Among the different approaches to achieve colon-selective drug delivery, the use of polymers, specifically biodegraded by colonic bacteria, holds great promise. In this work a new system which combines specific biodegradability and pH-dependent release is presented. The system consists of chitosan (CS) microcores entrapped within acrylic microspheres. Sodium diclofenac (SD), used as a model drug, was efficiently entrapped within CS microcores using spray-drying and then microencapsulated into Eudragit L-100 and Eudragit S-100 using an oil-in-oil solvent evaporation method. The size of the CS microcores was small (1.8-2.9 microns) and they were encapsulated within Eudragit microspheres (size between 152 and 233 microns) forming a multireservoir system. Even though CS dissolves very fast in acidic media, at pH 7.4, SD release from CS microcores was delayed, the release rate being adjustable (50% dissolved within 30-120 min) by changing the CS molecular weight (MW) or the type of CS salt. Furthermore, by coating the CS microcores with Eudragit, perfect pH-dependent release profiles were attained. No release was observed at acidic pHs, however, when reaching the Eudragit pH solubility, a continuous release for a variable time (8-12 h) was achieved. A combined mechanism of release is proposed, which considers the dissolution of the Eudragit coating, the swelling of the CS microcores and the dissolution of SD and its further diffusion through the CS gel cores. In addition, infrared (IR) spectra revealed that there was an ionic interaction between the amine groups of CS and the carboxyl groups of Eudragit, which provided the system with a new element for controlling the release. In conclusion, this work presents new approaches for the modification of CS as well as a new system with a great potential for colonic drug delivery.