In the present work, a method is described to prepare polymeric colloidal nanospheres, consisting of poly(ethyl-2-cyanoacrylate) (PE-2-CA) or poly(butylcyanoacrylate) (PBCA), loaded with the anticancer drug ftorafur. The method is based on the anionic polymerization procedure, often used in the synthesis of poly(alkylcyanoacrylate) nanospheres for drug delivery. A detailed investigation of the capabilities of both polymeric nanoparticles to load this drug is shown. The effect of synthesis residuals and degradation products on the absorbance of supernatants was considered in the loading and release measurement methodologies, because of their potential perturbing influence on the determination of ftorafur concentration in solution. We found the existence of two mechanisms of drug incorporation: absorption or entrapment in the polymeric network, and surface adsorption, detectable by means of zeta potential and spectrophotometric measurements. Among the factors affecting the drug incorporation to the polymer network, the type of polymer, the pH and the drug concentration are the main determining ones. Moreover, the acidity of the medium needs to be controlled in order to avoid the formation of macroaggregates of solids. The optimum loading conditions were used to perform ftorafur release evaluations from polymeric particles, and the influence of the mechanism of drug incorporation, the amount of drug loaded, and the type of polymer on the drug release were studied.