Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer

Abstract

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.

Selective Targeting of Cancer Cells by Copper Ionophores: An Overview

“…Since DSF is rapidly degraded in biological fluids and its activity is increased by Cu, DDSs able to selectively transport DSF at the tumor cells with the concomitant release of Cu could be more advantageous. To validate this hypothesis, different nanoparticle systems have been developed (Chen et al, 2018;Wu et al, 2019;Chang et al, 2020). Li group has proposed metalorganic nanoparticles (MONs) prepared through a method that has been defined as "Stabilized Metal Ion Ligand Nanocomplex (SMILE) technology" (Wehbe et al, 2018).…”

“…Li group has proposed metalorganic nanoparticles (MONs) prepared through a method that has been defined as "Stabilized Metal Ion Ligand Nanocomplex (SMILE) technology" (Wehbe et al, 2018). This method provided interesting results, for example, with biomimetic albumindecorated Cu-DTC MONs (Chang et al, 2020). These particles were prepared by mixing Cu and DTC in the presence of albumin (BSA) using a microfluidic device.…”

Chips for Biomaterials and Biomaterials for Chips: Recent Advances at the Interface between Microfabrication and Biomaterials Research

“…[ 103,104 ] In addition, microfluidic methods have been used to produce MOF‐laden membranes with micropores templated using monodisperse microfluidically generated droplets (Figure 1d), [ 105 ] and MOF‐containing hydrogel microfibers which exploit the ability of microfluidic spinning to produce fibers with tunable size and composition. [ 106 ] The category of organic–inorganic hybrid biomaterials produced on chip also includes corresponding composite core–shell microparticles, [ 107 ] metal‐organic hybrid nanoparticles for biomedical applications such as wound healing and cancer therapy, [ 108 ] polymer films containing calcium phosphate nanoparticles produced on chip for bone regeneration, [ 109 ] and bioinks for microfluidic 3D bioprinting containing calcium‐phosphate microparticles for cartilage regeneration. [ 110 ] All of these materials take advantage of the superior control of particle size and morphology and material composition in microfluidic synthesis compared to bulk methods.…”

Nanocarrier based precise approaches for anticancer agents in treatment of breast cancer.

“…The formulation had excellent drug loading efficiency, optimum particle size and strong antitumor potential. [40].…”