Optimal formulation of an angiogenesis inhibitor, TNP-470, for arterial injection determined by in vitro drug release and stability, and in vivo antitumor activity

TNP-470 (6-O-(N-chloroacetylcarbamoyl)fumagillol, AGM-1470) is an angiogenesis inhibitor, a new type of anticancer drug which prevents tumor neovascularization, thereby blocking the nutrient supply to tumors. In this study, we sought the optimal formulation of TNP-470 for arterial injection in order to achieve strong anticancer activity due to the tumor-selective targeting of the drug, by investigating in vitro release and stability and in vivo rabbit VX-2 antitumor activity. We found that a medium-chain triglyceride (MCT) solution containing TNP-470 facilitated the 2-week sustained release of TNP-470 in vitro and fairly good long-term stability of the agent, although it was very labile in aqueous solution. In a rabbit VX-2 tumor model, 3 weeks after inoculation on the inner side of the leg, the antitumor activities of various formulations of TNP-470 were evaluated by administration into the femoral artery feeding the tumor. Compared with Lipiodol solution or PLGA microspheres containing TNP-470, the MCT solution containing TNP-470 exerted stronger and more persistent antitumor activity accompanied by tumor regression for 3 weeks subsequently. The release sustainability of TNP-470 in the in vitro release test was suggested to be an important factor in the antitumor activity of each formulation. From these results, we conclude that the MCT solution is the most promising formulation of TNP-470 as an arterial injection for treatment of cancers.