叶酸修饰的双硫仑/Zn-IRMOF3 纳米粒子通过抑制 ALDH1A1+癌症干细胞用于口腔癌治疗。

Folic acid-modified disulfiram/Zn-IRMOF3 nanoparticles for oral cancer therapy by inhibiting ALDH1A1+ cancer stem cells.

机构信息

School and Hospital of Stomatology, Department of Oral Pathology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang 110001, China.

Research Center for Analytical Sciences, Department of Chemistry, College of Sciences, Northeastern University, P.O. Box 332, Shenyang 110819, China; College of Chemistry and Chemical Engineering, Xingtai University, Xingtai, Hebei 054001, China.

出版信息

Biomater Adv. 2022 Aug;139:213038. doi: 10.1016/j.bioadv.2022.213038. Epub 2022 Jul 21.

DOI:10.1016/j.bioadv.2022.213038

PMID:35908474

Abstract

The repurposing of old drugs can reduce the cost of drug development and speed up the availability of drugs for clinical use. Disulfiram (DSF) is an approved drug for alcohol abuse. In recent years, it has been established that DSF exerts an antitumor effect via targeted inhibition of ALDH1+ cancer stem cells (CSCs). However, due to its metal ion dependence, easy hydrolysis and low availability, the clinical application of DSF is limited. Previous studies have also shown that Zn can inhibit CSCs. Accordingly, we developed a novel metal organic framework (IRMOF3)-Zn, and DSF was incorporated in the IRMOF3. Folic acid (FA) was subsequently loaded on the surface yielding IRMOF3 (IRMOF3-DSF-FA) for targeted therapy of tumors. The nanoscale IRMOF3-DSF-FA exhibited a high loading capacity, good biocompatibility and strong cell uptake capacity, which could provide metal ions, target tumor tissues and inhibit ALDH1+ CSCs. In vivo experiments showed that IRMOF3-DSF-FA could significantly inhibit the growth of CSCs and tumors, with no significant vital organ damage during treatment. Accordingly, IRMOF3-DSF-FA has great prospects for application as a DSF carrier, opening new horizons for targeted therapy of oral cancer.

摘要

老药新用可以降低药物开发成本并加快药物临床应用。双硫仑（DSF）是一种已批准用于治疗酒精滥用的药物。近年来，已经确定 DSF 通过靶向抑制 ALDH1+癌症干细胞（CSCs）发挥抗肿瘤作用。然而，由于其对金属离子的依赖性、易水解和低可用性，DSF 的临床应用受到限制。先前的研究还表明，锌可以抑制 CSCs。因此，我们开发了一种新型金属有机骨架（IRMOF3）-Zn，并将 DSF 掺入到 IRMOF3 中。随后在表面负载叶酸（FA），得到靶向肿瘤治疗的 IRMOF3（IRMOF3-DSF-FA）。纳米级的 IRMOF3-DSF-FA 具有高载药能力、良好的生物相容性和较强的细胞摄取能力，能够提供金属离子、靶向肿瘤组织并抑制 ALDH1+CSCs。体内实验表明，IRMOF3-DSF-FA 能显著抑制 CSCs 和肿瘤的生长，治疗过程中对重要器官没有明显损伤。因此，IRMOF3-DSF-FA 作为 DSF 载体具有广阔的应用前景，为口腔癌的靶向治疗开辟了新的前景。