Intraperitoneal administration of paclitaxel solubilized with poly(2‐methacryloxyethyl phosphorylcholine‐co<i> n‐</i>butyl methacrylate) for peritoneal dissemination of gastric cancer

Soma, Daisuke; Kitayama, Joji; Konno, Tomohiro; Ishihara, Kazuhíko; Yamada, Jun; Kamei, Takao; Ishigami, Hironori; Kaisaki, Shoichi; Nagawa, Hirokazu

doi:10.1111/j.1349-7006.2009.01265.x

Cited by 55 publications

(34 citation statements)

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“…This high paclitaxel concentration in peritoneal nodules in the NK105 group, especially at an early time point after intraperitoneal administration, may be due to enhanced direct penetration of nanoparticulate paclitaxel from the surface of the nodules, which has been shown previously using a different nanomicellar paclitaxel formulation. (36,37) Another PEG-conjugated nanomicellar paclitaxel exhibited enhanced tumor accumulation and deeper penetration in a model of disseminated ovarian cancer. (24) Thus, the route of administration (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…(35) Previously, we showed that intraperitoneal administration of nanoparticulate paclitaxel results in deeper penetration of the drug into peritoneal nodules and enhanced antitumor effects compared with PTX-Cre. (36,37) In the present study, we evaluated the intraperitoneal and systemic antitumor effects of NK105 administered intraperitoneally in an animal model of mouse. Moreover, we evaluated, for the first time, the pharmacokinetics of nanoparticulate paclitaxel following intraperitoneal administration.…”

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Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

et al. 2012

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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 ngÁh/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. (Cancer Sci 2012; 103: 1304-1310 G astric cancer is the fourth leading cause of cancer-related deaths worldwide, and peritoneal dissemination is the most frequent and life-threatening form of metastasis and recurrence in patients with gastric cancer.(1,2) The current systemic chemotherapy regimens for gastric cancer have not achieved satisfactory results, particularly in the treatment of peritoneal dissemination.(3) One of the problems with this type of therapy is the limited delivery of systemically administered drugs to the peritoneal cavity.(4) Intraperitoneal chemotherapy has been shown to be safe and effective in ovarian cancer (5)(6)(7) and is expected to provide a breakthrough in the treatment of gastric cancer with peritoneal dissemination.(8-10) However, in addition to the intraperitoneal administration of drugs, it is necessary to develop new strategies for the treatment of gastric cancer to achieve better results. Research into drug delivery systems (DDS) is ongoing and is mostly aimed at improving the penetration of drugs...

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Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

et al. 2012

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“…The poly(MPC-co-BMA) (PMB), which forms nanoassemblies (polymeric aggregates) or nanoparticles in aqueous media depending on the degree of hydrophobicity and molecular weight of the polymers, has considerable potential for therapeutic nanomaterials [13]. Previously, a PMB carrying an antineoplastic drug was demonstrated to exhibit antitumor effects on cancer cells without cytotoxicity both in vitro and in vivo [14][15][16]; however, the mechanism whereby the drug in the PMB was delivered across the plasma membrane of cells remains poorly understood. In this study, we discovered direct penetration mechanism across the plasma membrane of living mammalian cells using fluorescence-tagged PMBs.…”

Section: Introductionmentioning

confidence: 99%

Cell-penetrating macromolecules: Direct penetration of amphipathic phospholipid polymers across plasma membrane of living cells

2010

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“…This is of great relevance since in preclinical studies the majority of therapies is administered i.p. Also, recent studies recommend intraperitoneal administration of paclitaxel in patients with advanced gastric cancer (Soma et al, 2009;Kinoshita et al, 2014).…”

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confidence: 99%

Systemic effects of angiogenesis inhibition alter pharmacokinetics and intratumoral delivery of nab-paclitaxel

et al. 2017

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Angiogenesis is critical to the growth of tumors. Vascularization-targeting agents, with or without cytotoxic drugs, are widely used for the treatment of several solid tumors including esophagogastric adenocarcinoma. However, little is known about the systemic effects of anti-angiogenic therapies and how this affects the pharmacokinetics and intratumoral delivery of cytotoxic agents. In this study, patient-derived xenograft mouse models of esophageal adenocarcinoma were used to identify the effects of DC101, a murine vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, on the pharmacokinetics and the intratumoral uptake of nab-paclitaxel (NPTX). We showed that DC101 had large systemic effects resulting in decreased vasculature of intraperitoneally located organs. As a consequence, after intraperitoneal administration of NPTX, plasma uptake (5.029 ± 4.35 vs. 25.85 ± 2.27 mM) and intratumoral delivery (5.48 ± 5.32 vs. 38.49 ± 2.805 pmol/mg) of NPTX were greatly impaired in DC101-treated animals compared to control animals. Additionally, routes of NPTX elimination were altered upon angiogenesis inhibition; unchanged renal clearance and intraperitoneal accumulation of NPTX were observed, but NPTX levels were significantly lower in the liver. Histological examination of the intestine revealed a reduced thickness of the intestinal wall following DC101 therapy and suggested seepage of intraperitoneally injected NTPX through the intestinal wall to explain its reduced uptake in liver, plasma, and tumor tissue. These data explain several adverse effects observed in the clinic when using anti-angiogenic therapies and also imply that the combined use of anti-angiogenesis and cytotoxic agents in both preclinical and clinical setting is still suboptimal. ARTICLE HISTORY

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Intraperitoneal administration of paclitaxel solubilized with poly(2‐methacryloxyethyl phosphorylcholine‐co n‐butyl methacrylate) for peritoneal dissemination of gastric cancer

Abstract: Intraperitoneal (i.p.) administration of paclitaxel (PTX) is a hopeful

Cited by 55 publications

References 41 publications

Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

Antitumor effect and pharmacokinetics of intraperitoneal NK105, a nanomicellar paclitaxel formulation for peritoneal dissemination

Cell-penetrating macromolecules: Direct penetration of amphipathic phospholipid polymers across plasma membrane of living cells

Systemic effects of angiogenesis inhibition alter pharmacokinetics and intratumoral delivery of nab-paclitaxel

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