Aqueous chemistry of the interaction of drugs with metal cations: from speciation studies to environmental and nanopharmaceutical applications

An in-depth speciation study on Metronidazole, Nalidixic acid, Gemcitabine and their interaction with various metal cations in aqueous solution is reported in this thesis. Firstly, the acid-base behavior of each ligand was investigated in NaCl aqueous solution by potentiometry and spectrophotometry under various temperature and ionic strength conditions. Then, the interactions towards various metal cations of both biological and environmental interest were subsequently investigated by potentiometric, spectrophotometric and, for some of them, 1H NMR titrations, varying the conditions of temperature, ionic strength and metal/ligand molar ratio. For each system, the values of the enthalpy of protonation and formation changes were also studied through the dependence of the values of the protonation and formation constants on the temperature. Furthermore, the dependence of the constants on the ionic strength was also determined. The sequestering ability for each system was evaluated by calculating the empirical parameter pL0.5 under different values of temperature, pH and ionic strength. Starting from the premise that the presence of complex species and their formation percentage could significantly affect the toxicity, simulations under real conditions of fluids (e.g. plasma, sea water) have been carried out on some of the studied systems. All the equilibria and the real pH, temperature, ionic strength values, and concentrations of the main inorganic constituents were considered. The antimicrobial and antiprotozoal activity of Metronidazole and Nalidixic acid and their metal complex species was tested by in vitro cytotoxicity assays. Some complexes have also been characterized by MALDI-TOF and MALDI-TOF-TOF analyses and quantum-computational calculations. The speciation study’s results on Gemcitabine systems were used to prepare Gemcitabine liposomal formulations with better quality attributes for the treatment of osteosarcoma lung metastasis. The liposomal formulations were characterized by dynamic light scattering, HPLC and Transmission Electron Microscopy (TEM), and their cytotoxicity in vitro was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assays.