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Rational design of a series of novel amphipathic cell-penetrating peptides
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-4604-6413
Stockholm University, Faculty of Science, Department of Neurochemistry. Mahidol University, Thailand.ORCID iD: 0000-0003-2265-557X
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
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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.

Place, publisher, year, edition, pages
2014. Vol. 464, no 1-2, 111-116 p.
Keyword [en]
Cell-penetrating peptide, Model amphipathic peptide, Plasmid transfection, Structure-activity, QSAR
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-100005DOI: 10.1016/j.ijpharm.2014.01.018ISI: 000331726000013OAI: oai:DiVA.org:su-100005DiVA: diva2:690398
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2017-05-05Bibliographically approved
In thesis
1. Rational design and applications of cell-penetrating peptides
Open this publication in new window or tab >>Rational design and applications of cell-penetrating peptides
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:nbn:se:su:diva-99849 (URN)978-91-7447-848-8 (ISBN)
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
2. Cell-penetrating peptide based nanocomplexes for oligonucleotide delivery
Open this publication in new window or tab >>Cell-penetrating peptide based nanocomplexes for oligonucleotide delivery
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oligonucleotide-based drugs hold great promise for the treatment of many types of diseases, ranging from genetic disorders to viral infections and cancer. The problem is that efficient delivery across the cell membrane is required for oligonucleotides to have their desired effect. Cell-penetrating peptides (CPPs) provide a solution to this problem. CPPs are capable of transporting cargoes such as drugs or nucleic acids for gene therapy into the cell, either by covalent conjugation to the cargo or by non-covalent complex formation. This thesis is focused on the development of a class of peptides called PepFects, peptides with fatty acid modifications capable of forming nanoparticle-sized complexes with oligonucleotides. These complexes are efficiently internalized by many different cell types and are generally non-toxic and non-immunogenic.

We have developed a number of novel PepFect peptides and a quantitative structure-activity model to predict the biological effect of our peptides. In addition, the involvement of scavenger receptors class A in the endocytic uptake of PepFect complexes as well as other CPPs and polymeric transfection agents was studied. Lastly, we have developed a series of PepFect peptides for delivery across the blood-brain barrier and a model system mimicking the blood-brain barrier in order to evaluate the passage of these peptides.

The general aim of this thesis is to improve the understanding of intracellular delivery of oligonucleotides with PepFect peptides from both a chemical and a biological viewpoint, and further improve the efficacy of this delivery system with the long-term goal of making it useful in clinical settings. 

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2016. 69 p.
Keyword
Cell-penetrating peptides, oligonucleotides, gene therapy, drug delivery, scavenger receptors, blood-brain barrier
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-133794 (URN)978-91-7649-479-0 (ISBN)
Public defence
2016-11-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2016-10-12 Created: 2016-09-15 Last updated: 2016-09-26Bibliographically approved
3. Cell-penetrating peptides targeting glioblastomas for nucleic acid delivery in the blood-brain barrier model
Open this publication in new window or tab >>Cell-penetrating peptides targeting glioblastomas for nucleic acid delivery in the blood-brain barrier model
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glioblastoma multiforme is the most aggressive form of malignant brain tumor with poor prognosis. The efficacy of brain cancer treatment by chemotherapeutics is limited by the blood-brain barrier (BBB) which allows less than 2% of the small molecules and blocks almost all the macromolecules to transport into the brain. Delivery of the large molecules such as proteins and nucleic acids across the BBB is a great challenge for brain-targeted drug delivery. To overcome this obstacle, cell-penetrating peptides (CPPs) were used as vectors for delivery of nucleic acids across the BBB targeting glioblastomas. The CPPs have shown such promising carriers to deliver various cargoes ranging from small molecules to large molecules into the cells. This thesis is focused on the development of glioblastoma-targeting vectors based on modifications of the CPPs and the targeting peptides. The peptide-based vectors were developed to improve the transport of the nucleic acids across the BBB and specifically target glioblastomas.

In this thesis, a series of peptide-based vectors targeting glioblastomas were synthesized and modified with targeting peptides by either covalent conjugation or non-covalent complex formation. The delivery of plasmid DNA (pDNA) in the complex with the peptide-based vectors was studied in the in vitro model of the BBB. The role of receptors expressed on the BBB was investigated. Scavenger receptors class A and B were found to be expressed on the BBB, and they were involved in the delivery of the pDNA across the BBB model. Moreover, various targeting peptides were modified with hexaglutamate to form non-covalent complexes with the CPPs for small interfering RNA (siRNA) delivery to glioblastoma cells. The non-covalent complex of the CPP and the targeting peptide showed greater gene-silencing efficiency than the consecutively covalent conjugation of the CPP and the targeting peptide for siRNA delivery to glioblastoma cells. Lastly, a number of novel, amphipathic peptides were developed based on the model amphipathic peptide. The prediction of the biological effect of the designed peptides using quantitative structure-activity relationship model showed a correlation with the experimental data.

Finally, the CPP-based nucleic acid delivery vectors with homing peptide strategy have a potential for the BBB shuttle and the future use as a glioblastoma-targeted drug carrier in the in vivo studies and the clinical applications.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2017
Keyword
Blood-brain barrier model, nucleic acid delivery, glioblastomas, cell-penetrating peptides
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-142109 (URN)978-91-7649-725-8 (ISBN)978-91-7649-726-5 (ISBN)
Public defence
2017-06-09, 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: 2017-05-17 Created: 2017-04-27 Last updated: 2017-05-17Bibliographically approved

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