A novel lipid-based nanomicelle of docetaxel: evaluation of antitumor activity and biodistribution

Abstract

Mingshu Ma,1 Yanli Hao,1 Nan Liu,1 Zhe Yin,1 Lan Wang,1 Xingjie Liang,2 Xiaoning Zhang11Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China; 2National Center for Nanoscience and Technology, Beijing, ChinaPurpose: A lipid-based, nanomicelle-loaded docetaxel (M-DOC) was designed and characterized. Optical imaging was employed to evaluate the pharmacokinetics and antitumor efficacy of docetaxel in vivo.Materials and methods: The M-DOC was prepared using the emulsion-diffusion method. Transmission electron microscopy and dynamic light scattering were used to assess the morphology and particle size of the M-DOC. Critical micelle concentrations, their stability under physiological conditions, and their encapsulation efficiency – as measured by high-performance liquid chromatography – were assessed. Pharmacological features were evaluated in two different animal models by comparing M-DOC treatments with docetaxel injections (I-DOC). Bioluminescence imaging was used to assess antitumor activity and docetaxel distribution in vivo, using nude mice injected with luciferase-expressing MDA-MB-231 human breast tumor cells. In addition, animals injected with B16 melanoma cells were used to measure survival time and docetaxel distribution.Results: The M-DOC was prepared as round, uniform spheres with an effective diameter of 20.8 nm. The critical micelle concentration of the original emulsion was 0.06%. Satisfactory encapsulation efficiency (87.6% ± 3.0%) and 12-hour stability were achieved. Xenograft results demonstrated that the M-DOC was more effective in inhibiting tumor growth, without significantly changing body weight. Survival was prolonged by 12.6% in the M-DOC group. Tumor growth inhibitory rates in the M-DOC and I-DOC groups were 91.2% and 57.8% in volume and 71.8% and 44.9% in weight, respectively. Optical bioluminescence imaging of tumor growths yielded similar results. Area under the curve(0–6 hour) levels of docetaxel in blood and tumors were significantly higher in the M-DOC group (15.9 ± 3.2 µg/mL-1, 601.1 ± 194.5 µg/g-1) than in the I-DOC group (7.2 ± 1.7 µg/mL-1, 357.8 ± 86.2 µg/g-1). The fluorescent dye 1,1-dioctadecyl-3,3,3,3’-tetramethylindotricarbocyanine iodide mimicked M-DOC in optical imaging, and accumulated more in tumors in comparison with I-DOC.Conclusion: These results suggest that the lipid-based nanomicelle system was effective in inhibiting tumor growth, with little toxicity. Moreover, we have developed a noninvasive optical imaging method for antitumor drug evaluation, which merits further analysis for potential clinical applications.Keywords: docetaxel, lipid-based micelles, antitumor activity, in vivo optical imaging