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Vascular disrupting agent-induced amplification of tumor targeting and prodrug activation boosts anti-tumor efficacy

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Abstract

Vadimezan, one of the typical vascular disrupting agents (VDAs) currently in clinical trials, has been extensively implemented for cancer research, whereas its clinical efficacy is adversely affected by the inevitable side effects. Inspired by Vadimezan-induced intratumoral coagulation activation and hypoxia aggravation, we report a strategy by utilizing these biological effects to achieve targeted delivery and activation of hypoxia-activated prodrug (HAP) thus to maximize the therapeutic effect of Vadimezan. By encapsulating HAP tirapazamine into poly (lactic-co-glycolic acid) (PLGA) nanocarriers along with the modification of clot-binding peptide, the obtained nanoplatform could target tumors under the coagulation activation effect of Vadimezan Meanwhile, the aggravated hypoxia tumor microenvironment induced by Vadimezan can also boost hypoxia-activated chemotherapy. In the murine tumor model, this strategy showed 80.0% suppression of tumor growth, indicating its great potential in tumor treatment. This study offers an ingenious tactic for the combination of vascular disrupting therapy and hypoxia-activated chemotherapy, which may open up a window of the VDAs-based combination therapy.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (51988102, 51833007, 22135005, 52173136 and 21721005).

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Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Biomedical Polymers of Ministry of Education; Department of Chemistry, Wuhan University, Wuhan, 430072, China

    Sheng Hong, Qian-Xiao Huang, Ping Ji, Yunxia Sun, Si-Xue Cheng & Xian-Zheng Zhang

  2. Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

    Xuan Pang & Xuesi Chen

Authors
  1. Sheng Hong
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  2. Qian-Xiao Huang
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  5. Yunxia Sun
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  6. Si-Xue Cheng
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  7. Xian-Zheng Zhang
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Correspondence to Xian-Zheng Zhang or Xuesi Chen.

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Supporting information The supporting information is available online at http://chem.scichina.com and http://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Hong, S., Huang, QX., Ji, P. et al. Vascular disrupting agent-induced amplification of tumor targeting and prodrug activation boosts anti-tumor efficacy. Sci. China Chem. 65, 1994–2004 (2022). https://doi.org/10.1007/s11426-022-1347-9

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  • DOI: https://doi.org/10.1007/s11426-022-1347-9

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