Supramolecular Radiosensitizer Based on Hypoxia-Responsive Macrocycle.

Abstract

Radiotherapy (RT) has been viewed as one of the most effective and extensively applied curatives in clinical cancer therapy. However, the radioresistance of tumor severely discounts the radiotherapy outcomes. Here, an innovative supramolecular radiotherapy strategy, based on the complexation of a hypoxia-responsive macrocycle with small-molecule radiosensitizer, is reported. To exemplify this tactic, a carboxylated azocalix[4]arene (CAC4A) is devised as molecular container to quantitatively package tumor sensitizer banoxantrone dihydrochloride (AQ4N) through reversible host-guest interaction. Benefited from the selective reduction of azo functional groups under hypoxic microenvironment, the supramolecular prodrug CAC4A•AQ4N exhibits high tumor accumulation and efficient cellular internalization, thereby significantly amplifying radiation-mediated tumor destruction without appreciable systemic toxicity. More importantly, this supramolecular radiotherapy strategy achieves an ultrahigh sensitizer enhancement ratio (SER) value of 2.349, which is the supreme among currently reported noncovalent-based radiosensitization approach. Further development by applying different radiosensitizing drugs can make this supramolecular strategy become a general platform for boosting therapeutic effect in cancer radiotherapies, tremendously promising for clinical translation.

• Authors: Xiaoxue Hou, Yu-Xuan Chang, Yu-Xin Yue, Ze-Han Wang, Fei Ding, Zhi-Hao Li, Hua-Bin Li, Yicheng Xu, Xianglei Kong, Fan Huang, Dong-Sheng Guo, Jianfeng Liu
• Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh)) Vol. 9 Issue 6 Pg. e2104349 (02 2022) ISSN: 2198-3844 [Electronic] Germany
• PMID: 34994113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.

Chemical References

• Macrocyclic Compounds
• Radiation-Sensitizing Agents

Topics

• Cell Line, Tumor
• Humans
• Hypoxia
• Macrocyclic Compounds (therapeutic use)
• Neoplasms (radiotherapy)
• Radiation-Sensitizing Agents (therapeutic use)