Fenretinide (N-(4-hydroxyphenyl)retinamide (4-HPR), is a synthetic derivative of retinoic acid, which proved high antitumor activity against a wide range of cancers. Thanks to its low toxicological profile, 4-HPR has been also used as chemo preventive agent in the treatment of breast and ovarian cancer. Unfortunately, 4-HPR is endowed with poor oral absorption due to its low solubility, and variable blood concentrations for a massive hepatic first pass effect. To overcome these drawbacks, we prepared nanoparticles (NPs) made of 4-Ammoniunbutylstyrene random copolymer (P5), highly soluble in water, with the aim to increase drug apparent solubility and thus enhancing its antitumor effects. The NPs were prepared by the anti-solvent co-precipitation technique, an easy and up-scalable way of obtaining the amorphization of the drug into the polymeric matrix. The encapsulation led to an increase in drug apparent solubility of 1134 folds with a drug loading of 37%. The NPs showed a faster and extended dissolution rate, a mean hydrodynamic diameter of 249 nm, and positive Zeta potential (+41.3 mV) confirming the suitability of the formulation also for the intravenous administration. The loaded were also characterized by a chemometric-assisted Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and assayed for their antitumor activity on neuroblastoma cell lines. 4-HPR-P5 NPs proved an anti-proliferative activity with IC50 values of 1.25 and 1.93 µM on IMR-32 and SH-SY5Y neuroblastoma cells, respectively. Our data suggested that the 4-HPR-P5 formulation could represent a valid approach to increase drug apparent aqueous solubility and thus its therapeutic efficacy.