BACKGROUND: Drug delivery systems (DDS) were designed using insulin as model drug and poly (lactic-co-glycolic) copolymers (PLGA) as polymeric matrix. The carriers were synthesized by direct self-assembly of the insulin and the polyester under mild conditions. RESULTS: The kind and level of association between the protein and the polymer were studied using computational methods (combined MM2/PM3) and spectroscopic tools (Fourier transform infrared (FTIR), energy dispersive X-ray (EDX) and X-ray fluorescence spectroscopy (XFS)). The effect of the number average molecular weight (M-n) of the copolymer on the association efficiency (AE) drug-polymer as well as on the release profile has been explored. Mathematical models were used to predict the insulin release kinetic and mechanism. CONCLUSIONS: Satisfactory protein/PLGA association efficiencies (between 77 and 99%) were registered depending on the Mn of the PLGA. Hydrophobic and hydrophilic interactions were detected between the protein and the polymeric network by computational analysis. In vitro release studies demonstrated that copolyesters of about 8600 and 1500 Da were suitable for the gradual release of insulin while PLGA oligomers of average molecular weight between 700 and 800 Da were unsuitable as DDS. The insulin release kinetics fits well with the Korsmeyer model, following the anomalous transport mechanism. (C) 2010 Society of Chemical Industry