Journal
MOLECULAR PHARMACEUTICS
Volume 17, Issue 10, Pages 3857-3869Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.0c00604
Keywords
Disulfiram; zinc oxide nanoparticles; synergistic effect; pH-sensitive; drug delivery
Funding
- National Natural Science Foundation of China [81903551, 81772316, 81803443]
- Key Research and Development Program of Zhejiang Province [2018C03013]
- Zhejiang Province Natural Science Foundation [LQ19H300001, LY19H180001, LY17H180008]
- Zhejiang provincial program for the cultivation of high-level innovative health talents
- 151 talent project of Zhejiang province
- 551 talent projects of Wenzhou
- Wenzhou Municipal Science and Technology Bureau [Y20190177, Y20180180, Y20180208]
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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.
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