title: Plasma lipoproteins as targeting carriers to tumour tissues after administration of a lipophilic agent to mice.
abstract: We synthesized 14C-warfarin hexadecyl ether (14C-WHE) by addition of a palmityl moiety to the hydroxyl group at the 4-position of 14C-warfarin, a compound known to bind to serum albumin. 14C-WHE preferentially bound to the lipoproteins, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), in mouse plasma both in vitro and in vivo. 14C-Warfarin mainly concentrated in the liver immediately after intravenous administration to mice bearing M5076 sarcoma, and was found at only low concentrations in other tissues including the tumour. 14C-WHE highly distributed to the tumour, adrenal, and spleen, as well as the liver. These tissues coincided with those in which human 125I-LDL was vigorously incorporated. The results indicate that chemical modification of an agent, giving it high lipophilicity, will enable it to bind to lipoproteins after intravenous administration. These modifications raise the possibility of lipoproteins as endogenous targeting carriers into tumour cells, which have high LDL-receptor activity.
authors.affiliation: Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tokui
authors.forename: C
authors.initials: C
authors.lastname: Kuroiwa
authors.forename: S
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Tokui
authors.forename: K
authors.initials: K
authors.lastname: Sasagawa
authors.forename: T
authors.initials: T
authors.lastname: Ikeda
authors.forename: T
authors.initials: T
authors.lastname: Komai
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000097:blood; D004337:Drug Carriers; D005260:Female; D008074:Lipoproteins / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015335:Molecular Probes; D010168:Palmitates / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D012513:Sarcoma, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution; D014859:Warfarin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000418:Albumins; D002352:Carrier Proteins; D004337:Drug Carriers; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D015335:Molecular Probes; D010168:Palmitates; D012709:Serum Albumin; C094088:warfarin hexadecyl ether; D014859:Warfarin