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Design, development and characterization of lipid-based nanosomes for siRNA delivery into human skin

Barbara Geusens UGent (2010)
abstract
The skin is the largest organ of our body that protects us from ingress of foreign material by its very efficient barrier properties. It is an interesting candidate for gene therapy because of its easy accessibility, and multiple potential applications. Cationic liposomes are often used as non-viral delivery systems for topical application of nucleic acids onto the skin. It is a painless, cheap method and can easily be applied to large body surface areas. However, they often display an insufficient therapeutic activity due to their limited transfection efficiencies. The primary aim of this thesis was to design, develop and characterize a new type of liposome for the efficient delivery of siRNA molecules into the skin. Transfection capacity of the liposomes and biological effects of the siRNA were investigated by evaluating the knockdown efficiency of pigmentary genes in in vitro models. We found that our newly developed SECosomes (Surfactant-Ethanol-Cholesterol) showed favourable physicochemical and biological properties for siRNA delivery in vitro due to their unique composition and morphological features. This was displayed by a high encapsulation efficiency of the siRNA, an extreme flexible character, high stability, low cytotoxicity and very efficient transfection and knockdown abilities in cultured skin cells. Moreover, when they were applied onto human skin, they were found to deliver siRNA molecules beyond the stratum corneum, into the keratinocytes of the stratum granulosum, as was investigated using MPT in combination with FLIM for additional validation. Their possible therapeutic effects were investigated on a UV-induced hyperpigmentation model, using human skin explants. Different siRNA molecules, targeted against several genes involved in the pigmentation process, were incapsulated in the SECosomes and topically applied. First preliminary data suggest that a mix of different SECosome/siRNA formulations was able to deplete and prevent UV-induced skin colour. This could only be accomplished in case of efficient permeation into the skin. However, these data need to be validated thoroughly in the months to come.
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author
promoter
UGent and UGent
organization
alternative title
Ontwerp, ontwikkeling en karakterisatie van lipide-gebaseerde nanosomen vor siRNA afgifte in humane huid
year
type
dissertation (composite)
subject
keyword
skin, cutaneous gene therapy, liposomes, transdermal drug delivery, siRNA
pages
290 pages
publisher
Ghent University. Faculty of Medicine and Health Sciences
place of publication
Ghent, Belgium
defense location
Gent : Aula Universiteit
defense date
2010-09-17 17:00
ISBN
9789080621503
language
English
UGent publication?
yes
classification
D1
additional info
dissertation consists of copyrighted materials
copyright statement
I have transferred the copyright for this publication to the publisher
id
1054882
handle
http://hdl.handle.net/1854/LU-1054882
date created
2010-10-06 16:12:43
date last changed
2010-10-12 11:10:52
@phdthesis{1054882,
  abstract     = {The skin is the largest organ of our body that protects us from ingress of foreign material by its very efficient barrier properties. It is an interesting candidate for gene therapy because of its easy accessibility, and multiple potential applications. Cationic liposomes are often used as non-viral delivery systems for topical application of nucleic acids onto the skin. It is a painless, cheap method and can easily be applied to large body surface areas. However, they often display an insufficient therapeutic activity due to their limited transfection efficiencies.
The primary aim of this thesis was to design, develop and characterize a new type of liposome for the efficient delivery of siRNA molecules into the skin. Transfection capacity of the liposomes and biological effects of the siRNA were investigated by evaluating the knockdown efficiency of pigmentary genes in in vitro models. 
We found that our newly developed SECosomes (Surfactant-Ethanol-Cholesterol) showed favourable physicochemical and biological properties for siRNA delivery in vitro due to their unique composition and morphological features. This was displayed by a high encapsulation efficiency of the siRNA, an extreme flexible character, high stability, low cytotoxicity and very efficient transfection and knockdown abilities in cultured skin cells. Moreover, when they were applied onto human skin, they were found to deliver siRNA molecules beyond the stratum corneum, into the keratinocytes of the stratum granulosum, as was investigated using MPT in combination with FLIM for additional validation.
Their possible therapeutic effects were investigated on a UV-induced hyperpigmentation model, using human skin explants. Different siRNA molecules, targeted against several genes involved in the pigmentation process, were incapsulated in the SECosomes and topically applied. First preliminary data suggest that a mix of different SECosome/siRNA formulations was able to deplete and prevent UV-induced skin colour. This could only be accomplished in case of efficient permeation into the skin. However, these data need to be validated thoroughly in the months to come.},
  author       = {Geusens, Barbara},
  isbn         = {9789080621503},
  keyword      = {skin,cutaneous gene therapy,liposomes,transdermal drug delivery,siRNA},
  language     = {eng},
  pages        = {290},
  publisher    = {Ghent University. Faculty of Medicine and Health Sciences},
  school       = {Ghent University},
  title        = {Design, development and characterization of lipid-based nanosomes for siRNA delivery into human skin},
  year         = {2010},
}

Chicago
Geusens, Barbara. 2010. “Design, Development and Characterization of Lipid-based Nanosomes for siRNA Delivery into Human Skin”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
APA
Geusens, B. (2010). Design, development and characterization of lipid-based nanosomes for siRNA delivery into human skin. Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium.
Vancouver
1.
Geusens B. Design, development and characterization of lipid-based nanosomes for siRNA delivery into human skin. [Ghent, Belgium]: Ghent University. Faculty of Medicine and Health Sciences; 2010.
MLA
Geusens, Barbara. “Design, Development and Characterization of Lipid-based Nanosomes for siRNA Delivery into Human Skin.” 2010 : n. pag. Print.