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Frontiers of Materials Science

ISSN 2095-025X

ISSN 2095-0268(Online)

CN 11-5985/TB

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Front. Mater. Sci.    2021, Vol. 15 Issue (4) : 553-566    https://doi.org/10.1007/s11706-021-0576-2
RESEARCH ARTICLE
A nanosystem of copper(II)-disulfiram for cancer treatment with high efficacy and few side effects
Liping ZHAO1, Xiaoxia WANG1, Mingxia JIANG1, Xinghan WU2, Mogen ZHANG3, Xiuwen GUAN1,4,5, Jinlong MA1,4,5(), Weifen ZHANG1,4,5()
1. College of Pharmacy, Weifang Medical University, Weifang 261053, China
2. Department of Pathology, Weifang Medical University, Weifang 261053, China
3. School of Clinical Medicine, Weifang Medical University, Weifang 261053, China
4. Collaborative Innovation Center for Target Drug Delivery System, Weifang Medical University, Weifang 261053, China
5. Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang Medical University, Weifang 261053, China
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Abstract

Developing chemotherapy drugs with high efficacy and few side effects has been a bottleneck problem that requires an efficient solution. The active cancer treatment ingredient disulfiram (DSF), inspired by the copper(II) diethyldithiocarbamate complex (CuET), can be used in a one-pot synthesis method to construct a CuET delivery nanosystem (CuET-ZIFCu@HA). Due to the high biocompatibility, targeting of CD44 overexpressed cancer cells, and acid response of zeolitic imidazolate framework (ZIF) materials of hyaluronic acid (HA), we realized that CuET-ZIFCu@HA could become an effective and highly selective cancer treatment. Both in vivo and in vitro experiments have demonstrated that CuET-ZIFCu@HA has robust anti-tumor properties without evident side effects. This research provided a promising strategy for DSF nanosystems that involves simple preparation and high efficacy, both of which are key to reusing DSF in cancer treatment.
Keywords disulfiram      copper(II) diethyldithiocarbamate complex      zeolitic imidazolate framework      targeted therapy     
Corresponding Author(s): Jinlong MA,Weifen ZHANG   
Online First Date: 10 November 2021    Issue Date: 28 December 2021
 Cite this article:   
Liping ZHAO,Xiaoxia WANG,Mingxia JIANG, et al. A nanosystem of copper(II)-disulfiram for cancer treatment with high efficacy and few side effects[J]. Front. Mater. Sci., 2021, 15(4): 553-566.
 URL:  
https://academic.hep.com.cn/foms/EN/10.1007/s11706-021-0576-2
https://academic.hep.com.cn/foms/EN/Y2021/V15/I4/553
Fig.1  Scheme 1 Schematic illustration of CuET delivery nanosystem (CuET-ZIFCu@HA) by one-pot synthesis method and in vivo efficacy evaluation for cancer.
Fig.2  (a) DLS profile of CuET-ZIFCu and CuET-ZIFCu@HA. (b) Zeta potentials of ZIFCu, CuET-ZIFCu, and CuET-ZIFCu@HA; results are presented as mean ± SD, n = 3. (c) The UV–Vis absorption spectra of ZIFCu, CuET-ZIFCu, and CuET-ZIFCu@HA. (d) TEM images of CuET-ZIFCu and CuET-ZIFCu@HA. (e) Mapping images of CuET-ZIFCu@HA.
Fig.3  The kinetics of drug release from (a) CuET-ZIFCu and (b) CuET-ZIFCu@HA under various buffer conditions; results are presented as mean ± SD, n = 3. Hemolysis activity of (c) CuET-ZIFCu and (d) CuET-ZIFCu@HA; results are presented as mean ± SD, n = 3. (e) The LIVE/DEAD assay of L929 cells after different treatments at the CuET concentration of 1.5 μg·mL−1. (f) Apoptosis rates of L929 cells by flow cytometry after 24 h co-incubation with CuET, CuET-ZIFCu, and CuET-ZIFCu@HA (concentration of 1.5 μg·mL−1).
Fig.4  (a) Cell viability of 231 cells after treatment with different concentrations of CuET; results are presented as mean ± SD. (b) The LIVE/DEAD assay of 231 cells after different treatments at the CuET concentration of 1.5 μg·mL−1. (c) Apoptosis rates of 231 cells by flow cytometry after 24 h co-incubation with CuET (concentration of 1.5 μg·mL−1).
Fig.5  ROS images and quantitative analyses of 231 cells after treatment with CuET at the concentrations of (a) 1 μg·mL−1 and (b) 1.5 μg·mL−1.
Fig.6  (a) Biodistribution of Cy5.5 and CuET-ZIFCu@HA-Cy5.5 in tumor-bearing nude mice at different times. (b) Biodistribution of Cy5.5 and CuET-ZIFCu@HA-Cy5.5 in the major organs (tumor, heart, liver, spleen, lung, and kidney) were harvested at 6 h. (c) Semi-quantitative analysis of the biodistribution profiles of Cy5.5 and CuET-ZIFCu@HA-Cy5.5 in tumor-bearing mice.
Fig.7  (a) Tumor growth curves after treatment with PBS, ZIFCu, CuET-ZIFCu, and CuET-ZIFCu@HA. (b) Weights of mice treated with PBS, ZIFCu, CuET-ZIFCu, and CuET-ZIFCu@HA during the 14-d treatment. (c) Weights of tumors in the groups of PBS, ZIFCu, CuET-ZIFCu, and CuET-ZIFCu@HA. (d) Images of tumors after treatment with PBS, ZIFCu, CuET-ZIFCu, and CuET-ZIFCu@HA. (e) H&E section of tumor after treatment at day 14. (f) H&E section of the heart, liver, spleen, lung, and kidney after treatment for 14 d. The data expressed as the arithmetic mean ± SD. ***p<0.001.
  Fig. S1 The size of ZIFCu.
  Fig. S2 Stability of CuET-ZIFCu and CuET-ZIFCu@HA in RPMI over a period of one week.
c(CuET)/(mg·mL−1) EE/% DL/%
CuET-ZIFCu CuET-ZIFCu@HA
1 75.68±0.80 15.33±0.14 10.57±0.08
1.2 76.00±0.40 19.90±0.08 12.47±0.05
1.4 75.95±0.15 20.28±0.03 14.25±0.05
1.6 74.00±0.28 22.07±0.05 15.61±0.03
1.8 72.96±0.12 23.90±0.03 17.03±0.02
2.0 70.66±0.11 25.27±0.03 18.09±0.02
  EE and DL values in CuET-ZIFCu and CuET-ZIFCu@HA
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