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New strategy for siRNA delivery to glioblastoma cells by cell-penetrating peptide
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0003-2265-557X
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-8947-6643
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
blood-brain barrier, siRNA, cell-penetraing peptides, glioblastoma
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-142101OAI: oai:DiVA.org:su-142101DiVA: diva2:1090909
Funder
EU, FP7, Seventh Framework ProgrammeSwedish Cancer SocietySwedish Research Council
Available from: 2017-04-25 Created: 2017-04-25 Last updated: 2017-05-05Bibliographically approved
In thesis
1. 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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