Permeability of 5-aminolevulinic acid oxime derivatives in lipid membranes
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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.
Keywords5-Aminolevulinic acid Oxime derivatives Photodynamic therapy Lipid membrane Permeation Molecular dynamics simulations
The University of Gothenburg and the Swedish Science Research Council (VR) are gratefully acknowledged for financial support. The authors wish to acknowledge the Swedish National Infrastructure Committee (SNIC) and the C3SE supercomputing facility for the provision of computational facilities and support.
- 1.Van Hillegersberg R, Van den Berg JW, Kort WJ, Terpstra OT, Wilson JH (1992) Gastroenterology 103:647Google Scholar
- 7.Rhodes LE, de Rie M, Enstrom Y, Groves R, Morken T, Goulden V, Wong GA, Grob JJ, Varma S, Wolf P (2004) Arch Dermatol 140:17Google Scholar
- 15.Eriksson, L. A.; Löfgren, L. WO 2010/024775; Austr patent 2009286182Google Scholar
- 21.Marrink SJ, Berger O, Tieleman P Jahnig, F. Biophys. J. 1998, 74:931; Biocomputing at the University of Calgary, structures and topologies. http://moose.bio.ucalgary.ca/index.php?page=Structures_and_Topologies. (Accessed 1 May 2009), File: dppc64.pdb
- 22.Gaussian 09, Revision B.01, Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian, Inc., Wallingford CT, 2009Google Scholar
- 24.Biocomputing at the University of Calgary, structures and topologies. http://moose.bio.ucalgary.ca/index.php?page=Structures_and_Topologies (Accessed 1 May 2009), Files: lipid.itp and dppc.itp
- 25.Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J. Interaction models in water in relation to protein hydration. In: Pullman B, editor. Intermolecular forces. Reidel Dordrecht: Publishing Company, 1981, pp 331–342Google Scholar
- 35.Allen MP, Tildesley DJ (1990) Computer simulation of liquids. Oxford University Press, OxfordGoogle Scholar