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Permeability of 5-aminolevulinic acid oxime derivatives in lipid membranes

Journal article
Authors Emma S. E. Eriksson
E. Erdtman
Leif A Eriksson
Published in Theoretical Chemistry accounts
Volume 135
Issue 1
Pages 1-9
ISSN 1432-881X
Publication year 2016
Published at Department of Chemistry and Molecular Biology
Pages 1-9
Language en
Links dx.doi.org/10.1007/s00214-015-1798-...
Keywords 5-Aminolevulinic acid, Lipid membrane, Molecular dynamics simulations, Oxime derivatives, Permeation, Photodynamic therapy
Subject categories Theoretical Chemistry, Biochemistry and Molecular Biology

Abstract

The endogenous molecule 5-aminolevulinic acid (5ALA) and its methyl ester (Me-5ALA) have been used as prodrugs in photodynamic treatment of actinic keratosis and superficial non-melanoma skin cancers for over a decade. Recently, a novel set of 5ALA derivatives based on introducing a hydrolyzable oxime functionality was proposed and shown to generate considerably stronger onset of the photoactive molecule protoporphyrin IX (PpIX) in the cells. In the current work, we employ molecular dynamics simulation techniques to explore whether the higher intercellular concentration of PpIX caused by the oxime derivatives is related to enhanced membrane permeability, or whether other factors contribute to this. It is concluded that the oximes show overall similar accumulation at the membrane headgroup regions as the conventional derivatives and that the transmembrane permeabilities are in general close to that of 5ALA. The highest permeability of all compounds explored is found for Me-5ALA, which correlates with a considerably lower fee energy barrier at the hydrophobic bilayer center. The high PpIX concentration must hence be sought in other factors, where slow hydrolysis of the oxime functionality is a plausible reason, enabling stronger buildup of PpIX over time. © 2016, Springer-Verlag Berlin Heidelberg.

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