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Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings

Authors Li D, Yang K, Li JS, Ke XY, Duan Y, Du R, Song P, Yu KF, Ren W, Huang D, Li XH, Hu X, Zhang X, Zhang Q

Received 8 October 2012

Accepted for publication 6 November 2012

Published 17 December 2012 Volume 2012:7 Pages 6105—6114

DOI https://doi.org/10.2147/IJN.S38927

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Dan Li,1 Ke Yang,1 Jie-Si Li,1 Xi-Yu Ke,1 Yu Duan,1 Ruo Du,1 Ping Song,1 Ke-Fu Yu,1 Wei Ren,1 Dan Huang,1 Xing-Huo Li,1 Xin Hu,1 Xuan Zhang,1 Qiang Zhang1,2

1
Department of Pharmaceutics, 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China

Background: 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.
Methods: 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.
Results: 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 IC50 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 LD50 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.
Conclusion: CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.

Keywords: CLA-PTX, microemulsion, pharmacokinetics, brain tumor, antitumor efficacy, safety

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