Second generation biodegradable poly(L-lysine) dendrigrafts functionalized with 12-48 arginine end-groups interact, at physiological pH, with insulin affording dendrigraft/insulin complexes as established by dynamic light scattering, zeta-potential, circular dichroism and isothermal titration calorimetry. Binding occurs in two steps; at low dendrigraft/insulin molar ratios (<= 0.07) interaction is accompanied with the endothermic dissociation of insulin dimers, while at higher molar ratios, complexation of insulin monomers with dendrigraft derivatives occurs exothermically. High levels of insulin complexation efficiencies (>99%) were determined for all derivatives. Stabilization of complexed insulin against enzymatic degradation by trypsin and alpha-chymotrypsin is observed especially for the highly arginine end-functionalized dendrigrafts. Insulin release rates in simulated intestinal fluid are being controlled by the number of arginine end-groups and released insulin retains its conformation. (C) 2010 Elsevier Inc. All rights reserved.