Interactions of drugs with biological model membranes :a physicochemical approach

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Aalto-yliopiston teknillinen korkeakoulu | Doctoral thesis (article-based)
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Date
2010
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Mcode
Degree programme
Language
en
Pages
Verkkokirja (1001 KB, 66 s.)
Series
TKK dissertations, 232
Abstract
The interactions of drugs with biological membranes affect the delivery of drugs to the target sites within the body. Usually, a drug has to pass through several membranes in order to reach the target location. Because of this, knowledge on the interactions of drugs with biological membranes is essential not only for the understanding of the therapeutic action of existing drugs, but also in the discovery process of new candidates. This thesis explores the possible use of the physicochemical methods in the study of drug-membrane interactions. The emphasis of the thesis is on the various physicochemical approaches in determining the partition coefficient of drugs. As the properties of the drug carriers are equally important in drug delivery, attention is also focused on the physicochemical properties of drug carriers and their interactions with biological membranes. The most widely used parameter in the assessment of membrane permeability is the lipophilicity of a drug, which is most often expressed as the partition coefficient between two phases. In this thesis, the liposome-water partition coefficients of drugs were determined using two different methods, isothermal titration calorimetry and a new electrochemical method, which utilizes an electrified liquid-liquid interface. In addition, the partitioning to the hydrocarbon core of the lipid bilayer was studied using contact angle measurements on three different hydrophobic model membranes. The physicochemical properties of cationic polymer/plasmid DNA complexes and their interactions with the cell surface glycosaminoglycans (GAGs) were studied using dynamic light scattering, isothermal titration calorimetry and agarose gel electrophoresis. It was shown that the aggregation of polyethylene imine/plasmid DNA complexes can be controlled with the surfactant polyoxyethylene stearate, which also protects the complexes against the negative effects of extracellular GAGs. These findings are particularly relevant for ocular gene delivery, as the membranes in the eye have a very high content of GAGs. As a whole, this research addresses a number of important aspects of drug-membrane interactions from the physicochemical perspective. Various approaches to the partitioning of drugs were explored and three different experimental methods were used to determine the partition coefficients of eight drugs. Furthermore, physicochemical explanations were presented for a broad range of phenomena from the electrostatics of the binding of drugs to the aggregation of the DNA complexes.
Description
Supervising professor
Kontturi, Kyösti, Prof.
Thesis advisor
Murtomäki, Lasse, Dr.
Keywords
drug, liposome, electrochemistry, liquid-liquid interface, partition coefficient, plasmid DNA
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Parts
  • [Publication 1]: Marjukka Ikonen, Lasse Murtomäki, and Kyösti Kontturi. 2007. An electrochemical method for the determination of liposome–water partition coefficients of drugs. Journal of Electroanalytical Chemistry, volume 602, number 2, pages 189-194. © 2006 Elsevier Science. By permission.
  • [Publication 2]: Marjukka Ikonen, Lasse Murtomäki, and Kyösti Kontturi. 2008. Controlled complexation of plasmid DNA with cationic polymers: Effect of surfactant on the complexation and stability of the complexes. Colloids and Surfaces B: Biointerfaces, volume 66, number 1, pages 77-83. © 2008 Elsevier Science. By permission.
  • [Publication 3]: Marjukka Ikonen, Lasse Murtomäki, and Kyösti Kontturi. 2009. Studying the interactions of drugs and hydrophobic model membranes using contact angle goniometry. Colloids and Surfaces B: Biointerfaces, volume 71, number 1, pages 107-112. © 2009 Elsevier Science. By permission.
  • [Publication 4]: Marjukka Ikonen, Lasse Murtomäki, and Kyösti Kontturi. 2010. Microcalorimetric and zeta potential study on binding of drugs on liposomes. Colloids and Surfaces B: Biointerfaces, volume 78, number 2, pages 275-282. © 2010 Elsevier Science. By permission.
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