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Controlled drug binding and release stand among top requirements postulated for targeted drug delivery systems of the new generations. "Smart" polymers and gels are highly suitable for the controlled delivery due to their structural sensitivity to minor environmental variations. The aim of this work was to study thermoresponsive polyanionic and polycationic hydrogels of N-isopropylacrylamide copolymers with acrylic acid and N-aminopropylmethacrylamide in terms of their interaction with two widely used drugs, propranolol and ibuprofen. Binding energetics of these drugs by the gels in swollen and collapsed state was estimated by means of high-sensitivity differential scanning calorimetry. Thermodynamic parameters of the gel collapse (transition temperature, enthalpy, heat capacity increment, and width) were determined as a dependence of the drug concentrations. From these data the excess free energy of collapse was calculated as a function of drug concentration. Deconvolution of this function resulted in the evaluation of binding parameters and contributions from interactions of various types to the free energy of binding. The binding mechanism of both drugs to the swollen and collapsed gels was elucidated. Its main features are the cooperative character of the drug binding by the collapsed gel and the predominant role of the hydrophobicity of drugs in their affinity for the swollen gel.

Ternary interpolyelectrolyte complexes of insulin with biodegradable synthetic cationic polymer, poly(methylaminophosphazene) hydrochloride (PMAP), and dextran sulfate (DS) were investigated by means of turbidimetry, dynamic light scattering, phase analysis, and high-sensitivity differential scanning calorimetry. Formation of ternary insoluble stoichiometric Insulin-PMAP-DS complexes was detected under conditions imitating the human gastric environment (pH 2, 0.15 M NaCl). A complete immobilization of insulin in the complexes was observed in a wide range of the reaction mixture compositions. The ternary complexes were shown to dissolve and dissociate under conditions imitating the human intestinal environment (pH 8.3, 0.15 M NaCl). The products of the complex dissociation were free insulin and soluble binary Insulin-PMAP complexes. The conformational stability of insulin in the soluble complexes of various compositions was investigated by high-sensitivity differential scanning calorimetry. The dependence of the excess denaturation free energy of insulin in these complexes on the PMAP content was obtained. The binding constants of the folded and unfolded forms of insulin to the PMAP polycation were estimated. Proteolysis of insulin involved in the insoluble ternary complexes by pepsin was investigated under physiological conditions. It was found that the complexes ensure an almost 100% protection of insulin against proteolytic degradation. The obtained results provide a perspective basis for development of oral insulin preparations.

The interaction of DNA with a synthetic biocompatible and biodegradable cationic polymer, poly(methylaminophosphazene) hydrochloride (PMAP·HCl), was investigated by high-sensitivity differential scanning calorimetry under conditions of strong and weak electrostatic interactions of the macroions. Thermodynamic parameters of the DNA double-helix melting were determined as a function of pH and the PMAP·HCl/DNA weight ratio. PMAP·HCL was shown to reveal two functions with respect to DNA: the polyelectrolyte function and the donor-acceptor one. The first function stabilizes the helical conformation of DNA, and the second one destabilizes it. The stabilizing effect of PMAP·HCl is of entropic origin, related to a displacement of mobile counterions from the DNA's nearest surroundings by the poly(methylaminophosphazene) charged groups. The donor-acceptor function of poly(methylaminophosphazene) dominates when its electrostatic interaction with DNA is either saturated (in the complex coacervate phase at high poly(methylaminophosphazene) concentrations) or completely suppressed (in a salt medium when the polycation carries a small charge). Under these conditions, poly(methylaminophosphazene) destabilizes DNA. It preferentially binds to the DNA coil form likely via the formation of multiple labile hydrogen bonds with the donor-acceptor groups of DNA.