Polycationic γ-Cyclodextrin with Amino Side Chains for a Highly Efficient Anti-Heparin Coagulant.

Abstract

Multicharged cyclodextrins have attracted significant attention because of their applications in biology and pharmaceuticals. This study reports an aminoethoxy-phenyl-pyridinium-modified γ-cyclodextrin (PyA-γ-CD) as a highly efficient coagulant for heparin through multivalent interactions. The UV titration experiment is performed to obtain apparent binding constants (K_obs) between PyA-γ-CD and heparin as high as 9.85 × 10⁶ M^-1. The activated partial thromboplastin time (aPTT) experiment in porcine plasma indicates that PyA-γ-CD not only exhibits nearly complete neutralization activity for unfractionated heparin (UFH), but more importantly, it also effectively neutralizes three LMWHs (dalteparin (Dalte), enoxaparin (Enoxa), and nadroparin (Nadro)) with a broader therapeutic window compared to protamine. The top neutralization activity of PyA-γ-CD for UFH, Dalte, Enoxa, and Nadro is 94%, 91%, 99%, and 85%, respectively. Interestingly, in vivo assays in mice further suggest that PyA-γ-CD significantly reverses the severe bleeding caused by heparin overdose while exhibiting remarkable biocompatibility. Therefore, PyA-γ-CD holds significant potential as a heparin antidote for clinical applications.