Wang Yang, Jing Danni, Yang Jiawen, Zhu Shajun, Shi Jian, Qin Xiru, Yin Wujie, Wang Jin, Ding Yue, Chen Tingting, Lu Bing, Yao Yong
School of Chemistry and Chemical Engineering, Nantong University, Nantong, Jiangsu 226019, PR China..
School of Chemistry and Chemical Engineering, Nantong University, Nantong, Jiangsu 226019, PR China.
Acta Biomater. 2022 Dec;154:467-477. doi: 10.1016/j.actbio.2022.10.018. Epub 2022 Oct 13.
Carbon monoxide (CO) as one of the therapeutic gaseous molecules has been widely applied for treating various diseases, especially in cancer therapy. However, the in situ-triggered and efficient transport of CO to tumors are the primary obstacles that limit its clinical applicability. To address this obstacle, herein, a HO-triggered CO gas releasing nanoplatform has been designed by embedding manganese carbonyl (MnCO) into Zr (IV)-based metal-organic frameworks (MOFs). The porous structures of MOFs provide encapsulation capacity for glucose oxidase (GOx) loading, thereby catalyzing the endogenous glucose into gluconic acid and HO to accelerate CO release and energy depletion. In the meantime, the Mn produced by MnCO can react with intracellular HO via the Fenton reaction to form cytotoxic •OH. Therefore, the synthesized gas nanogenerator demonstrated a synergistic efficacy of CO gas therapy, reactive oxygen species (ROS)-mediated therapy, and energy starvation to prevent tumor growth. Both in vitro and in vivo studies indicated that this multifunctional nanoplatform not only successfully inhibited tumors through a synergistic effect, but also provided a new technique for the creation of starvation/gas/chemodynamic combination therapy in a single material. STATEMENT OF SIGNIFICANCE: In this study, we developed a HO responsive CO gas nanogenerator to augment the in-situ generation of CO gas for combined modality therapy of tumors. The nanogenerator was constructed by encapsulating glucose oxidase (GOx) and manganese carbonyl (MnCO) into UiO-67-bpy, which can catalyze the conversion of intracellular glucose to HO for cutting off energy supply of cancer cells. Meanwhile, the cumulated HO can trigger the release of CO for gas therapy and generation of •OH for chemodynamic therapy (CDT) via the Fenton-like reaction, thereby resulting in apoptosis of the cancer cells. Collectively, our designed nanotherapeutic agent not only displays the synergistic therapy efficacy of starvation-enhanced CO gas therapy and CDT, but also provides an efficient strategy for developing the intelligent nanocarrier for CO gas delivery and release.
一氧化碳（CO）作为一种治疗性气体分子，已被广泛应用于治疗各种疾病，尤其是在癌症治疗中。然而，CO原位触发并高效运输至肿瘤是限制其临床应用的主要障碍。为解决这一障碍，本文通过将羰基锰（MnCO）嵌入基于锆（IV）的金属有机框架（MOF）中，设计了一种由HO触发的CO气体释放纳米平台。MOF的多孔结构为负载葡萄糖氧化酶（GOx）提供了封装能力，从而催化内源性葡萄糖转化为葡萄糖酸和HO，以加速CO释放和能量消耗。同时，MnCO产生的Mn可通过芬顿反应与细胞内的HO反应形成具有细胞毒性的•OH。因此，合成的气体纳米发生器展现出CO气体疗法、活性氧（ROS）介导疗法和能量饥饿协同作用以抑制肿瘤生长的效果。体外和体内研究均表明，这种多功能纳米平台不仅通过协同效应成功抑制了肿瘤，还为在单一材料中创建饥饿/气体/化学动力学联合疗法提供了新技术。
在本研究中，我们开发了一种HO响应型CO气体纳米发生器，以增强CO气体的原位生成用于肿瘤联合治疗。该纳米发生器通过将葡萄糖氧化酶（GOx）和羰基锰（MnCO）封装到UiO-67-bpy中构建而成，其可催化细胞内葡萄糖转化为HO以切断癌细胞的能量供应。同时，累积的HO可触发CO释放用于气体疗法，并通过类芬顿反应生成•OH用于化学动力学疗法（CDT），从而导致癌细胞凋亡。总体而言，我们设计的纳米治疗剂不仅展现出饥饿增强型CO气体疗法和CDT的协同治疗效果，还为开发用于CO气体递送和释放的智能纳米载体提供了有效策略。
