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Enzymic synthesis and biological evaluation of injectable glutathione-everolimus

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Abstract

An enzymic synthesis of glutathione-everolimus is reported. This process has been optimized and scaled up with high reproducibility and yields, which will facilitate the development of such conjugate. The stability of the conjugate supported that this prodrug can be prepared into lyophilized solid, which is to be reconstituted with 0.9% sodium chloride for injection before intravenous infusion. And the results of species-related drug release experiment displayed that the performance of the conjugate in human plasma, rat and monkey was similar. Moreover, the in vivo efficacy of glutathione-everolimus in the treatment of renal cell carcinoma was investigated in detail. The conjugate was proved to be an effective, safe and well-tolerated injectable prodrug in the treatment of renal cell carcinoma. The results indicated that three times injection with a high dosage in 1 week can achieve much better in vivo efficacy, and no obvious toxic response was observed.

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Acknowledgements

This work was financially supported by the Key Science and Technology Innovation Team of Zhejiang Province (2013TD10).

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    Authors and Affiliations

    1. Zhejiang Hongyuan pharmaceutical Co., Ltd., Linhai, 317016, Zhejiang, China

      Haibo Wang

    2. Zhejiang Hisun pharmaceutical Co., Ltd., Taizhou, 318000, Zhejiang, China

      Haibo Wang, Xiaohe Zheng, Lifei Mao, Liang Qin & Tianmin Zhu

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    1. Haibo Wang
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    2. Xiaohe Zheng
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    3. Lifei Mao
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    Correspondence to Tianmin Zhu.

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    The authors declare that they have no competing interests.

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    Haibo Wang and Xiaohe Zheng contributed equally to this work and are co-first authors.

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    Wang, H., Zheng, X., Mao, L. et al. Enzymic synthesis and biological evaluation of injectable glutathione-everolimus. Med Chem Res 27, 583–591 (2018). https://doi.org/10.1007/s00044-017-2084-6

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    • DOI: https://doi.org/10.1007/s00044-017-2084-6

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