Liposomal Binuclear Ir(III)–Cu(II) Coordination Compounds with Phosphino-Fluoroquinolone Conjugates for Human Prostate Carcinoma Treatment

Abstract

Novel heteronuclear Ir III −Cu II coordination compounds ([Ir(η 5 -Cp*)Cl 2 Pcfx-Cu(phen)](NO 3 )•1.75(CH 3 OH)•0.75(H 2 O) (1), [Ir(η 5 -Cp*)Cl 2 Pnfx-Cu(phen)](NO 3 )•1.75(CH 3 OH) 4)) bearing phosphines derived from fluoroquinolones, namely, sparfloxacin (Hsfx), ciprofloxacin (Hcfx), lomefloxacin (Hlfx), and norfloxacin (Hnfx), have been synthesized and studied as possible anticancer chemotherapeutics. All compounds have been characterized by electrospray ionization mass spectrometry (ESI-MS), a number of spectroscopic methods (i.e., IR, fluorescence, and electron paramagnetic resonance (EPR)), cyclic voltammetry, variable-temperature magnetic susceptibility measurements, and X-ray diffractometry. The coordination geometry of Ir III in all complexes adopts a characteristic piano-stool geometry with the η 5 -coordinated and three additional sites occupied by two chloride and phosphine ligands, while Cu II ions in complexes 1 and 2 form a distorted square-pyramidal coordination geometry, and in complex 3, the coordination geometry around Cu II ions is a distorted octahedron. Interestingly, the crystal structure of [Ir(η 5 -Cp*)Cl 2 Plfx-Cu(phen)] features the one-dimensional (1D) metal−organic polymer. Liposomes loaded with redox-active and fluorescent [Ir(η 5 -Cp*)Cl 2 Pcfx-Cu(phen)] (1L) have been prepared to increase water solubility and minimize serious systemic side effects. It has been proven, by confocal microscopy and an inductively coupled plasma mass spectrometry (ICP-MS) analysis, that the liposomal form of compound 1 can be effectively accumulated inside human lung adenocarcinoma and human prostate carcinoma cells with selective localization in nuclei. A cytometric analysis showed dominance of apoptosis over the other cell death types. Furthermore, the investigated nanoformulations induced changes in the cell cycle, leading to S phase arrest in a dose-dependent manner. Importantly, in vitro anticancer action on three-dimensional (3D) multicellular tumor spheroids has been demonstrated.

Let’s Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer

“…3D cultures are being used to develop novel carrier systems with the possibility to penetrate deeper into the structure of the tumor and deliver specific compounds, such as radionuclides, miRNA, and drugs. Several carriers have been tested that have shown increased permeability, even in 3D cultures [ 107 , 121 , 126 , 141 , 142 , 179 , 180 ].…”

Phototoxicity of Tridentate Ru(II) Polypyridyl Complex with Expanded Bite Angles toward Mammalian Cells and Multicellular Tumor Spheroids

“…Significant differences between the permeation and destination of luminescent probes between 2D and 3D cellular models have been reported . Therefore, in assessing potential PS sensitizers, permeation through 3D models should ideally also be considered but rarely have been to date in metal complex species, with only a small number of studies reported to date assessing metal complex PSs in spheroids. , A recent work includes lysosomal localizing Ru (II) complexes, studied by the Chao group in HeLa spheroids for two photon PDT, irradiating the spheroids at 10 J/cm 2 at 800 nm, and also the study of photoactive iridium (III) complexes in A549 spheroids by the Sadler group. , …”

“…50 Therefore, in assessing potential PS sensitizers, permeation through 3D models should ideally also be considered but rarely have been to date in metal complex species, with only a small number of studies reported to date assessing metal complex PSs in spheroids. 51,52 A recent work includes lysosomal localizing Ru (II) complexes, studied by the Chao group in HeLa spheroids for two photon PDT, irradiating the spheroids at 10 J/cm 2 at 800 nm, and also the study of photoactive iridium (III) complexes in A549 spheroids by the Sadler group. 53,54 Herein, we report on the application of tridentate coordinated [Ru(bqp)(bqpCOOEt)] 2+ (Ru-bqp-ester), where bqp = 2,6-bi(quinolin-8-yl)pyridine, and its peptide conjugates [Ru(bqp)(bqpCONH-ahx-FrFKFrFK(Ac)-CONH 2 )] 5+ (Ru- The parent complex (Figure 1), was selected as, when first reported by Hammarstrom et al, it showed an exceptionally long lived 3 MLCT excited state facilitated by the expanded coordination bite angle of the 2,6-bi(quinolin-8-yl)pyridine ligand so that the coordination geometry around the metal center is approximately octahedra.…”

Cellular Mechanistic Considerations on Cytotoxic Mode of Action of Phosphino Ru(II) and Ir(III) Complexes

“…[30][31][32] The above-mentioned different mechanisms of action, ligand substitution kinetics, and various oxidation states contributed to potential redox activity, lower toxic effect, and higher cellular uptake efficiency give advantages to ruthenium and iridium complexes over platinum-based compounds. [33][34][35] Currently, two piano-stool ruthenium(II) complexes Ru(η 6 -pcymene)Cl 2 PPh 2 CH 2 OH (RuPOH) and Ru(η 6 -p-cymene)Cl 2 P(p-OCH 3 Ph) 2 CH 2 OH (RuMPOH) and two half-sandwich iridium(III) complexes Ir(η 5 -Cp*)Cl 2 PPh 2 CH 2 OH (IrPOH) and Ir(η 5 -Cp*)Cl 2 P(p-OCH 3 Ph) 2 CH 2 OH (IrMPOH) have been synthesized, physiochemically characterized and evaluated in vitro in terms of their potential anticancer activity in our research groups. [36] We concluded that all the studied complexes undergo slow hydrolysis and the complexes with the methoxy group on the phenyl rings can catalyze the oxidation of NADH to NAD + with higher efficiency than complexes without this group.…”

“…Moreover, triphenylphosphine can intercalate between DNA base pairs which increases anticancer activity [30–32] . The above‐mentioned different mechanisms of action, ligand substitution kinetics, and various oxidation states contributed to potential redox activity, lower toxic effect, and higher cellular uptake efficiency give advantages to ruthenium and iridium complexes over platinum‐based compounds [33–35] …”