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Novel efficient cell-penetrating peptide-mediated strategy for enhancing telomerase inhibitor oligonucleotides
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-1228-9927
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-8813-1096
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-6107-0844
(English)Manuscript (preprint) (Other academic)
Keyword [en]
telomerase inhibitors, oligonucleotide, locked nucleic acid, cell-penetrating peptide, non-covalent conjugation, GRN163L, Imetelstat
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-116042OAI: oai:DiVA.org:su-116042DiVA: diva2:801487
Funder
Swedish Research Council
Available from: 2015-04-09 Created: 2015-04-09 Last updated: 2016-01-29Bibliographically approved
In thesis
1. Cell-penetrating peptides and oligonucleotides: Design, uptake and therapeutic applications
Open this publication in new window or tab >>Cell-penetrating peptides and oligonucleotides: Design, uptake and therapeutic applications
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regulation of biological processes through the use of genetic elements is a central part of biological research and also holds great promise for future therapeutic applications. Oligonucleotides comprise a class of versatile biomolecules capable of modulating gene regulation. Gene therapy, the concept of introducing genetic elements in order to treat disease, presents a promising therapeutic strategy based on such macromolecular agents. Applications involving charged macromolecules such as nucleic acids require the development of the active pharmaceutical ingredient as well as efficient means of intracellular delivery. Cell-penetrating peptides are a promising class of drug delivery vehicles, capable of translocation across the cell membrane together with molecules otherwise unable to permeate cells, which has gained significant attention. In order to increase the effectiveness of cell-penetrating peptide-mediated delivery, further understanding of the mechanisms of uptake is needed in addition to improved design to make the cell-penetrating peptides more stable and, in some cases, targeted.

This thesis encompasses four scientific studies aimed at investigating cell-penetrating peptide and oligonucleotide designs amenable to therapeutic applications as well as elucidating the mechanisms underlying uptake of cell-penetrating peptide:oligonucleotide nanoparticles. It also includes an example of a therapeutic application of cell-penetrating peptide-mediated delivery of oligonucleotides. Paper I presents a study evaluating a range of chemically modified anti-miRNAs for use in the design of therapeutic oligonucleotides. All varieties of oligonucleotides used in the study target miRNA-21 and are evaluated using a dual luciferase reporter system. Paper II introduces a novel cell-penetrating peptide, PepFect15, aiming at combining the desirable properties of improved peptide stability and efficient cellular uptake with a propensity for endosomal escape, to produce a delivery vector well suited for delivery of oligonucleotides. The performance of this new cell-penetrating peptide was evaluated based on its delivery capabilities pertaining to splice-correcting oligonucleotides and anti-miRNAs. Paper III investigates the involvement of scavenger receptor class A in the uptake of various cell-penetrating peptides together with their oligonucleotide cargo. Finally, paper IV aims at using cell-penetrating peptide-mediated delivery to improve the efficiency of telomerase inhibition by antisense oligonucleotides targeting the telomerase enzyme ribonucleotide component.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2015
Keyword
Cell-penetrating peptides, oligonucleotides, scavenger receptors, telomerase, gene therapy
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-116049 (URN)978-91-7649-085-3 (ISBN)
Public defence
2015-06-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2015-05-18 Created: 2015-04-09 Last updated: 2015-05-18Bibliographically approved

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