Interaction between the Polyelectrolytes Unfractionated Heparin and Universal Heparin Reversal Agents

The interaction of unfractionated heparin (UFH) with universal heparin reversal agent 7 (UHRA-7) is investigated. UHRA-7 is composed of a hyperbranched polyglycerol core onto which an array of methylated tris(2-aminoethylamine) (Me-TREN) charged groups is grafted, which in turn are shielded with a layer of small chain poly(ethylene glycol) methyl ether (mPEG) chains. This system has previously been shown to be biocompatible and to be effective at neutralizing heparin. The binding constant K_b was determined from isothermal titration calorimetry experiments, at temperatures ranging from 278 to 323 K and salt concentrations ranging from 0.06 to 0.20 M NaCl. The data were analyzed in terms of a number of different theoretical models to determine the contribution of counterion release and water release to driving the interaction between UFH and UHRA-7. With the support of NMR and molecular dynamics simulation data, a model of the interaction between UFH and UHRA-7 is proposed. The binding of heparin and universal heparin reversal agent 7 is mainly due to charge-charge interactions between the negatively charged units on UFH with positively charged Me-TREN and mPEG chains.