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Dual stimuli-responsive polymeric prodrug consisting of reversible covalent bonded celastrol for tumor targeted delivery

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Abstract

In this work, pH/GSH-responsive amphiphilic polymeric prodrug (EDA-GLA/CE/2-FPBA) was successfully prepared and could self-assembled into micelles in an aqueous solution. The EDA-GLA/CE/2-FPBA micelles possessed high stability in physiological condition and were pH and GSH sensitive due to the reversible borate ester bonds and disulfide bonds within the prodrug polymer. The structures of the prodrug polymers were characterized by NMR, FTIR, UV–vis spectroscopy. Transmission electron microscopy and dynamic light scattering measurement indicated that the resulting micelles have desirable size distribution and regular spherical shape. Free active Celastrol can be released under low pH and high GSH environment; In vitro cellular uptake and growth inhibition assays suggested that the blank polymer micelles showed good biocompatibility. EDA-GLA/CE/2-FPBA micelles were more efficiently internalized by monolayer tumor cells and demonstrated superior tumor targeting effects as compared to free Celastrol control. These results demonstrated that the novel prodrug self-assembled dual-responsive nano-delivery platform was able to improve the bioavailability and tumor targeting activity of Celastrol, which provides a basis for further clinical applications of Celastrol and its derivatives.

Graphical Abstract

Amphiphilic polymeric prodrug (EDA-GLA/CE/2-FPBA) containing gelatin, lipoic acid, ethylenediamine (EDA), 2-formylphenylboric acid (2-FPBA) was developed, which can self-assembled into micelles in an aqueous solution. Borate ester bond and sulfhydryl groups in the micelles endow the micelles with the ability to respond to high concentration of GSH.

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Acknowledgements

This research was funded by the Collaborative Grant-in-Aid of the HBUT National “111” Center for Cellular Regulation and Molecular Pharmaceutics (XBTK-2021009) and Research Funds from Hubei University of Technology(GCRC20200013).

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Authors and Affiliations

  1. School of Biological Engineering and Food Science, Hubei University of Technology, No.28, Nanli Road, Wuhan, 430068, China

    Jiangtao Su, Meng Rao, Heshuang Dai, Le Cai, Fan Ye, Lu Ye, Yuchen Hu, Ban Chen & Xiaoxia Guo

  2. National ‘111’ Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, 430068, China

    Jiangtao Su, Heshuang Dai & Xiaoxia Guo

  3. Key Laboratory of Industrial Microbiology in Hubei, Hubei University of Technology, Wuhan, 430068, China

    Jiangtao Su, Yuchen Hu & Xiaoxia Guo

  4. Hubei Province Cooperative Innovation Center for Industrial Fermentation, Hubei University of Technology, Wuhan, 430068, China

    Jiangtao Su & Ban Chen

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  1. Jiangtao Su
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  2. Meng Rao
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Su, J., Rao, M., Dai, H. et al. Dual stimuli-responsive polymeric prodrug consisting of reversible covalent bonded celastrol for tumor targeted delivery. Macromol. Res. 32, 173–186 (2024). https://doi.org/10.1007/s13233-023-00218-6

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