Mixing polyelectrolytes and (oppositely charged) multivalent ions is a well-known technique to produce nanoparticles (or nanogels) for various biomedical / biotechnological applications, such as drug, protein, or nucleic acid delivery. Quantitative prediction of the thermodynamics of complexation – in terms of polymer and ion properties, and solution conditions – remains challenging. We present here a counter-ion condensation model accounting for electrostatic and solvation effects, explore the influence of model parameters on the predicted extent of ion condensation, and test this model via isothermal titration calorimetry (ITC) experimental measurements of the complexation of the cationic biopolymer chitosan with the multivalent ionic nucleotides / nucleotide analogues adenosine, gemcitabine, and cytidine tri-phosphate. The model yields quantitative predictions, and the resulting parameters provide important insight into the non-electrostatic polymer-ion interactions governing nanoparticle assembly. In particular, iron incorporation within the chitosan polymer is seen to enhance binding enthalpy, but also to increase the associated entropic penalty.
