Soft nanocarriers for new poorly soluble conjugate of pteridine and benzimidazole: Synthesis and cytotoxic activity against tumor cells

Abstract New conjugated derivative of pteridine and benzimidazole, 7-(benzimidazol-2-yl)-6-(2,4-dichlorophenyl)-2-thioxo-2,3-dihydropteridin-4(1H)-one (BP) possessing antitumor activity was obtained and thoroughly characterized; its spectrophotometry control in solution was developed. To improve the solubility of the hydrophobic antitumor agent BP in aqueous solutions, amphiphilic systems (micellar solutions and modified liposomes) were fabricated, with their composition optimized. Stable 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-based liposomes modified with cationic surfactants, namely cetyltrimetylammonium bromide and 1-methyl-3-hexadecylimidazolium bromide (IA-16), were obtained. It was shown that the use of cationic surfactants for the formation of hybrid drug carriers and varying of the surfactant/lipid molar ratios can be the key factor for obtaining the optimized particles with high efficiency of encapsulation, favorable loading efficacy and prolonged release of the drug. The most beneficial parameters in terms of stability and loading/release efficacy were obtained for IA-16/DPPC hybrid liposomes with the surfactant/lipid molar ratio of 1:50. Free BP demonstrated cytotoxicity toward M-Hela tumor cells, along with the nearly the same toxic effect toward normal Chang liver cells. Importantly, double effect occurred upon the encapsulation of BP into hybrid cationic liposomes, i.e. a sharp decrease in viability of diseased cells and increase of viability of normal cells. Therefore, liposomal BP formulation can be recommended as therapeutics with improved stability and high selective cytotoxicity toward M-Hela tumor cells at the level of commercial drug doxorubicin, in combination with much less toxicity (by 37 times) toward the normal Chang liver cell line.