This study shows the potential of chitosan (CH) nanoparticles as both an oral and IV drug delivery system using the anticancer drug cladribine as a model drug. Smooth, spherical nanoparticles were prepared by the ionotropic gelation of CH with sodium tripolyphosphate. Nanoparticle size depended on degree of hydration, drug loading, and crosslinking conditions, with the smallest nanoparticles in the size range of 212 +/- 51 nm. Cladribine was entrapped in the CH matrix with an entrapment efficiency of up to 62%, depending on the initial loading. The release of cladribine followed a near-Fickian diffusion rate over the first several hours and then reached a plateau. A second release phase began after 3040 h of incubation in the release medium, and proceeded until approximate to 100 h. Loaded CH nanoparticles that were crosslinked with genipin showed a delayed release profile, with only 40% of loaded drug being released after 100 h. (c) 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013