Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Int J Nanomedicine. 2012;7:6105-14. doi: 10.2147/IJN.S38927. Epub 2012 Dec 17.
Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood-brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo.
The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumor-bearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice.
The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC(50) of the CLA-PTX microemulsion was 1.61 ± 0.83 μM for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P > 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol(®) had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD(50) of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg.
CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.
考虑到亚油酸与紫杉醇结合物（CLA-PTX）具有抗脑肿瘤活性、能够穿透血脑屏障但水溶性差的观察结果，本研究旨在制备新型 CLA-PTX 微乳液并评估其对脑肿瘤的体外和体内活性。
在 C6 神经胶质瘤细胞中研究 CLA-PTX 微乳液的体外细胞毒性。在荷瘤裸鼠和大鼠中评价 CLA-PTX 微乳液的体内抗肿瘤活性。在大鼠中研究 CLA-PTX 微乳液的药代动力学，并用小鼠评估其安全性。
CLA-PTX 微乳液的平均粒径约为 176.3±0.8nm，多分散指数为 0.294±0.024。体外细胞毒性结果表明，CLA-PTX 微乳液对 C6 神经胶质瘤细胞系的 IC50 为 1.61±0.83μM，与游离紫杉醇和 CLA-PTX 溶液相似（P＞0.05）。CLA-PTX 微乳液对脑肿瘤的抗肿瘤活性在体内 C6 神经胶质瘤荷瘤裸鼠以及大鼠模型中得到证实。相比之下，Taxol（®）在 C6 神经胶质瘤荷瘤大鼠中几乎没有明显的抗肿瘤作用，但能显著抑制 C6 神经胶质瘤荷瘤裸鼠中 C6 肿瘤的生长。药代动力学结果表明，CLA-PTX 溶液的循环时间更长，药物血浆浓度更高。急性毒性研究结果表明，CLA-PTX 溶液的 LD50 为 103.9mg/kg。相比之下，CLA-PTX 微乳液在高达 200mg/kg 的剂量下在小鼠中具有良好的耐受性。
CLA-PTX 微乳液是一种新型制剂，对脑肿瘤具有显著的抗肿瘤疗效，且比 CLA-PTX 溶液更安全。
