Low density lipoprotein as a targeted carrier for doxorubicin in nude mice bearing human hepatoma HepG2 cells.
Doxorubicin (DOX) was coupled to human low density lipoprotein (LDL) to form a complex (LDL-DOX). When injected into mice, LDL-DOX was more accumulated in liver than free DOX. In contrast, LDL-DOX was less accumulated in heart than free DOX. In in vitro studies on human hepatoma (HepG2) cells, although the cellular uptake of LDL-DOX was higher than that of DOX, the anti-proliferative effect of LDL-DOX on these tumor cells was smaller than that of LDL. However, when LDL-DOX or DOX was administered to nude mice bearing HepG2 cells implanted on the shoulder, the anti-proliferative effects on the tumor cells of both drugs were similar. Histological analyses indicated that organization of myocardial filaments was disrupted and vacuolization was observed in DOX-treated group when compared with control group whereas LDL-DOX-treatment did not exhibit any damage in the host's heart. Enzymatic analyses also demonstrated that plasma lactate dehydrogenase activity, which is a common indicator of heart damage, was elevated in DOX-treated group when compared with control group whereas the activity of this enzyme was unchanged in LDL-DOX-treated group. The results in present study indicate that LDL can be used as a targeted carrier for DOX because LDL-DOX can exhibit similar anti-proliferative effect as DOX on tumor but reduce the DOX-induced cardiotoxicity in the host.
Chu
A C
AC
Department of Biochemistry, The Chinese University of Hong Kong, Shatin.
Tsang
S Y
SY
Lo
E H
EH
Fung
K P
KP
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008077:Lipoproteins, LDL; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase