Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer
Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer
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DOI：
10.1016/j.apmt.2019.100492
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发表时间：
2020-03-01
影响因子：
8.3
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Chang, Ya;Jiang, Jizong;Li, Feng
双硫仑（DSF）目前在几项临床试验中与铜（Cu）离子联合用于癌症治疗。通常，DSF和Cu以两种单独的制剂施用。在体内，DSF与Cu离子形成二乙基二硫代氨基甲酸铜配合物[Cu（DDC）（2）]，具有很强的抗肿瘤活性。然而，“两种制剂”方法通常在肿瘤区域实现低Cu（DDC）（2）浓度，并导致抗癌功效受损。因此，在单一制剂中施用的预制Cu（DDC）（2）络合物将具有更好的抗癌功效。然而，Cu（DDC）（2）的水溶性差对其临床应用是一个重大挑战。在这项工作中，Cu（DDC）（2）的仿生纳米颗粒制剂是用我们实验室开发的新型SMILE（稳定金属离子配体络合物）方法生产的，以解决药物递送挑战。金属有机纳米粒子（MON）是以Cu（DDC）（2）金属有机配合物为核心，表面修饰牛血清白蛋白（BSA）而成。重要的是，我们设计了一种3D打印的微流体装置，以进一步改善BSA/Cu（DDC）（2）MONs的制造。该方法可以精确控制MON的制备过程，并具有大规模生产Cu（DDC）（2）MON配方的巨大潜力。我们还使用了计算建模方法来模拟微流控器件中的MON形成过程。优化后的BSA/Cu（DDC）（2）MONs具有良好的理化性质。MONs还在乳腺癌细胞单层以及3D培养的肿瘤球体中显示出有效的抗肿瘤活性。BSA/Cu（DDC）（2）MONs还有效地抑制原位4 T1乳腺肿瘤模型中的肿瘤生长。本研究提供了一种新的方法来制备用于DSF/Cu癌症治疗的仿生MON制剂。(C)2019爱思唯尔有限公司版权所有。
Disulfiram (DSF) is currently tested in several clinical trials for cancer treatment in combination with copper (Cu) ions. Usually, DSF and Cu are administered in two separate formulations. In the body, DSF and Cu ions form diethyldithiocarbamate copper complex [Cu(DDC)(2)] which has potent antitumor activities. However, the "two formulation" approach often achieved low Cu(DDC)(2) concentration at tumor regions and resulted in compromised anticancer efficacy. Therefore, preformed Cu(DDC)(2) complex administered in a single formulation will have better anticancer efficacy. However, the poor aqueous solubility of Cu(DDC)(2) is a significant challenge for its clinical use. In this work, a biomimetic nanoparticle formulation of Cu(DDC)(2) was produced with a novel SMILE (Stabilized Metal Ion Ligand complex) method developed in our laboratory to address the drug delivery challenges. The Metal-organic Nanoparticle (MON) is composed of Cu(DDC)(2) metal-organic complex core and surface decorated bovine serum albumin (BSA). Importantly, we designed a 3D-printed microfluidic device to further improve the fabrication of BSA/Cu(DDC)(2) MONs. This method could precisely control the MON preparation process and also has great potential for large scale production of Cu(DDC)(2) MON formulations. We also used a computational modeling approach to simulate the MON formation process in the microfluidic device. The optimized BSA/Cu(DDC)(2) MONs demonstrated good physicochemical properties. The MONs also showed potent antitumor activities in the breast cancer cell monolayers as well as the 3D-cultured tumor spheroids. The BSA/Cu(DDC)(2) MONs also effectively inhibited the growth of tumors in an orthotopic 4T1 breast tumor model. This current study provided a novel method to prepare a biomimetic MON formulation for DSF/Cu cancer therapy. (C) 2019 Elsevier Ltd. All rights reserved.