Silk Fibroin-Modified Disulfiram/Zinc Oxide Nanocomposites for pH Triggered Release of Zn2+ and Synergistic Antitumor Efficacy
Silk Fibroin-Modified Disulfiram/Zinc Oxide Nanocomposites for pH Triggered Release of Zn2+ and Synergistic Antitumor Efficacy
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丝素蛋白改性双硫仑/氧化锌纳米复合材料用于 pH 触发 Zn2 释放和协同抗肿瘤功效
DOI：
10.1021/acs.molpharmaceut.0c00604
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发表时间：
2020-10-05
影响因子：
4.9
通讯作者：
Yao, Qing
中科院分区：
文献类型：
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作者：
Zhao, Ying-Zheng;Lin, Meng-Ting;Yao, Qing
双硫仑 (DSF) 是 FDA 批准的一种抗酒精药物，最近被证明对癌症治疗有效。然而，其血流半衰期短以及金属离子依赖性抗肿瘤活性极大地限制了DSF在临床领域的进一步应用。为此，我们构建了丝素蛋白修饰的双硫仑/氧化锌纳米复合材料（SF/DSF@ZnO）来溶解和稳定DSF，更重要的是，实现pH触发的Zn2+释放和随后的协同抗肿瘤活性。所制备的SF/DSF@ZnO纳米复合材料呈球形且具有高载药量。在溶酶体pH值的触发下，SF/DSF@ZnO可以在酸性条件下诱导Zn2+的快速释放，并随着DSF的释放而引起纳米颗粒的分解。体外实验表明，Zn2+的存在可以增强DSF的细胞毒性，并且当封装到SF/DSF@ZnO纳米复合材料中时，其细胞毒性进一步增强。经证实，SF/DSF@ZnO 的细胞毒性显着增强是由于 pH 触发的 Zn2+ 释放、抑制细胞迁移和增加 ROS 产生所致。体内研究表明，SF/DSF@ZnO纳米复合材料显着增加了肿瘤的积累并延长了保留时间。异种移植模型体内抗肿瘤实验表明，SF/DSF@ZnO在所有药物治疗中具有最高的抑瘤率。因此，这项精致的研究建立了丝素蛋白修饰的双硫仑/氧化锌纳米复合材料，SF/DSF@ZnO，其中ZnO不仅充当递送载体，还充当金属离子库，以实现协同抗肿瘤功效。所建立的 DSF 纳米制剂在未来的癌症治疗中显示出优异的治疗潜力。
Disulfiram (DSF) is an FDA-approved anti-alcoholic drug that has recently proven to be effective in cancer treatment. However, the short half-life in the bloodstream and the metal ion-dependent antitumor activity significantly limited the further application of DSF in the clinical field. To this end, we constructed a silk fibroin modified disulfiram/zinc oxide nanocomposites (SF/DSF@ZnO) to solubilize and stabilize DSF, and, more importantly, achieve pH triggered Zn2+ release and subsequent synergistic antitumor activity. The prepared SF/DSF@ZnO nanocomposites were spherical and had a high drug loading. Triggered by the lysosomal pH, SF/DSF@ZnO could induce the rapid release of Zn2+ under the acidic conditions and caused nanoparticulate disassembly along with DSF release. In vitro experiments showed that cytotoxicity of DSF could be enhanced by the presence of Zn2+, and further amplified when encapsulated into SF/DSF@ZnO nanocomposites. It was confirmed that the significantly amplified cytotoxicity of SF/DSF@ZnO was resulted from pH-triggered Zn2+ release, inhibited cell migration, and increased ROS production. In vivo study showed that SF/DSF@ZnO nanocomposites significantly increased the tumor accumulation and prolonged the retention time. In vivo antitumor experiments in the xenograft model showed that SF/DSF@ZnO exerted the highest tumor-inhibition rate among all the drug treatments. Therefore, this exquisite study established silk fibroin-modified disulfiram/zinc oxide nanocomposites, SF/DSF@ZnO, where ZnO not only acted as a delivery carrier but also served as a metal ion reservoir to achieve synergistic antitumor efficacy. The established DSF nanoformulation displayed excellent therapeutic potential in future cancer treatment.