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 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...

Paclitaxel-Loaded Polymersomes for Enhanced Intraperitoneal Chemotherapy

“…In our case, tumor burden of the mice treated with PTX-polymersomes was 8 times lower than in PTX-Cre group and 7 times lower compared with ABX. Remarkably, the total dose of PTX we used in our treatment was only 7 mg/kg - the lowest reported PTX dose used in experimental tumor treatment with free PTX or ABX (7,8,10,44–46). The rationale for using the PTX dose below the MTD, with which the PTX-polymersomes are still effective, was to demonstrate that it is possible to reduce the PTX side effects while preserving therapeutic antitumor activity.…”

“…When PTX-polymersomes were used for experimental therapy of mice bearing IP MKN-45P gastric tumors, they showed potent anti-tumor activity, superior to ABX or PTX-Cre. It has been reported that in the treatment of MKN-45P mice with IP administered NK105 - a PTX-incorporating micellar nanoparticle formulation (8) - or a copolymer conjugated with PTX (10), the weight of peritoneal tumor nodules was ~ 5 times lower than in mice treated with PTX-Cre. In another study of IP treatment of ovarian tumors, dendrimer-based nanoparticles loaded with PTX reduced the growth of tumors about 5-fold more than ABX (7).…”

Comparative study of the antitumor activity of Nab-paclitaxel and intraperitoneal solvent-based paclitaxel regarding peritoneal metastasis in gastric cancer

“…In addition, the enhanced permeability and retention (EPR) effect, which is known as selective accumulation of nanoparticle drugs by passive targeting is thought to be another reason (37). Through the EPR effect, nanoparticle drugs are retained for a long period in the systemic circulation, are easily extravasated from tumor vessels into the interstitium of tumor tissue, and accumulate there for longer periods than conventional small-molecule agents (38)(39)(40). On the basis of these findings, i.v.…”

Targeted Nanoparticles for Colorectal Cancer

“…For instance, NK105 (PEG-P[Asp]-paclitaxel) showed an area under the curve significantly higher than paclitaxel alone between 0 and 48 h after iv. administration (191,000 ± 32,100 vs 1500 ± 108 ng·h/ml, respectively) [81]. Other formulations in clinical trials such as NK911 (PEG-P[Asp]-doxorubicin) have shown high accumulation in solid tumors in mice [16], and SP1049C (Pluronic L61, F127-doxorubicin) exhibited notable single-agent activity in patients with adenocarcinoma of the esophagus and gastroesophageal junction with high efficacy and fewer side effects compared with drug alone [82].…”