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Delivery of short interfering RNA using endosomolytic cell-penetrating peptides
Stockholm University, Faculty of Science, Department of Neurochemistry.
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2007 In: FASEB Journal, ISSN 0892-6638, Vol. 21, no 11, 2664-2671 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2007. Vol. 21, no 11, 2664-2671 p.
URN: urn:nbn:se:su:diva-24535ISI: 000249237500008OAI: diva2:197755
Part of urn:nbn:se:su:diva-7167Available from: 2007-11-15 Created: 2007-11-07Bibliographically approved
In thesis
1. Vectorization of oligonucleotides with cell-penetrating peptides: Characterization of uptake mechanisms and cytotoxicity
Open this publication in new window or tab >>Vectorization of oligonucleotides with cell-penetrating peptides: Characterization of uptake mechanisms and cytotoxicity
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The hydrophobic plasma membrane constitutes an indispensable barrier for cells in living animals. Albeit being pivotal for the maintenance of cells, the inability to cross the plasma membrane is still one of the major obstacles to overcome in order to progress current drug development. A group of substances, with restricted access to the interior of cells, which has shown great promise for future clinical use is oligonucleotides that are exploited to interfere with gene expression. Short interfering RNAs that are utilized to confer gene silencing and splice correcting oligonucleotides, applied for the manipulation of splicing patterns, are two classes of oligonucleotides that have been explored in this thesis.

Cell-penetrating peptides (CPPs) are a class of peptides that has gained increasing focus in last years. This ensues as a result of their remarkable ability to convey various, otherwise impermeable, macromolecules across the plasma membrane of cells in a relatively non-toxic fashion. This thesis aims at further characterizing well-established, and newly designed, CPPs in terms of toxicity, delivery efficacy, and internalization mechanism.

Our results demonstrate that different CPPs display different toxic profiles and that cargo conjugation alters the toxicity and uptake levels. Furthermore, we confirm the involvement of endocytosis in translocation of CPPs, and in particular the importance of macropinocytosis. All tested peptides facilitate the delivery of splice correcting oligonucleotides with varying efficacy, the newly designed CPP, M918, being the most potent. Finally we conclude that by promoting endosomolysis, by exploring new CPPs with improved endosomolytic properties, the biological response increases significantly. In conclusion, we believe that these results will facilitate the development of new CPPs with improved delivery properties that could be used for transportation of oligonucleotides in clinical settings.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2007. 86 p.
CPP, endocytosis, splice correction, siRNA, PNA, cargo delivery, M918
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Research subject
Neurochemistry and Molecular Neurobiology
urn:nbn:se:su:diva-7167 (URN)9789171555052 (ISBN)
Public defence
2007-12-07, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00 (English)
Available from: 2007-11-15 Created: 2007-11-07 Last updated: 2011-03-24Bibliographically approved

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