Intracellular targeting therapy of cisplatin-encapsulated transferrin-polyethylene glycol liposome on peritoneal dissemination of gastric cancer.
Peritoneal dissemination in gastric cancer is a common fatal clinical condition with few effective therapies available. We studied the therapeutic effect of a tumor-targeting drug delivery system that uses cisplatin-encapsulated and Tf-conjugated PEG liposomes (Tf-PEG liposomes) in nude mice with peritoneal dissemination of human gastric cancer cells. Small unilamellar Tf-PEG, PEG or DSPC/CH liposomes (bare liposomes) encapsulating cisplatin were prepared by reverse-phase evaporation followed by extrusion. Electron microscopic studies revealed that Tf-PEG liposomes were internalized into tumor cells by receptor-mediated endocytosis. To examine the biodistribution of each liposome and cisplatin level, nude mice were inoculated i.p. with 10(7) MKN45P human gastric tumor cells. On the fourth day after tumor inoculation, (3)H-CHE-labeled and cisplatin-encapsulated Tf-PEG, PEG or bare liposome were inoculated i.p. The Tf-PEG liposome-administered group maintained high liposome and cisplatin levels in ascites and showed a prolonged residence time in the peripheral circulation. Uptake of Tf-PEG liposomes into the liver and spleen was significantly lower than that of bare liposomes. Uptake of Tf-PEG liposomes in disseminated tumor cells of ascites and the greater omentum was significantly higher than that of PEG or bare liposomes and a significant increase in cisplatin levels was observed in these tumor cells. Mice receiving Tf-PEG liposomes 1 and 4 days after the day of tumor inoculation showed significantly higher survival rates compared with those receiving PEG liposomes without Tf, bare liposomes or free cisplatin solution. These results suggest that cisplatin-encapsulated Tf-PEG liposomes may be useful as a new intracellular targeting carrier for treatment of gastric cancer with peritoneal dissemination.
Iinuma
Hisae
H
Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan. iinuma@med.teikyo-u.ac.jp
Maruyama
Kazuo
K
Okinaga
Kota
K
Sasaki
Katsunori
K
Sekine
Toshiyuki
T
Ishida
Osamu
O
Ogiwara
Naoko
N
Johkura
Kohei
K
Yonemura
Yutaka
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage*; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D011092:Polyethylene Glycols; D011990:Receptors, Transferrin / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014168:Transferrin
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D011990:Receptors, Transferrin; D014168:Transferrin; D011092:Polyethylene Glycols; D002945:Cisplatin