Fenretinide (N-(4-hydroxyphenyl)-retinamide, 4-HPR) is a synthetic retinoid with fewer adverse effects than natural retinoids, effective against ovarian, prostate, small cell lung, brain, neuroectodermal-derived tumors. Clinical responses in adult and pediatric patients are often partial, revealing a limited activity of 4-HPR against existing disease. The underlying causes of this slight therapeutic efficacy consist in 4-HPR poor water solubility, low bioavailability and high first-pass hepatic effect. To overcome these drawbacks, nanomedicine could represent a valid alternative. We have already developed nanostructured drug delivery systems able to encapsulate 4-HPR. Indeed, polymeric micelles made of branched polyethylene glycol or amphiphilic dextrin have been prepared and investigated for their effectiveness both in vitro and in vivo. We have also designed a liposomal 4-HPR endowed with an active targeting moiety. Recently, we have focused our attention on a more physiological and not immunogenic drug delivery system. With this in mind 4-HPR-loaded mesenchymal stem cells-derived extracellular vesicles have been prepared. The drug amount encapsulated into the vesicles was determined by HPLC. Briefly, prior 4-HPR quantification an extraction procedure was optimized and, to estimate the analyte recovery an internal standard was employed. Since for this purpose, N-(4-ethoxyphenyl)-retinamide (4-EPR) has been reported, we developed a new operator-friendly one-step procedure to synthetize highly pure 4-EPR in quantitative yield. Studies aim to establish the best drug loading conditions are ongoing.