Síntese e caracterização dos complexos anfifílicos de gadolínio e térbio para emprego como agentes de contraste e antitumorais

Abstract

Gadolinium(III) and terbium(III) complexes(III) with amphiphilic ligands, derivatives of N-alkyl-N-methyl-glucamides, were synthesized and characterized by elemental analysis (C, H and N), molar electric conductivity, infrared absorption spectroscopy, electron paramagnetic resonance, thermogravimetric analysis (TG and DTG), melting temperature and mass spectrometry. The complexes possess a metalligand stoichiometry of 1:2, are cationic, electrolytes 1:1, with a chloride as a counter ion. The amphiphilic complexes of gadolinium (III) were studied for their activity as contrast agents for imaging by MRI. These complexes showed high relaxivity compared to commercial contrast agents, both in concentrations below the critical micelleconcentration (with values ranging from 11.90 to 12.30 s-1 mM-1 for r1 and from 13.00 13.60 s-1 mM-1 for r2) and above the critical micelle concentration (with values ranging from 8.34 to 12.22 s-1 mM-1 for r1 and from 8.94 to 13.61 s-1 mM-1 for r2). T1 weighted images showed a high brightness for the amphiphilic complexes in aqueous solutionin comparison to the commercial contrast agent Gd-DTPA analyzed under the same conditions (1 mM to 20 MHz). The relaxivity of gadolinium(III) complexes incorporated into liposomes was also studied, showing values ranging from 11.92 to 15.53 s-1 mM-1 for r1 and from 13.41 to 16.95 s-1 mM-1 for r2). High relaxivity was observed for complexes gadolinium(III) incorporated into liposomes. The high relaxatividade observed for the synthesized complexes can be attributed to molecular rotation that occurs more slowly due to high molecular weight of the complexes and their incorporation into liposomes. The results obtained for relaxivity show that these paramagnetic complexes are highly potent contrast agents, which makes them excellent candidates for MRI imaging. The luminescence of terbium(III) complex was investigated in the solid state and in aqueous, ethanol and chloroform solutions. The emission spectra of the complex [Tb(OCT)2]Cl recorded in excitation 300 nm and 370 nm emission lines show characteristics of terbium(III) ion showing the transitions of 5D4 7F6 (around 490 nm) , 5D4 7F5 (around 545 nm), 5D4 7F4 (around 590 nm) and 5D4 7F3 (around620 nm). The maximum transition observed in the emission spectra was the 5D4 7F5 of 545 nm, which may be the f-f transitions, which is to contribute to an intense green luminescence, qualifying him to act as effective luminescence sensitizers both in solid form and in solution.The cytotoxicity of the all the complexes, free ligands and respective metalprecursors was studied in mouse fibroblasts L292 cells. The cytotoxic concentration of gadolinium(III) and terbium(III) complexes were from 30 to 120 µM, showing higher concentrations than the standard drug used in cancer treatment, cisplatin (29 µM), which indicates that the synthesized complexes show less cytotoxicity to normal cells than the standard drug (Cisplatin). The complexes along the respective free ligands and metal precursors were also evaluated for their therapeutic potential in tumor cell lines (K562 and B16F10 tumor cell lines). The concentration at which the drug inhibit the growth of the tumor cells (IC50) was obtained. The in vitro cytotoxic activities of the complexes in fibroblasts and tumor cell lines showed that terbium(III) complexes were more active to tumor cells than the standard drug, cisplatin.