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  • Strand, Sabina PUppsala universitet,Institutionen för farmaci (author)

Molecular design of chitosan gene delivery systems with an optimized balance between polyplex stability and polyplex unpacking

  • Article/chapterEnglish2010

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  • Elsevier BV,2010
  • printrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:uu-123111
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-123111URI
  • https://doi.org/10.1016/j.biomaterials.2009.09.102DOI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

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  • Chitosan is an attractive gene delivery vehicle, but the criteria and strategies for the design of efficient chitosan gene delivery systems remain unclear. The purpose of this work was to investigate how the strength of the charge-based interaction between chitosan and DNA determines the gene expression levels and to design chitosan vectors with an optimized balance between polyplex stability and polyplex unpacking. Using 21 formulations based on low molecular weight chitosans with constant charge density and a number-average degree of polymerization (DPn) in the range of 21-88 (M(w) 4.7-33kDa), we studied the relationship between the chain length and the formulation properties, cellular uptake of polyplexes and gene transfer efficacy. We were able to identify a narrow interval of DPn31-42 that mediated the maximum level of transgene expression. An increase in chain length and/or the amino-phosphate (A/P) ratio reduced and delayed transgene expression. Compared to DPn31, transfection with the same amount of DPn72 or DPn88 resulted in 10-fold-lower expression levels. The gene transfer pattern correlated with the ability of heparin to release DNA from the polyplexes. As a tool to facilitate the unpacking of the polyplexes, we substituted the chitosans with uncharged oligosaccharides that reduced the interaction with DNA. The substitution of chitosans that originally yielded too stable polyplexes, such as DPn72 and DPn88 resulted in a 5-10-fold enhancement of the expression levels. However, the substitution of chitosans shorter than DP28 completely abolished transfection. Tailoring of the chain length and the substitution of chitosan were shown to be feasible tools to modulate the electrostatic interactions between the chitosan and DNA and to design chitosans with an optimized balance between polyplex stability and polyplex unpacking.

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  • Lelu, Sylvie (author)
  • Reitan, Nina K (author)
  • de Lange Davies, Catharina (author)
  • Artursson, PerUppsala universitet,Institutionen för farmaci(Swepub:uu)perartur (author)
  • Vårum, Kjell M (author)
  • Uppsala universitetInstitutionen för farmaci (creator_code:org_t)

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  • In:Biomaterials: Elsevier BV31:5, s. 975-9870142-96121878-5905

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By the author/editor
Strand, Sabina P
Lelu, Sylvie
Reitan, Nina K
de Lange Davies, ...
Artursson, Per
Vårum, Kjell M
About the subject
MEDICAL AND HEALTH SCIENCES
MEDICAL AND HEAL ...
and Basic Medicine
and Pharmaceutical S ...
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Biomaterials
By the university
Uppsala University

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Strand, Sabina P
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