Hepatic stellate cell-targeted delivery of M6P-HSA-glycyrrhetinic acid attenuates hepatic fibrogenesis in a bile duct ligation rat model.
OBJECTIVE
Hepatic stellate cells (HSCs) play a key role in fibrogenesis. Here, we used mannose-6-phosphate-modified human serum albumin (M6P(26)-HSA) as a selective carrier to deliver antifibrotic drug 18beta-glycyrrhetinic acid (18beta-GA) in experimental fibrosis animals, and tested its effect in injured liver tissues.


METHODS
Bile duct ligation (BDL) was performed to induce liver damage in rats. Masson's stain and immunocytochemistry were used to assess hepatic collagen deposits and uptakes of M6P(26)-HSA-GA in HSCs in rat livers. Gene expression profiles of procollagen type I alpha2, smooth muscle actin (SMA), and transforming growth factor-beta1 (TGF-beta1) were analysed by TaqMan and quantitative polymerase chain reaction assays. The depositions of M6P(26)-HSA-GA in the HSC-T6 cell line and primary HSCs were assessed by immunofluorescent staining.


RESULTS
Treatment with M6P(26)-HSA-GA at 10 mg/kg (three times/week for 2 weeks), but not the equivalent doses of free 18beta-GA and M6P(26)-HSA carrier alone, could significantly attenuate collagen deposits in BDL rat liver. Masson's stain and TaqMan assay revealed significant modulation of procollagen type I alpha2 in the BDL-injured liver. The depositions of M6P(26)-HSA-GA in HSCs were revealed by immunostaining with HSA and SMA markers. M6P(26)-HSA bound activated HSCs in vitro and the immunoreactivity of M6P(26)-HSA-GA was detected in the cytoplasm and cell surface of HSCs and HSC-T6 cells. The gene transcript levels of SMA and TGF-beta1 were modulated in HSC-T6 cells treated with M6P(26)-HSA-GA.


CONCLUSIONS
The M6P(26)-HSA holds promise as a targeting carrier for the liver or HSCs, which may be used to deliver 18beta-GA as a therapeutic agent to treat liver fibrosis.
Luk
John M
JM
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Hong Kong.
Zhang
Qi-Sheng
QS
Lee
Nikki P
NP
Wo
Jana Y
JY
Leung
Pauline P
PP
Liu
Ling-Xiao
LX
Hu
Mei-Yu
MY
Cheung
Kwok-Fan
KF
Hui
Chee-Kin
CK
Lau
George K
GK
Fan
Sheung-Tat
ST
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods; D020869:Gene Expression Profiling; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology; D020286:Pericytes / Q000187:drug effects / Q000473:pathology*; D051381:Rats
D000893:Anti-Inflammatory Agents; D006034:Glycyrrhetinic Acid