Ru^III Complexes for Anticancer Therapy: The Importance of Being Nucleolipidic

Abstract

Ruthenium complexes are attracting increasing attention as second‐generation metal‐based anticancer agents, with NAMI‐A and KP1019 as the major representatives of this class having undergone clinical trials. Our recent interest has been focused on the synthesis and characterization of new amphiphilic derivatives of nucleosides (nucleolipids). These compounds have been selected as core scaffolds linked to RuIII complexes and capable of self‐assembly into stable nanostructures in aq. solutions so to transport the metal ions efficiently into the cell. Through the use of ribo‐ and deoxyribonucleosides as starting building blocks, a mini‐library of nucleolipidic RuIII complexes decorated with diverse hydrophilic and lipophilic chains and incorporating the NAMI‐A analogue AziRu has been prepared. When co‐aggregated with biocompatible lipids, these RuIII‐containing nucleolipids proved to be stable for months under physiological conditions. Detailed microstructural characterization, carried out by a combined approach including different physico‐chemical techniques, allowed their stability, size and shape to be determined. Tested on a panel of human and non‐human cells, all of the studied RuIII complexes showed potent in vitro anticancer activity, significantly higher than that of NAMI‐A‐like analogues, and minimal toxicity. Here we summarize the design and synthetic procedures developed to prepare these new Ru‐containing candidate drugs, discussing the beneficial effects achievable through exploiting nucleolipid appendages in the delivery of metal‐based drugs.

Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action

“…This result, consistent with our previous reports, is likely associated to the positive charge of DOTAP formulations which can promote the interaction with the plasma membranes allowing a faster and quantitative drug cellular uptake19. Moreover, in relation to their effectiveness in vitro , there are no significant differences between the ToThyRu and DoHuRu nucleolipidic Ru(III) complexes used in our liposomial formulations, consistently with the rationale that the ruthenium center is the bioactive species, and the nucleolipids are simply carrier molecules24. IC 50 data normalization in favour of the actual ruthenium content enclosed in ToThyRu/DOTAP and DoHuRu/DOTAP liposomes (15% mol/mol), leads up to values of IC 50 of about 3–4 μM in CG-5 cells and of about 10 μM in MCF-7 cells, suggestive of a marked antiproliferative bioactivity in vitro .…”

“…Moreover, on the lookout for biomimetic nanosystems, stable nucleolipidic Ru(III) complexes were produced by co-aggregation with either the zwitterionic phospholipid POPC (1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine) or the cationic lipid DOTAP (1,2-dioleoyl-3-trimethylammoniumpropane chloride). The final nanoaggregates - which exhibit liposomial structure and have been subjected to an in-depth microstructural characterization - are ad hoc designed to present high stability under physiological conditions as well as to transport high ruthenium amounts in cells, thereby ensuring more effective metal-based treatments24252627. Indeed, recent in vitro bioactivity investigations have shown the great potential of our biocompatible ruthenium-containing liposomes as active antineoplastic agents against human carcinoma cells of different histological origin24.…”

“…The final nanoaggregates - which exhibit liposomial structure and have been subjected to an in-depth microstructural characterization - are ad hoc designed to present high stability under physiological conditions as well as to transport high ruthenium amounts in cells, thereby ensuring more effective metal-based treatments24252627. Indeed, recent in vitro bioactivity investigations have shown the great potential of our biocompatible ruthenium-containing liposomes as active antineoplastic agents against human carcinoma cells of different histological origin24. Of special interest have been the results obtained on estrogen and progesterone receptor positive MCF-7 adenocarcinoma cells, an in vitro model reflecting to a large extent the features of luminal breast cancer cells in vivo , worldwide the most common invasive cancer in women.…”

Synthesis and X-ray Structural Analysis of the Ruthenium(III) Complex Na[trans-RuCl4(DMSO) (PyrDiaz)], the Diazene Derivative of Antitumor NAMI-Pyr

“…7 As a result, some ruthenium-based compounds of unique properties, surpassing cisplatin in activity, particularly on resistant tumours, and with reduced host toxicity at active doses have been discovered. 8,9 In the treatment of a complex disease like cancer it is unlikely for a single drug to be effective. To increase the chemotherapeutic success, a combination of two or more active agents having separate targets is commonly administered at the therapy.…”

“…9 Derivatives with functionalized pyridine ligand have also been investigated. 32 Unfortunately, no biological studies of 3 were possible due to its instability and decomposition in protic solvents (vide supra).…”