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Novel fast-acting pyrazole/pyridine-functionalized N-heterocyclic carbene silver complexes assembled with nanoparticles show enhanced safety and efficacy as anticancer therapeutics

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Abstract

In this study, we designed and synthesized four novel multi-nuclear silver complexes (1–4) coordinated with pyrazole- or pyridine-functionalized N-heterocyclic carbene (NHC) ligands. The crystal structures of the silver–NHC complexes were confirmed by X-ray diffraction analysis. In vitro assays showed that the silver–NHC complexes effectively killed a broad range of cancer cells after short-term drug exposure, serving as fast-acting cytotoxic agents. Of note, in cisplatin-resistant A549 cancer cells, the silver complexes were not cross-resistant with the clinically used cisplatin agent. Detailed mechanistic studies revealed that complex 2 triggered caspase-independent cell necrosis associated with intracellular reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) depletion. By exploiting a facile nano-assembly process, silver–NHC complexes 1, 2 and 4 were successfully integrated into the hydrophobic cores of amphiphilic matrices (DSPE-PEG2K), enabling systemic injection. The silver complex-loaded nanotherapeutics (1-NPs, 2-NPs, and 4-NPs) showed high safety margins with reduced systemic drug toxicities relative to cisplatin in animals. Furthermore, in a xenograft model of human colorectal cancer, the administration of the nanotherapeutics resulted in a marked inhibition of tumor progression.

Graphical abstract: Novel fast-acting pyrazole/pyridine-functionalized N-heterocyclic carbene silver complexes assembled with nanoparticles show enhanced safety and efficacy as anticancer therapeutics

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Supplementary files

Article information


Submitted
14 Dec 2019
Accepted
24 Jan 2020
First published
28 Jan 2020

Dalton Trans., 2020, Advance Article
Article type
Paper

Novel fast-acting pyrazole/pyridine-functionalized N-heterocyclic carbene silver complexes assembled with nanoparticles show enhanced safety and efficacy as anticancer therapeutics

C. Chen, L. Zhou, B. Xie, Y. Wang, L. Ren, X. Chen, B. Cen, H. Lv and H. Wang, Dalton Trans., 2020, Advance Article , DOI: 10.1039/C9DT04751D

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