5-Fluorouracil(5-FU)-loaded chitosan microgels for oral and topical chemotherapy were prepared applying a superhydrophobic surface-based encapsulation technology. Drug-loaded chitosan dispersions were cross-linked and then coated with drug-free chitosan or pectin layers at the solid-air interface in a highly
efficient and environment-friendly way. The size of the microgels (with diameters of ca.280 and 557um for the chitosan seeds and pectin-coated microgels respectively) was the lowest obtained until now using similar biomimetic methodologies. The microgels were characterized regarding 5-FU release pro-files in vitro in aqueous media covering the pH range of the gastrointestinal tract, and cytotoxicity against two cancer cell lines sensitive to 5-FU. Owing to their control of 5-FU release in acidic medium, calcium pectinate-coated microgels can be considered as suitable for oral administration. Growth inhibition of cancer cells by 5-FU was greater when incorporated to chitosan microgels; these being potentially useful for treatment of skin and colorectal tumors.