Comparison Between Polypyridyl and Cyclometalated Ruthenium(II) Complexes: Anticancer Activities Against 2D and 3D Cancer Models

Abstract

The aim of this study was to illustrate the dramatically different anticancer activities between coordinatively saturated polypyridyl (1 a-4 a) and cyclometalated (1 b-4 b) ruthenium(II) complexes. The cyclometalated complexes 1 b-4 b function as DNA transcription inhibitors, exhibiting switch-on cytotoxicity against a 2D cancer cell monolayer, whereas the polypyridyl complexes 1 a-4 a are relatively inactive. Moreover, complexes 1 b-4 b exhibit excellent cytotoxicity against 3D multicellular tumor spheroids (MCTSs), which serve as an intermediate model between in vitro 2D cell monolayers and in vivo 3D solid tumors. The hydrophobicity, efficient cell uptake, and nucleus targeting ability, as well as the high DNA binding affinity of complexes 1 b-4 b, likely contribute to their enhanced anticancer activity. We surmise that cyclometalation could be a universal approach to significantly enhance the anticancer activity of substituted polypyridyl Ru(II) complexes. We also suggest that 3D MCTSs may be a more practical platform for anticancer drug screening than 2D cancer monolayer approaches.

Evaluation of Perylene Bisimide‐Based RuII and IrIII Complexes as Photosensitizers for Photodynamic Therapy

“…This result is in line with the anticancer activity reported for some structurally similar Ru II complexes. [24,[64][65][66][67] The Ir III complex 2 showed, as a general trend, a higher cytotoxic activity in the dark on all cell lines than 1 (see Table S1). We can speculate that the planar, highly conjugated L2 ligand plays a role in the dark cytotoxicity of 2.…”

A multifunctional DNA origami as carrier of metal complexes to achieve enhanced tumoral delivery and nullified systemic toxicity

“…Based on the previous reports, Ru complexes act by intercalating with DNA in nucleus to inhibit DNA replication and transcription [3]. Therefore, delivery of Ru complexes to cell nucleus would be an ideal method to enhance their anticancer efficacy.…”

“…So far, the synthesized Ru complexes such as NAMI-A and KP1019 have gone through phase I clinical trials. Despite this partial success, the new class of Ru-based chemotherapeutics is still associated with drawbacks such as unstability in aqueous solution, unsatisfied cytotoxicity and uncertained antitumoral mechanism for the cancer therapy [3,4].…”

“…To address these issues, researchers focus on synthesis of new types of nanocarriers that process advanced properties including (1) superior biocompatibility that can be effectively degraded in vivo, (2) high loading / entrapment efficacy to ferry pharmaceutical drugs, (3) strong cancer-targeted ability and effective tumoral accumulation, (4) controllable release of drugs without premature leaking [6,9].…”

A ruthenium(II) complex-based lysosome-targetable multisignal chemosensor for in vivo detection of hypochlorous acid

“…Since the MLCT emission strongly depends on the orbital combination of polypyridyl ligands, the emission properties could be readily modulated by the variation of ligand properties [9,12,17,31,32], which provides a useful approach for the development of polypyridyl-ruthenium(II) complex-based luminescent chemosensors [33e39]. In previous works, we identified that the MLCT excited state of ruthenium(II) complexes could be corrupted by the intramolecular photoinduced electron transfer (PET) process when an electron donor or acceptor was attached to polypyridyl ligands, and the elimination of PET by the analyte-triggered reaction could restore the MLCT state to switch on the luminescence of the complexes [40e42].…”