Improved formulations of antisense oligodeoxynucleotides using wrapped liposomes.
Previously, we demonstrated that wrapping dextran fluorescein anionic/cationic lipid complexes with neutral lipids produced a stable formulation that markedly increased the duration of the compound in plasma after intravenous administration to rats. The improved drug-delivery properties of the wrapped liposomes (WL) relative to other formulations suggested that this technology could offer important advantages for the administration of other polyanionic drugs, including antisense oligodeoxynucleotides (ODN). In the present study, we investigated the value of WL for formulating fluorescence-labeled phosphorothioated ODN (F-ODN). WL encapsulating F-ODN/cationic lipid complexes were prepared efficiently using similar methodology to that used in our earlier study. Studies confirmed that these WL were stable in vitro. Following intravenous administration to mice, free F-ODN and naked F-ODN/cationic lipid complexes were rapidly eliminated whereas administration of the WL resulted in high blood concentrations of drug that were maintained for several hours. Additional studies were conducted in mice that were inoculated with tumor cells (Caki-1 xenograft model, human kidney); in these experiments, intravenous administration of WL delivered 13 times more F-ODN to the tumor site than achieved after injection of free F-ODN.
Yamauchi
Masahiro
M
Drug Formulation Research Laboratories, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188, Shimotogari, Nagaizumi-Cho, Sunto-Gun, Shizuoka 411-8731, Japan. masahiro.yamauchi@kyowa.co.jp
Kusano
Hiroko
H
Saito
Etsuko
E
Iwata
Takeshi
T
Nakakura
Masashi
M
Kato
Yasuki
Y
Uochi
Takaaki
T
Akinaga
Shiro
S
Aoki
Noboru
N
D000818:Animals; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D004355:Drug Stability; D000431:Ethanol; D016650:Fluorescein-5-isothiocyanate; D007275:Injections, Intravenous; D007680:Kidney Neoplasms / Q000378:metabolism; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D010316:Particle Size; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D012995:Solubility; D012997:Solvents
D008081:Liposomes; D016376:Oligonucleotides, Antisense; D014677:Pharmaceutical Vehicles; D012997:Solvents; D000431:Ethanol; D011092:Polyethylene Glycols; D016650:Fluorescein-5-isothiocyanate