Smart pH-responsive polymeric micelles for programmed oral delivery of insulin.

The development of intelligent oral drug delivery carrier aiming at efficiently bring insulin to intestine is of great significance for diabetes mellitus therapy. In the present study, a series of amphiphilic pH-sensitive block copolymer poly(methyl methacrylate-co-methacrylicacid)-b-poly(2-amino ethyl methacrylate) [P(MMA-co-MAA)-b-PAEMA] was synthesized via activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and further self-assembled into pH-responsive cationic polymeric micelles (PCPMs) for oral insulin delivery. The structure and molecular weight were confirmed by proton nuclear magnetic resonance (1H-NMR), Fourier transforming infrared spectrum (FT-IR) and gel permeation chromatography (GPC), respectively. The critical micelle concentration (CMC) values of these copolymers were measured by fluorescent probe method at pH 1.2 (8-15 μg/mL) and pH 7.4 (22-42 μg/mL), respectively, demonstrating high stability at acidic environment. A decrease in the particle size of PCPMs was associated with an increased pH at beginning, which reached around 200 nm at neutral pH, while the particle size increased obviously with pH increase, indicating the pH-sensitivity of PCPMs. The insulin was entrapped into the core of PCPMs (Ins-loaded PCPMs) with high loading efficiency via diafiltration method. The in vitro experiments show Ins-loaded PCPMs have low toxicity and exhibit pH-triggered release profile with remitted initial burst release. The results indicate that the PCPMs self-assembled from P(MMA-co-MAA)-b-PAEMA may be potential carriers for efficient oral delivery of insulin with controlled release property.