Ruthenium(III) complexes as cytotoxic agents entrapped in liposomes

The success of platinum complexes as chemiotherapeutic drugs pushed the scientific community to design new transition metal based complexes. to fight cancer and overcome the severe side effects and the insurgence of platinum resistance [1]..Among these compound ruthenium (III) complexes have been demonstrated very powerful against metastatic tumour but very poor is their action as cytotoxic agent.[2] The first aim of the present study was the development of a new ruthenium(III) complex, belonging to NAMI-A class, bearing to pyridine ligand a fully protected sugar moiety (RuPyTri). The presence of carbohydrate in coordination sphere should increase the complex ability to cross cellular membranes and sets this molecule in the area of biocompatible agents as tumour drug. The stability of the complex was studied and compared to RuPy complex in solution at different pH following UV-VIS spectra. The second, more relevant, purpose was to verify the ruthenium complexes activity after loading into liposomes. Liposomes can induce different mechanisms of delivery, increase the ability to cross cell membrane and stabilize the complexes reducing the water exchange. The lipid composition Egg L-α-phosphatidylcholine cholesterol / DSPE-PEG liposomes was selected to reproduce analog supramolecular aggregates in clinical use to vehicle doxorubicin (Doxil). Ruthenium complexes were loaded into liposomes using the passive equilibration loading method estimating the entrapped metal amount by ICP-MS. Full drug containing liposomes were structurally characterized by dynamic light scattering (DLS). Measurements confirm that sizes of all liposomes are in the 100 nm range, suitable for in vivo use. Loading ability and release kinetic allowed to select the best ratio between the lipid fraction and the metal to be tested in cellular experiments. Stability and drug release properties of ruthenium containing liposomes were confirmed in buffer. The growth inhibitory effects of both liposomal and free complex in PC3 prostate cancer cell lines validate a high cytotoxic ability of the liposome entrapped ruthenium (III) complexes.