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Rational design and applications of cell-penetrating peptides
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-4604-6413
2014 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Cell-penetrating peptides are peptides capable of translocating the cellular membrane and entering the cell, either alone or together with a cargo. Potential applications of cell-penetrating peptides include drug delivery and gene therapy. This thesis is focused on the development of novel cell-penetrating peptides and applications for passage across the blood-brain barrier. We have developed a series of novel cell-penetrating peptides based on the model amphipathic peptide and modifications developed for the PepFect peptides. Our general goal is to improve our understanding of the structural requirements for efficient cell penetration and to apply this knowledge in the development of improved cell-penetrating peptides. We have also developed an in vitro model of the blood brain barrier based on brain endothelial cells grown on a semi-permeable membrane. This model has been used together with a series of novel peptides modified with targeting sequences in order to study the passage of peptides across the barrier and into an underlying layer of glioma cells.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry , 2014. , 80 p.
National Category
Chemical Sciences Neurosciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-99849ISBN: 978-91-7447-848-8 (print)OAI: oai:DiVA.org:su-99849DiVA: diva2:689168
Presentation
2014-02-04, C458, Department of Neurochemistry, Stockholm University, Stockholm, 12:15 (English)
Opponent
Supervisors
Note

At the time of the seminar, the papers were not published and had a status as follows: Paper 1: Accepted; Paper 2: Epub ahead of print.

Available from: 2014-01-23 Created: 2014-01-20 Last updated: 2015-03-16Bibliographically approved
List of papers
1. Rational design of a series of novel amphipathic cell-penetrating peptides
Open this publication in new window or tab >>Rational design of a series of novel amphipathic cell-penetrating peptides
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2014 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 464, no 1-2, 111-116 p.Article in journal (Refereed) Published
Abstract [en]

A series of novel, amphipathic cell-penetrating peptides was developed based on a combination of the model amphipathic peptide sequence and modifications based on the strategies developed for PepFect and NickFect peptides. The aim was to study the role of amphipathicity for peptide uptake and to investigate if the modifications developed for PepFect peptides could be used to improve the uptake of another class of cell-penetrating peptides. The peptides were synthesized by solid phase peptide synthesis and characterized by circular dichroism spectroscopy. Non-covalent peptide-plasmid complexes were formed by co-incubation of the peptides and plasmids in water solution. The complexes were characterized by dynamic light scattering and cellular uptake of the complexes was studied in a luciferase-based plasmid transfection assay. A quantitative structure-activity relationship (QSAR) model of cellular uptake was developed using descriptors including hydrogen bonding, peptide charge and positions of nitrogen atoms. The peptides were found to be non-toxic and could efficiently transfect cells with plasmid DNA. Cellular uptake data was correlated to QSAR predictions and the predicted biological effects obtained from the model correlated well with experimental data. The QSAR model could improve the understanding of structural requirements for cell penetration, or could potentially be used to predict more efficient cellpenetrating peptides.

Keyword
Cell-penetrating peptide, Model amphipathic peptide, Plasmid transfection, Structure-activity, QSAR
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-100005 (URN)10.1016/j.ijpharm.2014.01.018 (DOI)000331726000013 ()
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2017-05-05Bibliographically approved
2. Peptide-Based Delivery of Oligonucleotides Across Blood-Brain Barrier Model
Open this publication in new window or tab >>Peptide-Based Delivery of Oligonucleotides Across Blood-Brain Barrier Model
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2014 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3904, Vol. 20, no 2, 169-178 p.Article in journal (Refereed) Published
Abstract [en]

Delivery of pharmaceutical agents across a blood–brain barrier (BBB) is a challenge for brain cancer therapy. In this study, an in vitro BBB model was utilized to study the delivery of oligonucleotides across brain endothelial cells targeting to glioma cells in a Transwell™ setup. A series of novel peptides were synthesized by covalent conjugation of cell-penetrating peptides with targeting peptides for delivery of gene-based therapeutics. These peptides were screened for passage across the Transwell™ and we found the most efficient peptide PepFect32 from originating PepFect 14 coupled with the targeting peptide angiopep-2. PepFect32/pDNA nanocomplexes exhibited high transcytosis across the BBB in vitro model and the highest transfection efficiency to glioma cells. In conclusion, PepFect32 revealed the most efficient peptide-based vector for pDNA delivery across in vitro BBB model.

Keyword
Blood–brain barrier model, Cell-penetrating peptide, bEnd.3, Glioma cells, Plasmid transfection, Gene-based therapy
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-100010 (URN)10.1007/s10989-013-9378-4 (DOI)000334420100007 ()
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2017-05-05Bibliographically approved

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