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PEGylated lipid microspheres loaded with cabazitaxel for intravenous administration: stability, bioavailability, antitumor efficacy, and toxicity

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Abstract

This paper aimed to develop a novel lipid microsphere delivering cabazitaxel (CTX) using phosphatidylcholine combined with DSPE-PEG2000 as emulsifier, and evaluate its stability, pharmacokinetics, antitumor efficacy, and toxicity. The pegylated cabazitaxel-loaded lipid microspheres (CTX-PLMs) were prepared by high-pressure homogenization methods; the biological samples were analyzed by the UPLC-MS/MS method. CTX-PLMs had a drug concentration of 1.2 mg/ml and a mean particle size of 180.0 ± 51.119 nm. CTX-PLMs showed a superior physical stability as it could remain nearly intact after 1-year storage. The AUC0-t of the CTX-PLMs was 1562.6 ± 520.1 μg h L−1 compared with the CTX-solution of 860.734 ± 312.4 μg h L−1. CTX-PLMs exhibited a strong antitumor efficacy against NCI-N87 and DU145 tumor models with tumor growth inhibition rates of 93.5 and 88.5%, respectively. The LD50 of CTX-PLMs in rats was 20.89 mg/kg. As for the long-term toxicity, the thymus, mesenteric lymph nodes, and bone marrow were the main toxic target organs and systemic toxicity induced by CTX-PLMs was alleviated relative to that of the CTX-solution. Safety assessment studies including hemolysis test, dermal sensitization test, systemic anaphylaxis, and vascular stimulation test indicated that CTX-PLMs is safe enough for intravenous administration. In a word, CTX-PLMs are a promising carrier for intravenous administration with satisfactory stability, stronger tumor inhibition, and superior safety profile.

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Acknowledgments

We thank Suzhou Xishan Zhongke Drugs Research and Development Co., Ltd. for the assistance in the antitumor activity and safety test, which includes providing instruments, equipment, or related experimental materials and animals. All the experiments reported comply with Institutional Animal Care and Use Committee.

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Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China

    Yang Liu, Bin Xie, Lin Li, Xinyu Zhang, Yu Zhang, Haibing He, Xing Tang, Cuifang Cai & Jingxin Gou

  2. School of Functional food and Wine, Shenyang Pharmaceutical University, Wen Hua Road No, Shenyang, 103, China

    Tian Yin

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  1. Yang Liu
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  2. Bin Xie
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Correspondence to Jingxin Gou.

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Liu, Y., Xie, B., Li, L. et al. PEGylated lipid microspheres loaded with cabazitaxel for intravenous administration: stability, bioavailability, antitumor efficacy, and toxicity. Drug Deliv. and Transl. Res. 8, 1365–1379 (2018). https://doi.org/10.1007/s13346-018-0562-0

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