Stimuli-sensitive statistical terpolymers of N-isopropylacrylamide (NIPAAm) (temperature-sensitive), butyl methacrylate (BMA) and acrylic acid (AA) (pH-sensitive) of various molecular weight (MW) with NIPAAm/BMA/AA feed mol ratio of 85/5/10 were used to modulate release of insulin, a model protein drug, from pH/thermosensitive polymeric beads. Protein drug loading from an aqueous medium into the beads was achieved by preparing a 7 or 10% (w/v) polymer solution with 0.2% (w/v) insulin at low pH and below the lower critical solution temperature (LCST) of the polymer (pH 2.0 and 4 degrees C), and then dropping the solution into an oil bath above the LCST of the solution (35 degrees C). This loading procedure maintained protein stability while achieving high loading efficiency, between 90 and 95% in the beads. Insulin-release studies from beads prepared from terpolymers of the same composition but increasing MW were performed at pH 2.0 and 7.4, at 37 degrees C. It was observed that there was negligible loss of insulin at pH 2.0 from the beads, indicating no burst effect. At pH 7.4, insulin release was seen from all the beads and the release rate was a function of the MW of the polymer. The low MW polymeric beads eroded, dissolved and released most of the insulin within 2 h at pH 7.4 and 37 degrees C, the intermediate MW polymeric beads swelled slightly, dissolved and released most of the insulin within 4 h, whereas the high MW polymeric beads swelled slowly and gradually released the loaded insulin over a period of 8 h. Thus, the release of protein from the low MW polymeric beads is controlled by the rate of dissolution of the polymer, whereas the release from the high MW polymeric beads is controlled by swelling of the beads and drug diffusion. Studies using fluorescein-labeled insulin revealed that insulin was uniformly distributed in the beads regardless of polymer MW. The loaded and released insulin were fully bioactive. Based on the described results, the low MW polymeric beads may be used for immediate delivery of protein drugs in the duodenum, the intermediate MW polymeric beads may be used for lower small intestine targeting, while the high MW polymeric beads may be used to target protein drugs predominantly to the colon.