Tetrasulfide bond boosts the anti-tumor efficacy of dimeric prodrug nanoassemblies.

Shiyi Zuo, Tian Liu, Lingxiao Li, Hezhen Xu, Jiayu Guo, Qing Wang, Yinxian Yang, Zhonggui He, Jin Sun, Bingjun Sun

Cell reports. Medicine 2024 Mar 19

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Dimeric prodrug nanoassemblies (DPNAs) stand out as promising strategies for improving the efficiency and safety of chemotherapeutic drugs. The success of trisulfide bonds (-SSS-) in DPNAs makes polysulfide bonds a worthwhile focus. Here, we explore the comprehensive role of tetrasulfide bonds (-SSSS-) in constructing superior DPNAs. Compared to trisulfide and disulfide bonds, tetrasulfide bonds endow DPNAs with superlative self-assembly stability, prolonged blood circulation, and high tumor accumulation. Notably, the ultra-high reduction responsivity of tetrasulfide bonds make DPNAs a highly selective "tumor bomb" that can be ignited by endogenous reducing agents in tumor cells. Furthermore, we present an "add fuel to the flames" strategy to intensify the reductive stress at tumor sites by replenishing exogenous reducing agents, making considerable progress in selective tumor inhibition. This work elucidates the crucial role of tetrasulfide bonds in establishing intelligent DPNAs, alongside the combination methodology, propelling DPNAs to new heights in potent cancer therapy. Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Shiyi Zuo, Tian Liu, Lingxiao Li, Hezhen Xu, Jiayu Guo, Qing Wang, Yinxian Yang, Zhonggui He, Jin Sun, Bingjun Sun. Tetrasulfide bond boosts the anti-tumor efficacy of dimeric prodrug nanoassemblies. Cell reports. Medicine. 2024 Mar 19;5(3):101432