Design and synthesis of novel amphiphilic dendritic galactosides for selective targeting of liposomes to the hepatic asialoglycoprotein receptor.
A series of glycolipids have been prepared which contain a cluster galactoside moiety with high affinity for the hepatic asialoglycoprotein receptor and a bile acid ester moiety which mediates stable incorporation into liposomes. Loading of liposomes with these glycolipids at a ratio of 5% (w/w) resulted in efficient recognition and uptake of the liposomes by the liver. Preinjection with asialofetuin almost completely inhibited the uptake, establishing that the liposomes were selectively recognized and processed by the asialoglycoprotein receptor on liver parenchymal cells. In contrast, a glycolipid content of 50% (w/w) led to a liver uptake that could not be inhibited by preinjection with asialofetuin, indicating that the liposomes were now processed by the Gal/Fuc-recognizing receptor on liver macrophages. The results presented in this study are important for future targeting of water-soluble and amphiphilic drugs, enveloped in these glycolipid-laden liposomes, to parenchymal liver cells.
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Sylvius Laboratories, P.O. Box 9503, 2300 RA Leiden, The Netherlands.
L A
LA
Sliedregt
P C
PC
Rensen
E T
ET
Rump
P J
PJ
van Santbrink
M K
MK
Bijsterbosch
A R
AR
Valentijn
G A
GA
van der Marel
J H
JH
van Boom
T J
TJ
van Berkel
E A
EA
Biessen
D000818:Animals; D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins / Q000378:metabolism*; D001667:Binding, Competitive; D015195:Drug Design; D005697:Galactosides / Q000138:chemical synthesis* / Q000737:chemistry; D006017:Glycolipids / Q000138:chemical synthesis* / Q000737:chemistry; D066298:In Vitro Techniques; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects*; D013329:Structure-Activity Relationship
C117653:((oleoyloxy)-5-cholenoyl)-GABA-Gly-TRISGal(3); C117655:((oleoyloxy)-5beta-cholanoyl)-GABA-Gly-TRISGal(3); C117656:((oleoyloxy)-bis-5-cholenoyl)-GABA-Gly-TRISGal(3); D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D005697:Galactosides; D006017:Glycolipids; D008081:Liposomes; D011956:Receptors, Cell Surface