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EGF-targeting lipodisks for specific delivery of cationic amphiphilic peptides to tumour cells
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
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Identifikatorer
URN: urn:nbn:se:uu:diva-305375OAI: oai:DiVA.org:uu-305375DiVA, id: diva2:1037588
Tilgjengelig fra: 2016-10-17 Laget: 2016-10-17 Sist oppdatert: 2016-11-11
Inngår i avhandling
1. Development of lipodisks as carriers for cationic amphiphilic peptides
Åpne denne publikasjonen i ny fane eller vindu >>Development of lipodisks as carriers for cationic amphiphilic peptides
2016 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Antibiotics have made a tremendous contribution to mankind. They are one of the most successful medicines in human history. However, more and more bacterial strains develop resistance and the risk to public health can hardly be overstated. New types of antibiotics are urgently needed. Antimicrobial peptides (AMPs) have emerged as potential antibiotics because of their broad-spectrum activities and non-conventional mechanism of action. More recently, they have also received attention as promising anticancer agents. The clinical and commercial development of AMPs as a new generation of antibiotics and anticancer drugs is hampered, however, by issues concerning the toxicity, specificity and stability of the peptides.

The aim of this thesis has been to explore if formulation in a novel type of nanocarriers, referred to as lipodisks, can be used to increase the therapeutic potential of AMPs as antimicrobial and anticancer agents. Focus has been on AMPs classified as cationic amphiphilic peptides.

Encouragingly, the data presented suggests that the therapeutic potential of the AMP melittin as an antimicrobial and anticancer agent can be substantially increased by formulation in lipodisks. When formulated in the lipodisk, melittin is protected against enzymatic degradation. The lipodisk also offer a slow-release effect that sustains the bacterial cell-killing effect. We also show that specific delivery of melittin to tumour cells can be obtained by formulating the peptide in small EGF-targeting lipodisks.

Melittin contains a tryptophan residue and its interaction with lipodisks can be characterized by means of fluorimetric binding assays. In order to investigate the binding behavior also for peptides that lack intrinsic fluorescence, we developed a method based on measurements using the QCM-D technique. Studies using this, and other techniques, confirmed that it is a general behavior for cationic amphiphilic peptides to preferentially bind to the highly curved rim of lipodisks. Results of our binding studies show that the peptide to lipid ratio in the lipodisks can be tuned and optimized by varying the size and charge of the disks.

Taken together, the findings in this thesis point towards PEG-stabilized lipodisks as promising nanocarriers for antibacterial and anticancer peptides.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 48
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1442
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Identifikatorer
urn:nbn:se:uu:diva-305443 (URN)978-91-554-9729-3 (ISBN)
Disputas
2016-12-02, B41, BMC, Husargatan 3, Uppsala, 10:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2016-11-11 Laget: 2016-10-18 Sist oppdatert: 2016-11-16

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