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<p>Irinotecan, one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer, suffers from extremely low activatability and non-selective tumor activation. 7-Ethyl-10-hydroxy-camptothecin (SN38), the active metabolite of irinotecan, has been limited in clinical development due to poor water solubility and stability. Here, the thioether bond and disulfide bond were employed as response modules to construct tumor-selective SN38 prodrug nanoassemblies (SN38-S-C<sub>21</sub> NPs and SN38-SS-C<sub>21</sub> NPs). 11-Henicosanol was chosen as a self-assembly module to enhance stability. Both SN38-S-C<sub>21</sub> NPs and SN38-SS-C<sub>21</sub> NPs presented ultra-high <i>in vivo</i> stability with a 12146-fold and 23151-fold elevation in the area under the curve (AUC) compared to SN38. Moreover, SN38-S-C<sub>21</sub> NPs and SN38-SS-C<sub>21</sub> NPs showed a significant reduction of SN38 exposure in blood compared to irinotecan. Importantly, the prodrug nanoassemblies enabled selective activation within tumor cells, and the conversion rates of SN38-SS-C<sub>21</sub> NPs and SN38-S-C<sub>21</sub> NPs to SN38 were 10- and 7-fold higher than irinotecan. Compared with SN38-S-C<sub>21</sub> NPs, the superior <i>in vivo</i> stability, SN38 conversion efficiency and tumor selectivity of SN38-SS-C<sub>21</sub> NPs resulted in potent antitumor effects and safety. Our findings proved that the disulfide bond was more suitable for constructing high-performance SN38 prodrug nanoassemblies, which showed significant promise for the rational design of SN38 nanomedicines.</p>

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Dual advantages of SN38 prodrug nanoassemblies overcome defects of irinotecan and SN38: enhanced stability and activatability

  • 期刊论文

  • 发表日期：

    2025年7月7日

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  • Jialin Xing,
  • Cuiyun Liu,
  • Weiyan Zhang,
  • Rong Chai,
  • Yaqi Li,
  • Zuo Zhang,
  • Zhenzhen Zhao,
  • Jin Sun,
  • Zhonggui He,
  • Xueyang Jiang,
  • Yixin Sun,
  • Bingjun Sun

摘要

Irinotecan, one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer, suffers from extremely low activatability and non-selective tumor activation. 7-Ethyl-10-hydroxy-camptothecin (SN38), the active metabolite of irinotecan, has been limited in clinical development due to poor water solubility and stability. Here, the thioether bond and disulfide bond were employed as response modules to construct tumor-selective SN38 prodrug nanoassemblies (SN38-S-C21 NPs and SN38-SS-C21 NPs). 11-Henicosanol was chosen as a self-assembly module to enhance stability. Both SN38-S-C21 NPs and SN38-SS-C21 NPs presented ultra-high in vivo stability with a 12146-fold and 23151-fold elevation in the area under the curve (AUC) compared to SN38. Moreover, SN38-S-C21 NPs and SN38-SS-C21 NPs showed a significant reduction of SN38 exposure in blood compared to irinotecan. Importantly, the prodrug nanoassemblies enabled selective activation within tumor cells, and the conversion rates of SN38-SS-C21 NPs and SN38-S-C21 NPs to SN38 were 10- and 7-fold higher than irinotecan. Compared with SN38-S-C21 NPs, the superior in vivo stability, SN38 conversion efficiency and tumor selectivity of SN38-SS-C21 NPs resulted in potent antitumor effects and safety. Our findings proved that the disulfide bond was more suitable for constructing high-performance SN38 prodrug nanoassemblies, which showed significant promise for the rational design of SN38 nanomedicines.