Synergy effects of copper ion in doxorubicin-based chelate prodrug for cancer chemo-chemodynamic combination therapy

Abstract

Doxorubicin (DOX) is a commonly studied chemotherapeutic agent for the treatment of solid tumors, but the severe side effects limit its clinical application. It is shown that DOX-metal chelate has lower in vitro cytotoxicity compared with DOX, as the anthracyclines of DOX can form coordinative interaction with transition metal ions. In addition, the transition metal ions could catalyze the production of hydroxyl radicals (·OH) via Fenton/Fenton-like reactions to achieve antitumor chemodynamic therapy (CDT). In this study, copper ions (Cu²⁺) were applied to obtain DOX/Cu(II) prodrug, and a liposomal formulation was used to avoid the rapid blood clearance and optimize the biodistribution of this prodrug. In vitro and in vivo antitumor results demonstrated that this pH sensitive Cu-chelating prodrug can reduce adverse effects of DOX but improve the antitumor efficiency due to the combination of chemotherapy and chemodynamic therapy. Our study provided a facile and effective approach of metal-chelating prodrug strategy for combination cancer therapy strategy.

Keywords:

• Chemodynamic therapy
• chemotherapy
• combination therapy
• cytotoxicity
• antitumor
• safety

Disclosure statement

The authors report there are no competing interests to declare.

Ethical approval statement

Nude mice were provided from the Jinan Pengyue Experimental Animal Breeding Co., Ltd (Jinan, China). All animal procedures were carried out per the Regulations for the Care and Use of Laboratory Animals: Eighth Edition. (Washington, DC: The National Academies Press). All animal experiments were approved by Yantai University Laboratory Animal Ethics Committee, affiliated to Yantai University (Approval number, YTDX 20210312). The ARRIVE criteria were followed in all animal experiments. All animals were housed in a specific pathogen free environment, and up to five mice per cage were housed in individually ventilated cages (ventilated room, 22 °C ± 2 °C, 55% +/10% humidity, 12 h light/dark cycle and standard water and food). 35 nude mice were used in this work, since it is necessary to explore the in vivo distribution, antitumor effect and safety evaluation of this system.

Author contribution

Wen Zhang: Experiment, Software, Analysis, Investigation, Writing—original draft preparation, Visualization. Peng Zhang: Conception, Design, Writing—original draft and revised draft, final approval of draft, Supervision. Xiaopeng Xu: Software, Analysis, Investigation. Minghui Li: Methodology, Analysis, Investigation. Shasha Wang: Reference search. Hongjie Mu: Instrument Operation. Kaoxiang Sun: Conception, Revision, Supervision.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 82001961) and Youth Innovation Team Plan of Shandong Province (Grant No. 2022KJ344).