Sphingomyelin-based PEGylation Cu (DDC)2 liposomes prepared via the dual function of Cu2+ for cancer therapy: Facilitating DDC loading and exerting synergistic antitumor effects.

Abstract

The old alcohol-aversion drug disulfiram (DSF) has aroused wide attention as a drug repurposing strategy in terms of cancer therapy because of the high antitumor efficacy in combination with copper ion. However, numerous defects of DSF (e.g., the short half-life and acid instability) have limited the application in cancer treatment. Cu (DDC)2, the complex of diethyldithiocarbamate (DDC, DSF metabolite) and Cu2+, have been proven as the vital active component on cancer, which have aroused the attention of researchers from DSF to Cu (DDC)2. However, the poor water solubility of Cu (DDC)2 increase more difficulties to the treatment and in-depth investigations of Cu (DDC)2. In this study, sphingomyelin (SM)-based PEGylated liposomes (SM/Chol/DSPE-mPEG2000 (55:40:5, mole%)) were produced as the carriers for Cu (DDC)2 delivery to enhance the water solubility. DDC was added to Cu-containing liposomes with a higher encapsulation efficiency of more than 90%, and it reacted with Cu2+ to synthesize Cu (DDC)2. Due to the high phase transition temperature of SM and strong intermolecular hydrogen bonds with cholesterol, SM-based liposomes would be conducive to enhancing the stability of Cu (DDC)2 and preventing drug leakage during delivery. As proven by pharmacokinetic studies, loading Cu (DDC)2 into liposomes improve bioavailability, and the area under the curve (AUC0-t) and the mean elimination half-life (t1/2) increased 1.9-time and 1.3-time to those of free Cu (DDC)2, respectively. Furthermore, the anticancer effect of Cu (DDC)2 was enhanced by the liposomal encapsulation, thus resulting in remarkable cell apoptosis in vitro and a tumor-inhibiting rate of 77.88% in vivo. Thus, it was concluded that Cu (DDC)2 liposomes could be promising in cancer treatment.

• Authors: Hao Liu, Yihan Kong, Zixu Liu, Xueting Guo, Bing Yang, Tian Yin, Haibing He, Jingxin Gou, Yu Zhang, Xing Tang
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 621 Pg. 121788 (Jun 10 2022) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 35504431 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Liposomes
• Sphingomyelins
• Water
• Copper
• Ditiocarb
• Aromatic-L-Amino-Acid Decarboxylases
• DDC protein, human
• Disulfiram

Topics

• Aromatic-L-Amino-Acid Decarboxylases (therapeutic use)
• Cell Line, Tumor
• Copper (chemistry)
• Disulfiram (chemistry)
• Ditiocarb (chemistry, pharmacokinetics)
• Humans
• Liposomes (chemistry)
• Neoplasms (drug therapy)
• Sphingomyelins (therapeutic use)
• Water