title: Lactosylated liposomes for targeted delivery of doxorubicin to hepatocellular carcinoma.
abstract: BACKGROUND
  N-lactosyl-dioleoylphosphatidylethanolamine (Lac-DOPE) was synthesized and evaluated as a liver-specific targeting ligand via asialoglycoprotein receptors for liposomal delivery of doxorubicin.
  
  
  METHODS
  Lactosylated liposomes encapsulating calcein (Lac-L-calcein) or doxorubicin (Lac-L-DOX) composed of egg phosphatidylcholine, cholesterol, monomethoxy polyethylene glycol 2000-distearoyl phosphatidylethanolamine, and Lac-DOPE at 50:35:5:10 (mol/mol) were prepared by polycarbonate membrane extrusion and evaluated in human hepatocellular carcinoma HepG2 cells. Cellular uptake of Lac-L-calcein was monitored by confocal microscopy and by flow cytometry. The cytotoxicity of Lac-L-DOX was evaluated by MTT assay. The pharmacokinetic properties of Lac-L-DOX were studied in normal mice, and its biodistribution and antitumor activity were studied in nude mice with HepG2 xenografts.
  
  
  RESULTS
  The size of Lac-L-DOX was less than 100 nm and the liposomes demonstrated excellent colloidal stability. In vitro uptake of Lac-L-calcein by HepG2 cells was four times greater than that of non-targeted L-calcein. In the presence of 20 mM lactose, the uptake of Lac-L-calcein was inhibited, suggesting that asialoglycoprotein receptors mediated the observed cellular uptake. Lac-L-DOX exhibited enhanced in vivo cytotoxicity compared with the nontargeted liposomal doxorubicin (L-DOX), and its pharmacokinetic parameters indicate that Lac-L-DOX has a long blood circulation time (t(1/2) 8.73 hours). Tissue distribution and therapeutic efficacy studies in nude mice bearing HepG2 xenografts show that Lac-L-DOX had significantly stronger tumor inhibitory activity compared with L-DOX and free doxorubicin, along with a higher accumulation of drug within the tumor site and greater cellular uptake by tumor cells.
  
  
  CONCLUSIONS
  These data suggest that lactosylated liposomes are promising drug delivery vehicles for hepatocellular carcinoma.
authors.affiliation: State Key Laboratory of Virology, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, People's Republic of China.
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Zhou
authors.forename: Mengzi
authors.initials: M
authors.lastname: Zhang
authors.forename: Bryant
authors.initials: B
authors.lastname: Yung
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhou
authors.forename: L James
authors.initials: LJ
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D006017:Glycolipids / Q000737:chemistry / Q000493:pharmacokinetics*; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D053769:Nanocapsules / Q000737:chemistry*; D010742:Phospholipid Ethers / Q000737:chemistry / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D006017:Glycolipids; D008081:Liposomes; D053769:Nanocapsules; D010742:Phospholipid Ethers; C029429:lactosyl-phosphatidylethanolamine; D004317:Doxorubicin
keywords: asialoglycoprotein receptor; drug targeting; hepatocellular carcinoma; liposomes