Cell-penetrating peptides for oligonucleotide delivery: Design and uptake mechanisms
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
The use of oligonucleotides for gene therapy has the potential to efficiently treat a plethora of diseases with minimal side effects. However, the use of oligonucleotides is hampered by the properties of these molecules, which make it essentially impossible for them to permeate the cellular membrane. Therefore, a great deal of research has been focused on developing delivery vectors, which can efficiently and safely deliver oligonucleotides into cells. Cell-penetrating peptides (CPPs) constitute a class of delivery vectors that have received much attention since they were discovered over 20 years ago. CPPs can deliver a wide variety of cargos into cells, such as small molecules, proteins, oligonucleotides and particles, in an efficacious and non-toxic manner.
In this thesis two new CPPs for oligonucleotide delivery were designed. The purpose of the design was to create CPPs, which form stable complexes with oligonucleotides and have endosomolytic properties. The new peptides showed superior potency in intracellular oligonucleotide delivery compared to previously reported CPPs. These results demonstrate that it is possible to drastically improve the efficiency of existing CPPs with relatively simple modifications.
It is well known that CPPs use endocytosis to gain entry into cells, however, why cells endocytose CPPs has never been clearly established. In this thesis we determine that several CPP:oligonucleotide complexes interact with scavenger receptors, and that this interaction leads to endocytosis. The results presented in this thesis provides a deeper understanding of how CPPs function and thereby insights how to improve CPP design.
Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University , 2014. , 62 p.
Cell-penetrating peptides, gene therapy, scavenger receptors
Research subject Neurochemistry with Molecular Neurobiology
IdentifiersURN: urn:nbn:se:su:diva-108344ISBN: 978-91-7649-023-5OAI: oai:DiVA.org:su-108344DiVA: diva2:757228
2014-11-28, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Jones, Arwyn, Professor
Langel, Ülo, Professor
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.2014-11-062014-10-212015-04-21Bibliographically approved
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