title: Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination.
abstract: The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel-incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX-Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX-Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX-Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4 h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX-Cre group (P < 0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX-Cre. Serum paclitaxel concentrations 6, 12, 24, and 48 h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX-Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX-Cre group (24 100 ± 3560 vs 108 ± 25 ng/mL, respectively; P < 0.001), as was the area under the concentration-time curve from 0 to 48 h (191 000 ± 32 100 vs 1500 ± 108 ng·h/mL, respectively; P < 0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation.
authors.affiliation: Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan. semoto-tky@umin.ac.jp
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Emoto
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Junko
authors.initials: J
authors.lastname: Kishikawa
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Yamashita
authors.forename: Hironori
authors.initials: H
authors.lastname: Ishigami
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000737:chemistry; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; C500671:NK105; D000431:Ethanol; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol