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Rational design of novel cell-penetrating peptides
Stockholm University, Faculty of Science, Department of Neurochemistry. (Ülo Langel)ORCID iD: 0000-0001-7746-8574
2012 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Although cell-penetrating peptides (CPPs) have been an active field of research for over 20 years there are still properties such as efficiency and stability that must be improved for CPPs to reach their full potential as delivery vectors.

In this thesis two peptides were designed for non-covalent oligonucleotide delivery, in an attempt to overcome two major issues hampering wider use of CPPs, namely low stability and endosomal entrapment.

In Paper I we designed a new peptide named PepFect14, which has unnatural amino-acid ornithine as the source of positive charge, to address the stability issue. PepFect14 was shown to deliver SCOs in a highly efficient manner into different cell-lines. Furthermore, formulation of non-covalent PepFect14:SCO complexes into solid form, suitable for storage and transportation, was developed. The formulated complexes were stable for weeks and retained high activity.

In Paper II we modified PepFect14 with endosomolytic groups to facilitate endosomal escape, the resulting peptide was named PepFect15. Delivery of SCO and miRNA was efficiently mediated by PepFect15 into HeLa cells and endosomolytic property was validated. Additionally, uptake of Pepfect15:SCO complexes was shown to be mediated by scavenger receptor class A.

Place, publisher, year, edition, pages
Stockholm: Stockholm University, 2012.
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-80474ISBN: 978-91-7447-475-6 (print)OAI: oai:DiVA.org:su-80474DiVA: diva2:555521
Presentation
2012-03-30, Heilbronnsalen, Svante Arrhenius väg 21A, Stockholm, 13:30 (English)
Opponent
Supervisors
Available from: 2012-10-30 Created: 2012-09-20 Last updated: 2017-11-28Bibliographically approved
List of papers
1. PepFect15, a novel endosomolytic cell-penetrating peptide for non-covalent oligonucleotide delivery
Open this publication in new window or tab >>PepFect15, a novel endosomolytic cell-penetrating peptide for non-covalent oligonucleotide delivery
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(English)Manuscript (preprint) (Other academic)
Keyword
cell-penetrating peptide, drug delivery, oligonucleotide
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-74368 (URN)
Available from: 2012-03-08 Created: 2012-03-08 Last updated: 2016-01-29Bibliographically approved
2. PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation
Open this publication in new window or tab >>PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation
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2011 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no 12, 5284-5298 p.Article in journal (Refereed) Published
Abstract [en]

Numerous human genetic diseases are caused by mutations that give rise to aberrant alternative splicing. Recently, several of these debilitating disorders have been shown to be amenable for splice-correcting oligonucleotides (SCOs) that modify splicing patterns and restore the phenotype in experimental models. However, translational approaches are required to transform SCOs into usable drug products. In this study, we present a new cell-penetrating peptide, PepFect14 (PF14), which efficiently delivers SCOs to different cell models including HeLa pLuc705 and mdx mouse myotubes; a cell culture model of Duchenne's muscular dystrophy (DMD). Non-covalent PF14-SCO nanocomplexes induce splice-correction at rates higher than the commercially available lipid-based vector Lipofectamine™ 2000 (LF2000) and remain active in the presence of serum. Furthermore, we demonstrate the feasibility of incorporating this delivery system into solid formulations that could be suitable for several therapeutic applications. Solid dispersion technique is utilized and the formed solid formulations are as active as the freshly prepared nanocomplexes in solution even when stored at an elevated temperatures for several weeks. In contrast, LF2000 drastically loses activity after being subjected to same procedure. This shows that using PF14 is a very promising translational approach for the delivery of SCOs in different pharmaceutical forms.

National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-56147 (URN)10.1093/nar/gkr072 (DOI)000292564900040 ()21345932 (PubMedID)
Available from: 2011-04-11 Created: 2011-04-11 Last updated: 2017-12-11Bibliographically approved

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