Sustained liver targeting and improved antiproliferative effect of doxorubicin liposomes modified with galactosylated lipid and PEG-lipid.
In this study, a cleavable PEG-lipid (methoxypolyethyleneglycol 2000-cholesteryl hemisuccinate, PEG(2000)-CHEMS) linked via ester bond and galactosylated lipid ((5-cholesten-3beta-yl) 4-oxo-4-[2-(lactobionyl amido) ethylamido] butanoate, CHS-ED-LA) were used to modify doxorubicin (DOX) liposome. DOX was encapsulated into conventional liposomes (CL), galactosylated liposomes (modified with CHS-ED-LA, GalL), pegylated liposomes (modified with PEG(2000)-CHEMS, PEG-CL), and pegylated galactosylated liposomes (modified with CHS-ED-LA and PEG(2000)-CHEMS, PEG-GalL) using an ammonium sulfate gradient loading method and then intravenously injected to normal mice. Both PEG-GalL DOX and GalL DOX gave relatively high overall drug targeting efficiencies to liver ((T(e))(liver)) and were mainly taken up by hepatocyte. However, PEG-GalL DOX showed unique "sustained targeting" characterized by slowed transfer of DOX to liver and reduced peak concentrations in the liver. The biodistribution and antitumor efficacy of various DOX preparations were studied in hepatocarcinoma 22 (H22) tumor-bearing mice. The inhibitory rate of PEG-GalL DOX to H22 tumors was up to 94%, significantly higher than that of PEG-CL DOX, GalL DOX, CL DOX, and free DOX, although the tumor distribution of DOX revealed no difference between PEG-GalL DOX and PEG-CL DOX. Meanwhile, the gradual increase in the liver DOX concentration due to the sustained uptake of PEG-GalL DOX formulations resulted in lower damage to liver. In conclusion, the present investigation indicated that double modification of liposomes with PEG(2000)-CHEMS, and CHS-ED-LA represents a potentially advantageous strategy in the therapy of liver cancers or other liver diseases.
Wang
Shaoning
S
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. wsn.spu@gmail.com
Xu
Hui
H
Xu
Jinghua
J
Zhang
Ying
Y
Liu
Yingchun
Y
Deng
Yi-hui
YH
Chen
Dawei
D
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D004339:Drug Compounding / Q000379:methods; D005690:Galactose / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000138:chemical synthesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008657:Metabolic Clearance Rate; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D008055:Lipids; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005690:Galactose