Drug-delivery carriers must endure harsh pH conditions in the gastrointestinal tract and still maintain a high drug loading (DL) for oral therapeutic drugs to be effectively delivered to the colon area. In this research, a pH-sensitive drug-delivery system with an enhanced DL was developed by the coating of 5-fluorouracil (5-FU)-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) with Eudragit S100 with an oil-in-oil solvent evaporation technique. The enhanced DL and encapsulation efficiency were achieved by the optimization of the fabrication parameters and by the use of particles of a proper size. A DL of 5.8% was obtained by a moderate initial drug feeding, a high volume ratio of the outer water phase to the organic phase, and by the adjustment of the pH value of the outer aqueous phase to the isoelectric point of 5-FU. An in vitro drug-dissolution test showed that the coating of the Eudragit S100 microspheres could effectively prevent drugs from being released in an environment with a pH lower than 7. The PLGA NPs showed an initial burst release followed by a slow and sustained release over an extended period of over 120 h at pH value of 7.4. Therefore, the prepared systems have great potential for practical applications in the treatment of colorectal cancer. (c) 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013