PURPOSE Develop and characterize a micellar formulations of N-{[(2-hydroxy-5-nitrophenyl)amino]carbonothioyl}-3,5-dimethylbenzamide (DM-PIT-1) – a new small molecule non-lipid antagonist of phopshotidylinositol-3.4.5-triphopshate and inhibitor of the PI3-kinase pathway. METHODS Micelle-forming PEG2000-PE was used to solubilize DM-PIT-1. To improve the specificity of the micellar DM-PIT-1, cancer-targeting anti-nucleosomal mAb2C5 antibodies as well as Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) were attached to the surface of polymeric micelles. RESULTS DM-PIT-1 was effectively incorporated (>70%) into 14–16 nm micelles, which had a negative surface zeta potential of 4–5 mV. Micellar DM-PIT-1 demonstrated high in vitro cytotoxicity against various cancer cells. An improved potency of the dual-activity DM-PIT-1/TRAIL combination nanoparticles in inducing death of TRAIL-resistant cancer cells was shown. Efficacy of the TRAIL therapy was enhanced by combining it with the 2C5 antibody cancer-targeted micellar form of DM-PIT-1. CONCLUSIONS DM-PIT-1 micellar preparations can be used for targeted combination therapy against TRAIL-resistant cancers.