Polymeric micelle-mediated delivery of half-sandwich ruthenium(II) complexes with phosphanes derived from fluoroloquinolones for lung adenocarcinoma treatment

Abstract

Novel half-sandwich ruthenium(II) complexes with aminomethyl(diphenyl)phosphine derived from fluoroloquinolones (RuPCp, RuPSf, RuPLm, RuPNr) were being investigated as alternatives to well-established metal-based chemotherapeutics. All compounds were characterized by elemental analysis, selected spectroscopic methods (i.e., absorption and fluorescence spectroscopies, ESI-MS, NMR, circular dichroizm), X-ray diffractometry, ICP-MS, and electrochemical techniques. To overcome low solubility, serious side effects connected with systemic cytotoxicity of ruthenium complexes, and acquiring the resistance of cancer cells, polymeric nanoformulations based on Pluronic P-123 micelles loaded with selected Ru(II) complexes were prepared and characterized. Resulting micelles (RuPCp_M, RuPNr_M) enabled efficient drug accumulation inside human lung adenocarcinoma (A549 tumor cell line), proved by confocal microscopy and ICP-MS analysis, allowing cytotoxic action. Studied complexes exhibited promising cytotoxicity in vitro with IC50 values significantly lower than the reference drug - cisplatin. The fluorescence spectroscopic data (CT-DNA titration, in vitro cell staining) together with analysis of DNA fragmentation (pBR322 plasmid, comet assay) provided clear evidence for the interaction with DNA inducing apoptotic cell death.

Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug

“…Considering the results presented above, we can expect that the resulting complexes will not exhibit high genotoxicity, as opposed to previously reports of similarly mixed copper(I) or ruthenium(II) complexes bearing phosphines derived from fluoroquinolones [ 11 , 41 , 42 , 43 , 44 ] that exert high systemic toxicity related to strong intercalations with DNA.…”

“…The strength of the compounds’ interactions with DNA is similar for all complexes discussed ( Figure 2 ; Supplementary Materials, Figure S1 , Table 1 ). Notably, the trend in its ability to displace intercalator EB from CT DNA was different than in the case previously studied by our group regarding ruthenium(II) and copper(I) complexes based on the same phosphine ligands [ 11 , 13 , 41 , 42 , 43 , 44 ]. This trend suggests that the type of metal ions (Cu(I), Ru(II), Ir(III)) have a significant influence on the type and intensity of intercalations with DNA.…”

“…Furthermore, the affinity of HSA for all the considered Ir(III) complexes with fluoroquinolone derivatives is much higher than for copper(I) complexes with the same organic derivates [ 11 , 13 , 41 , 42 , 43 ]. It is noteworthy that the tendency of the strength of HSA quenching is different from observations for all complexes (Cu(I) and Ru(II)) with the same phosphines derived from fluoroquinolones [ 11 , 41 , 42 , 43 , 44 ].…”

Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

“…Along with other fluoroquinolones, previous reports identified promising anti-Toxoplasma effects upon treatments with certain ciprofloxacin derivatives [64,65]. Ruthenium(II)-arene complexes bearing fluoroquinolone-based ligands showed interesting anticancer and antimicrobial activities (e.g., F and G in Figure 2) [66][67][68]. The drug can be either directly coordinated to the metal (F), or covalently linked to a ligand (G).…”

“…Coordinating 7-(4-(decanoyl)piperazin-1-yl)-ciprofloxacin, to the ruthenium(II)(η 6 -p-MeC 6 H 4 Pr i ) unit in compound F [67] yielded multifunctional properties: high cytotoxicity in several cancer cell lines and moderate dose-dependent antibacterial activity in Escherichia coli as well as in a clinical E. coli isolate resistant to β-lactams. Compound G, bearing ciprofloxacin connected to an aminomethyl(diphenyl)phosphine ligand, was loaded in polymeric nanoformulations and exhibited promising cytotoxicity in vitro [66].…”