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Cellular Dyes and Bioactive Peptides - Cell Membrane Interactions and Cellular Uptake

Maria Matson Dzebo (Institutionen för kemi- och bioteknik, Fysikalisk kemi)
Göteborg : Chalmers University of Technology, 2014. ISBN: 978-91-7597-096-7.
[Doktorsavhandling]

Knowledge about mechanisms behind interactions of molecules with biomembranes and cellular uptake is very important for understanding biological processes and for drug design. The work described in this thesis has focused on interactions of cellular dyes and bioactive peptides with cells and the cell membrane. Cellular dyes can be used to investigate processes occurring in the cell since they enhance the contrast of specific intracellular areas or molecules. Here, two types of dyes have been investigated; ruthenium dipyridophenazine complexes and voltage-sensitive dyes. Further, bioactive peptides have gained an increased attention for promising therapeutic applications. In this thesis, the cellular uptake of cell-penetrating peptides, interesting as drug delivery systems, and of the antisecretory peptide, AF-16, is examined. For the development of compounds of both categories, a large challenge is to overcome the poor cellular uptake, which is restricted by the cell membrane, and to understand the mechanisms of interactions with the cell membrane. The results show that ruthenium dipyridophenazine complexes, interesting as cellular dyes because of their low background emission, have tunable affinity for biomembranes and nucleic acids upon slight changes of their lipophilicity and stereochemistry. These complexes enter cells in two different ways, by endocytosis and by a photoactivated uptake mechanism. The voltage-sensitive dyes, which are used for visualization of the membrane potential variation by microscopy, seem to interact with lipid membranes in a dimeric form. For the studied series of arginine- and tryptophan-rich cell-penetrating peptides, the cellular uptake efficiency was found to be sequence specific, both regarding the number and the position of the tryptophan residues. Concerning the therapeutic peptide AF-16, its cellular uptake is mediated by endocytosis, which is enhanced by the presence of cell-surface proteoglycans. The results in this thesis give insights in membrane binding properties and cellular uptake of dyes and bioactive peptides as well as factors influencing these interactions, important knowledge for inspiring in future development of diagnostic and therapeutic molecules.

Nyckelord: Cell Membrane, Membrane Interactions, Cellular Uptake, Cell Dyes, Ruthenium Complexes, Voltage-Sensitive Dyes, Bioactive Peptides, Cell-Penetrating Peptides, Antisecretory Factor, AF-16, Spectroscopy, Confocal Laser Scanning Microscopy, Flow-Cytometry, Isothermal Titration Calorimetry



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Denna post skapades 2014-10-31. Senast ändrad 2014-11-12.
CPL Pubid: 205161