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Journal of Lipid Research, Vol. 46, 2325-2338, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Synthesis of phospholipid-conjugated bile salts and interaction of bile salt-coated liposomes with cultured hepatocytes¹

G. Pütz^2,*, W. Schmider, R. Nitschke, G. Kurz^*,1 and H. E. Blum^*

^* University Medical Clinic Freiburg, D-79106 Freiburg, Germany
Aventis Pharma Germany GmbH, Sanofi-Aventis Group, D-65929 Frankfurt/M, Germany
Life Imaging Center, Institute of Biology I, University of Freiburg, D-79104 Freiburg, Germany

¹ This paper is dedicated to the memory of Prof. Dr. G. Kurz, deceased May 29, 2002.

Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500144-JLR200

² To whom correspondence should be addressed. e-mail: puetz{at}medizin.ukl.uni-freiburg.de

To examine the possibility of targeting liposomes to hepatocytes via bile salts, the bile salt lithocholyltaurine was covalently linked to a phospholipid. The isomeric compounds disodium 3-(2-(1,2-O-distearoyl-sn-glycero-3-phospho-2'-ethanolamidosuccinyloxy)ethoxy)-5ß-cholan-24-oyl-2'-aminoethansulfonate and disodium 3ß-(2-(1,2-O-distearoyl-sn-glycero-3-phospho-2'-ethanolamidosuccinyloxy)ethoxy-5ß-cholan-24-oyl-2'-aminoethansulfonate (DSPE-3ß-LCT) were synthesized and incorporated into liposomal membranes. Confocal laser scanning microscopy studies showed that bile salt-bearing liposomes (BSLs) attach to the surface of rat hepatocytes in culture. Studies with radioactively labeled liposomes revealed that the bile salt linked via the 3ß-conformation resulted in a higher attachment efficiency than that with the 3-derivative. In the presence of BSLs corresponding to 2 mM liposomal phosphatidylcholine, uptake of 50 µM cholyltaurine (CT) into hepatocytes was reduced by 40% by the 3ß-derivative and by 17% by the 3-derivative. When added simultaneously with the liposomes, CT up to 75 µM inhibited the binding of DSPE-3ß-LCT-bearing liposomes. By contrast, increasing concentrations reversed this inhibition and resulted in an increased bile salt-mediated binding. The same was true when CT was added 10 min before the liposomes were added.

The attachment of BSLs to the surface of hepatocytes opens up promising possibilities for hepatocyte-specific drug delivery. More generally, not only substrates for cellular endocytosing receptors but also substrates for cellular carrier proteins should be suitable ligands for the cell-specific targeting of nanoscale particles such as liposomes.

Abbreviations: BSL, bile salt-bearing liposome; CH, cholesterol; COL, control liposome; CT, cholyltaurine; DCCI, N,N'-dicyclohexylcarbodiimide; DPPC, 1,2-O-dipalmitoyl-sn-glycero-3-phosphocholine; DPPS, 1,2-O-dipalmitoyl-sn-glycero-3-phosphoserine; DSPE, 1,2-O-distearoyl-sn-glycero-3-phosphoethanolamine; DSPE-3-LCT, disodium 3-(2-(1,2-O-distearoyl-sn-glycero-3-phospho-2'-ethanolamidosuccinyloxy)ethoxy)-5ß-cholan-24-oyl-2'-aminoethansulfonate; DSPE-3-LCT, disodium 3-(2-(1,2-O-distearoyl-sn-glycero-3-phospho-2'-ethanolamidosuccinyloxy)ethoxy)-5ß-cholan-24-oyl-2'-aminoethansulfonate; DSPE-3ß-LCT, disodium 3ß-(2-(1,2-O-distearoyl-sn-glycero-3-phospho-2'-ethanolamidosuccinyloxy) ethoxy-5ß-cholan-24-oyl-2'-aminoethansulfonate; DSPG, 1,2-O-distearoyl-sn-glycero-3-phospho-rac-(1-glycerol); LSM, laser scanning microscopy; NBD, 4-nitrobenzo-2-oxa-1, 3-diazol; MP, melting point; MS, mass spectrum; Ntcp, Na⁺/cholyltaurine-cotransporting polypeptide; PC, phosphatidylcholine; Ph₂-DiOC18, 3,3'-dioctadecyl-5,5'-diphenyloxacarbocyanine chloride; PSL, phosphatidylserine-bearing liposome; RT, room temperature; SS, solvent system

Supplementary key words hepatic drug delivery • bile salt carrier • modified liposomes • hepatocyte-specific drug targeting

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