Institute of Bismuth Science and College of Science, University of Shanghai for Science and Technology, Shanghai 200093, China.
Department of Research and Development & Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Shanghai Cancer Center, Shanghai 201321, China; Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China.
Acta Biomater. 2021 Jul 15;129:280-292. doi: 10.1016/j.actbio.2021.05.016. Epub 2021 May 24.
Various physiological characteristics of the tumor microenvironment (TME), such as hypoxia, overexpression of glutathione (GSH) and hydrogen peroxide (HO), and mild acidity, can severely reduce the efficacy of many cancer therapies. Altering the redox balance of the TME and increasing oxidative stress can accordingly enhance the efficacy of tumor therapy. Herein, we developed a bismuth-based Cu-doped BiOCl nanotherapeutic platform, BCHN, able to self-supply HO for TME-regulated chemodynamic therapy (CDT) combined with sensitized radiotherapy (RT). BCHN released HO and consumed GSH to degrade the composite in the slightly acidic TME, and generated hydroxyl radicals (•OH) via a Fenton-like reaction catalyzed by copper ions, to achieve oxidative stress-enhanced CDT. The Fenton-like reaction also catalyzed HO to produce O to relieve tumor hypoxia, and combined with the X-ray-blocking property of bismuth to realize TME-enhanced radiotherapy. Synergistic CDT/RT has previously been shown to effectively inhibit tumor cell proliferation and achieve effective tumor control. The current results demonstrated a highly efficient multifunctional bio-degradable nanoplatform for oncotherapy. STATEMENT OF SIGNIFICANCE: Tumor microenvironment-modulated synergy of radiotherapy and chemodynamic therapy is conducive to rapid tumor ablation. Based on this principle, we fabricated a biodegradable BiOCl-based nanocomposite, BCHN. By supplying HO, a Fenton-like reaction generated •OH and O catalyzed by copper ions, and consumed glutathione to biodegrade the composite. Overall, these actions increased tumor oxidative stress and realized the synergistic anti-tumor actions of chemodynamic therapy combined with bismuth-based sensitization radiotherapy. This strategy thus provides a unique approach to oncology therapy.
肿瘤微环境（TME）的各种生理特征，如缺氧、谷胱甘肽（GSH）和过氧化氢（HO）过表达以及微酸性等，会严重降低许多癌症疗法的疗效。改变 TME 的氧化还原平衡并增加氧化应激，相应地可以提高肿瘤治疗的效果。在此，我们开发了一种基于铋的铜掺杂 BiOCl 纳米治疗平台 BCHN，能够为 TME 调控的化学动力学治疗（CDT）联合敏化放射治疗（RT）自供 HO。BCHN 在微酸性 TME 中会释放 HO 并消耗 GSH 以降解复合材料，并通过铜离子催化的类 Fenton 反应生成羟基自由基（•OH），从而实现氧化应激增强的 CDT。类 Fenton 反应还会催化 HO 产生 O 以缓解肿瘤缺氧，并结合铋的 X 射线阻断特性实现 TME 增强的放射治疗。先前的研究表明，协同 CDT/RT 可有效抑制肿瘤细胞增殖并实现有效的肿瘤控制。本研究结果展示了一种高效的多功能可生物降解纳米平台，可用于肿瘤治疗。
放射治疗和化学动力学治疗的肿瘤微环境调节协同作用有利于肿瘤快速消融。基于这一原理，我们制备了一种可生物降解的基于 BiOCl 的纳米复合材料 BCHN。通过供应 HO，铜离子催化的类 Fenton 反应产生了•OH 和 O，并消耗了 GSH 以降解复合材料。总体而言，这些作用增加了肿瘤的氧化应激，并实现了化学动力学治疗与基于铋的敏化放射治疗的协同抗肿瘤作用。该策略为肿瘤治疗提供了一种独特的方法。
