Hydrogen bonding and electrostatic interaction contributions to the interaction of a cationic drug with polyaspartic acid

Purpose. To determine the mechanism and identify forces of interaction between polyaspartic acid and diminazene (a model drug). Such knowledge is essential for the design of polymeric drug delivery systems that are based on molecular self-assembly into complexes or micellar type systems. Methods. Complex formation was studied by isothermal titration microcalorimetry and the McGhee von Hippel model was applied to obtain K-obs, Delta H-obs, and n(obs). The calorimetry data were compared with both an optical density study and the amount of free/complexed drug. Results. The diminazene-polyaspartic acid interaction is enthalpically driven, whereby one diminazene molecule interacts with two monomers of polyaspartic acid. The dependence of K-obs on salt concentration reveals a contribution of electrostatic interactions. However, applying Manning's counter ion condensation theory shows that the major driving force for the complex formation is hydrogen bonding, with interfacial water molecules remaining buried within the complex. The modelling of the pH dependence of Kobs and Delta H-obs demonstrates that the ionization of carboxylic groups of polyaspartic acid is a prerequisite for the interaction. Conclusions. Complex formation between diminazene and polyaspartic acid is driven by both electrostatic interactions and hydrogen bonding, with the latter being the dominating force. Although electrostatic interactions are not the major driving force, ionization of the drug and polymer is essential for complex formation.