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The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells. However, the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions. Supplementing with an additional reductant is a promising strategy to further boost drug release. Herein, inspired by the specific absorption mechanism of triglyceride fat, structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin (SN38) were designed to improve intestinal permeability and bypass the first-pass effect. SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract. Surprisingly, we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38, indicating an effective oral delivery. In addition, the reduction-responsive disulfide bond was used as a linker, and ascorbic acid (ASC) was coadministrated to further promote the efficient release of SN38 from the prodrug. ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety. In summary, the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.

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Publication history
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Acknowledgements

Publication history

Received: 21 February 2022
Revised: 10 May 2022
Accepted: 16 May 2022
Published: 15 July 2022
Issue date: October 2022

Copyright

© Tsinghua University Press 2022

Acknowledgements

Acknowledgements

This work was financially supported by the National Key Research and Development Program of China (No. 2021YFA0909900) and the National Natural Science Foundation of China (Nos. 82073777, 82104109, and 82173766).

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