A new design for nucleolipid-based Ru(iii) complexes as anticancer agents

Abstract

In continuation with our studies concerning the synthesis, characterization and biological evaluation of nucleolipidic Ru(III) complexes, a novel design for this family of potential anticancer agents is presented here. As a model compound, a new uridine-based nucleolipid has been prepared, named HoUrRu, following a simple and versatile synthetic procedure, and converted into a Ru(III) salt. Stable formulations of this highly functionalized Ru(III) complex have been obtained by co-aggregation with either the zwitterionic lipid POPC or the cationic DOTAP, which have been subjected to an in-depth microstructural characterization, including DLS, SANS and EPR measurements. The in vitro bioactivity profile of HoUrRu, as a pure compound or in formulation with POPC or DOTAP, reveals high antiproliferative activity against MCF-7 and WiDr human cancer cell lines.

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

“…Current research efforts are focused on a deeper understanding of the cellular response and/or resistance to anticancer treatments, including the role of cell death pathways activation, such as apoptosis and autophagy, by chemotherapeutics32. Recently, we have developed new biocompatible ruthenium-based nanosystems, proved to be particularly effective against specific cell lines derived from human solid tumours192224252627. Starting from these encouraging data, in the present work we have first confirmed their efficacy focusing on a panel of human tumour cells arising from breast cancer.…”

“…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.…”

“…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. Most remarkably, liposomes loaded with the Ru(III)-containing nucleolipids have shown a promising selectivity towards cancer cells in bioscreens in vitro 1922252627.…”

RuIII Complexes for Anticancer Therapy: The Importance of Being Nucleolipidic

“…This leads to partial hydrolysis of the complexes and eventually to formation of polyoxo species. [88][89][90][105][106][107][108][109] [101,104] Thus, in order to obtain long-lived Ru III -based antineoplastic agents, a prodrug approach, involving the decoration of the ruthenium complex with amphiphilic nanovectors, has been proposed by Paduano et al for the in vivo delivery of these compounds.…”

“…[108] In the first series of amphiphilic nucleolipids (ToThyRu, HoThyRu, DoHuRu and ToThyCholRu), discussed in Section 5, the pyridine residue, chosen as the privileged ligand for ruthenium, was anchored to the N-3 position of the pyrimidine moiety. [108] In the first series of amphiphilic nucleolipids (ToThyRu, HoThyRu, DoHuRu and ToThyCholRu), discussed in Section 5, the pyridine residue, chosen as the privileged ligand for ruthenium, was anchored to the N-3 position of the pyrimidine moiety.…”