title: Inhibition of liver metastasis by targeting of immunomodulators using mannosylated liposome carriers.
abstract: Mannosylated liposomes were prepared by incorporating cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiomannosylethyl)amino)butyl)formamide (Man-C4-Chol) into small unilamellar liposomes consisting of cholesterol and distearoyl phosphatidylcholine (DSPC). The biodistribution of liposomes labeled with [3H]cholesteryl hexadecyl ether was examined in mice. The rate and extent of the hepatic uptake of those [3H]liposomes increased proportionally on increasing the mixing ratio of Man-C4-Chol. Their hepatic uptake was reduced by increasing the administered dose due to the limited number of mannose receptors. The liver uptake of [3H]Man-liposomes was preferentially mediated by liver non-parenchymal cells (NPC) and significantly inhibited by co-injection with an excess of Man-BSA, indicating the involvement of a mannose receptor-mediated mechanism in the hepatic uptake of Man-liposomes. Muramyl dipeptide (MDP), an immunomodulator, was also incorporated into the liposomes and its inhibitory effect in an experimental liver metastasis model was examined. In contrast to free MDP treatment, which showed little effect on the inhibition of metastasis, liposomal MDP significantly reduced the number of metastatic colonies in the liver. Active targeting of MDP to liver NPC by Man-liposomes resulted in more effective inhibition than delivery of MDP by liposomes without mannose. Treatment with MDP/Man-liposomes further increased the survival of the tumor-bearing mice. These results suggest that Man-liposomes are effective carriers for targeted delivery of bioactive compounds to liver NPC.
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Praneet
authors.initials: P
authors.lastname: Opanasopit
authors.forename: Megumi
authors.initials: M
authors.lastname: Sakai
authors.forename: Makiya
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamashita
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D008081:Liposomes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D008358:Mannose / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D012709:Serum Albumin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; D008081:Liposomes; D012709:Serum Albumin; C023840:mannose-bovine serum albumin conjugate; D008358:Mannose