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

Area of Science:

• Biochemistry
• Pharmaceutical Chemistry
• Pharmacology

Background:

• Multicharged cyclodextrins are crucial in pharmaceutical and biological applications.
• Heparin and its derivatives are widely used anticoagulants, necessitating effective reversal agents.
• Current heparin antidotes, like protamine, have limitations in their therapeutic window and specificity.

Purpose of the Study:

• To develop and evaluate a novel multivalent coagulant for heparin neutralization.
• To characterize the binding affinity of the new agent with heparin.
• To assess the efficacy and safety of the agent as a heparin antidote in vitro and in vivo.

Main Methods:

• Synthesis of aminoethoxy-phenyl-pyridinium-modified γ-cyclodextrin (PyA-γ-CD).
• UV titration to determine binding constants between PyA-γ-CD and heparin.
• Activated partial thromboplastin time (aPTT) assays in porcine plasma to evaluate neutralization of unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs).
• In vivo bleeding reversal studies in mice.

Main Results:

• PyA-γ-CD demonstrated strong binding to heparin with an apparent binding constant (K_obs) of 9.85 × 10⁶ M^-1.
• PyA-γ-CD achieved high neutralization activity for UFH (94%), dalteparin (91%), enoxaparin (99%), and nadroparin (85%).
• The agent exhibited a broader therapeutic window compared to protamine and effectively reversed heparin-induced bleeding in vivo with good biocompatibility.

Conclusions:

• PyA-γ-CD is a highly efficient coagulant for various forms of heparin.
• The compound offers effective heparin neutralization with a favorable safety profile.
• PyA-γ-CD presents significant potential as a clinical antidote for heparin overdose.