11-29 Created: 2006-11-29Bibliographically approved

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