Improvement of the antitumor activity of poorly soluble sapacitabine (CS-682) by using Soluplus® as a surfactant

Sapacitabine (CS-682 or CYC682; 1-[2-C-cyano-2-deoxy-β-D-arabino-pentfuranosyl]N4-palmitoyl cytosine), a novel antitumor 2'-deoxycytidine analogue, shows a marked reduction in the water solubility because of the fatty acid side chain on the N4 group of the cytosine moiety. Poor water solubility is one of the important reasons why sapacitabine does not exert maximum antitumor activity. Therefore, we attempted to improve the water solubility of sapacitabine using a novel surfactant, Soluplus®, which consisted of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In this study, we examined whether Soluplus® increased the water solubility and an antitumor activity of sapacitabine. The cytotoxicity of Soluplus® alone was lower than that of Tween 80 and Kolliphor® D-α-tocopherylpolyethylene glycol 1000 succinate (TPGS). The water solubility and the chemosensitivity of sapacitabine against several tumor cell lines to sapacitabine markedly increased upon using Soluplus®. In addition, the potential of Soluplus® including sapacitabine in increasing the antitumor activity was compared with sapacitabine alone in vivo. Although the total dose in the experimental period was considerably lower than the effective dose of sapacitabine alone, the life span of mice treated with sapacitabine containing 40 mg/mL Soluplus® increased by 150%. If Soluplus® was used as the solubilizing agent in clinical trials of sapacitabine, a low administration dose was appeared to require, and thus side effects might be prevented.