Iridium(III) complexes with phosphine-fluoroquinolone conjugates - design, synthesis, bioactivity and nanoformulation as a potential platform for drug delivery

Many anti-cancer medicines are currently used in clinical treatment, their effectiveness is still hampered by clinical problems, including acquired or congenital resistance and high toxicity. One strategy adopted to overcome these limitations is the development of new and promising alternative transition metal (e.g. Cu, Ru, Pd, and Au) anti-cancer agents. They appear to be an attractive alternative to their platinum counterparts, mainly because they are less toxic and exhibit interesting anticancer properties. Fluoroquinolones are broad-spectrum antibiotics used to treat bacterial infections not only in humans but also in animals they have also shown immunomodulatory and antitumor effects. The main aim of my work was to design, synthetize and test new organometallic iridium(III) complexes with phosphines derived from fluoroquinolone antibiotics possessing anticancer potential. During my work, I prepared four iridium(III) complexes, the physicochemical properties in both solution and solid-state of each one obtained were investigated using elemental analysis, mass spectrometry, cyclic voltamperometry, and spectroscopic methods. The crystal structures of every synthesized complex was obtained using the X-ray single-crystal diffraction method. The mononuclear iridium(III) complexes adopt half-sandwich pseudo-octahedral “three-leg piano-stool” geometry with an η5-coordinated cyclopentadienyl and three additional sites of ligation occupied by one phosphine ligand and two chloride ligands. The cytotoxicity of all compounds was tested in vitro against the five most common cancer cell lines: MCF7 (human breast adenocarcinoma), A549 (human lung adenocarcinoma), PANC-1 (human pancreatic/duct carcinoma), WM2664 (metastatic human melanoma) and DU-145 (human prostate carcinoma) as well as one normal, human embryonic kidney (HEK293T). Based on these results, examined complexes exhibited promising cytotoxicity in vitro with IC50 values significantly lower than that of the cisplatin. The introduction of the fluoroquinolone in complexes significantly increased the antitumor cytotoxicity of the final compounds against the lung, breast, and melanoma cell line. Preliminary investigation focused on elucidation of the action mode allowed to formulate the following conclusions: (i) iridium(III) complexes are accumulated in both nucleus and cytoplasm, (ii) cytometric analysis showed clear evidence for predominance of apoptosis in the induced cell death, (iii) the activation of caspase-3/7 along with the decrease of mitochondrial membrane potential also confirmed the apoptotic cell death, (iv) iridium(III) complexes may induce the changes in cell cycle leading to G2/M phase arrest, (v) ROS generation (involving hydroxyl radical, singlet oxygen and superoxide anion radical) as plausible pathway responsible for the cytotoxicity (vi) efficient anticancer action on 3D multicellular tumor spheroids assemblies was demonstrated, (vii) inorganic compounds exhibited multimodal DNA interaction with predominance of minor groove binding, (viii )and they bind to HSA tryptophan residues at site I (subdomain II A) and bind to all four possible apo-Tf binding sites containing tyrosine or tryptophan residues. To overcome poor solubility and serious side effects the resulting homonuclear complexes were encapsulated in nanoemulsions and Pluronic-123 micelles, improving the effective accumulation in human lung adenocarcinoma and human prostate cancer and increased their cytotoxicity by an order of magnitude.