Interaction of targeted liposomes with primary cultured hepatic stellate cells: Involvement of multiple receptor systems.
OBJECTIVE
In designing a versatile liposomal drug carrier to hepatic stellate cells (HSC), the interaction of mannose 6-phosphate human serum albumin (M6P-HSA) liposomes with cultured cells was studied.


METHODS
M6P-HSA was covalently coupled to the liposomal surface and the uptake and binding of 3H-labelled M6P-HSA liposomes by primary rat HSC and liver endothelial cells was determined. The targeting ability of M6P-HSA liposomes to HSC was tested in bile duct ligated rats using immunohistochemical methods.


RESULTS
The association of M6P-HSA liposomes with HSC was 4-fold higher than of control liposomes. An excess of M6P-HSA inhibited this association by 58%, indicating M6P receptor specificity. The scavenger receptor competitor polyinosinic acid abolished association of M6P-HSA liposomes with HSC. M6P-HSA liposomes also amply associated with endothelial cells, which abundantly express scavenger receptors. Endocytosis of M6P-HSA liposomes by HSC was temperature dependent and could be inhibited by monensin. In the fibrotic liver M6P-HSA liposomes co-localised with HSC.


CONCLUSIONS
Coupling of M6P-HSA to liposomes strongly increases the in vitro uptake of these liposomes by HSC and endothelial cells. Both the mannose 6-phosphate receptor and the scavenger receptors are involved in the uptake process. M6P-HSA liposomes are potential drug carriers to HSC in the fibrotic liver.
Adrian
Joanna E
JE
Department of Pathology and Laboratory Medicine, Medical Biology section, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands.
Poelstra
Klaas
K
Scherphof
Gerrit L
GL
Molema
Grietje
G
Meijer
Dirk K F
DK
Reker-Smit
Catharina
C
Morselt
Henriëtte W M
HW
Kamps
Jan A A M
JA
D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008081:Liposomes; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008360:Mannosephosphates / Q000008:administration & dosage*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008081:Liposomes; D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; C027693:mannose-6-phosphate; D012313:RNA