Introduction: TAXOL® (paclitaxel, PTX), one of the first microtubule stabilizing agents, is among the most widely used chemotherapy agents in various cancers, especially ovarian and breast cancer. However, because of its poor water-solubility, paclitaxel must be dissolved in ethanol and Cremophor® EL. Cremophor has been proved to be associated with a number of severe side effects, including hypersensitivity, neurotoxicity and dramatic allergic reactions. These side effects are a major limitation in the use of paclitaxel in the clinic. To avoid these side effects, there is a need to develop alternative formulations of paclitaxel with better aqueous solubility and reduced risk of associated serious adverse effects. In this study, paclitaxel was formulated in Lipid NanoCapsules (LNC), prepared via the phase inversion temperature method. The pharmacokinetics/pharmacodynamic (PK/PD) parameters of PTX-LNC were evaluated in a BALB/C nude mice model bearing human ovarian tumor implanted subcutaneously. Methods: Both PK and antitumor activity (PD) of PTX-LNC were studied in BALB/C nude mice bearing human SK-OV-3 ovarian adenocarcinoma. In PD studies, PTX-LNC and TAXOL® were injected intravenously at 12 mg/kg/inj for 5 consecutive days (Q1Dx5) to 12 mice/group. Body weights, tumor volumes, signs of toxicity, and animal survival were recorded during the course of the study. In PK studies, mice received a single intravenous injection of PTX-LNC and TAXOL® at 20 mg/kg and were terminated 0.083, 0.25, 0.5, 1, 3, 8, 12, 24 and 48 hours after the injection (3 mice/timepoint). PTX concentration was then quantitated by HPLC/MS-MS in blood, tumor, liver, spleen and kidney. Results: Neither lethality nor adverse side effects of PTX-LNC were observed in tumor-bearing nude mice during the course of the study. A significant inhibition of tumor growth was observed for nude mice treated with PTX-LNC when compared to vehicle control group (T/C: 20%, P < 0.001). Although not significant under these experimental conditions, superior tumor growth inhibition was observed in mice treated with PTX-LNC, as compared to TAXOL® treated group (T/C: 30%). PTX pharmacokinetics for PTX-LNC have shown a shorter half-life of elimination than this of TAXOL®. Moreover, the area under the time-concentration curve (AUC) of PTX in tumor was higher for mice receiving PTX-LNC than in the case of mice receiving TAXOL® (+24%). Conclusions: These results have demonstrated that PTX-LNC, a new formulation of PTX, has increased the exposure of PTX in tumors resulting in an increased antitumor activity as compared to TAXOL®. These results suggest that PTX-LNC is a promising agent that should be evaluated in clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2895. doi:1538-7445.AM2012-2895
