Organometallic Half-Sandwich Complexes of 1,10-Phenanthroline Derivatives with Improved Solubility, Albumin-Binding, and Nanoformulation Potential Targeting Drug Resistance in Cancer.

The development of Rh(III)(η(5)-C(5)Me(5)) and Ru(II)(η(6)-p-cymene) complexes of 4,7-dichloro-1,10-phenanthroline (DCP) and bathophenanthroline (BP) aims to increase aqueous solubility and potential bioavailability of the lipophilic ligands while also enabling selective activity against multidrug-resistant (MDR) cancer cells. Complexes [M(η(6)-arene/η(5)-arenyl)(DCP/BP)Cl]Cl were prepared and characterized by means of nuclear magnetic resonance, infrared, electrospray ionization mass spectrometry, and single crystal X-ray diffraction for [Rh(III)(η(5)-C(5)Me(5))(DCP)Cl]PF(6) and [Ru(II)(η(6)-p-cymene)(BP)Cl]PF(6). The complexes are highly stable in a wide pH range with increased hydrophilicity, and the Rh complexes showed fast and significant binding to human serum albumin (HSA). Cytotoxicity tests were conducted in various breast cancer cells and in cocultured cell lines of the uterine sarcoma parental MES-SA and its MDR counterparts. Both the ligands and their organorhodium complexes displayed a higher cytotoxicity against the MDR MES-SA/Dx5 cells than against the parental cells. As the complex [Rh(III)(η(5)-C(5)Me(5))(BP)Cl]Cl showed the most promising results (IC(50) = 0.23 μM (MES-SA/Dx5) with selectivity ratio 6.7), it was selected for nanoformulation using HSA and also combined with d-α-tocopheryl polyethylene glycol 1000 succinate and poly(lactic-co-glycolic acid). Both composites showed a good encapsulation efficiency and colloidal stability. Based on the in vitro cytotoxicity assays, the use of HSA as a carrier is a promising strategy to enhance the pharmacological properties of the MDR-selective Rh(III)(η(5)-C(5)Me(5)) complexes of 1,10-phenanthroline derivatives.