Polycationic calix[8]arene receptors grafted onto polymeric matrix: smart material for heparin neutralization

Abstract

Heparin is widely prescribed as an anticoagulant medicine and is beneficial to millions of patients. However, the use of heparin in open-heart surgery, where it enables a continuous flow of blood throughout the process, is still problematic. Its anticlotting properties are crucial for a successful operation, but after surgery the patient's blood needs to return normal and acquire its former ability to coagulate. If this process fails, the outcome may prove fatal. Currently, protamine sulfate is used to neutralize heparin after open-heart surgery. However, protamine itself causes allergic reactions and other side effects and is sometimes fatal. For this reason, the finding of new heparin antagonists or much safer methods for heparin removal from blood is currently of great interest. Recently we have reported on the synthesis of calix[8]arene polycations that have shown an exceptional neutralization power towards heparin both in physiological solution and in blood. In this work, we have studied the grafting of these calix[8]arene derivatives onto a polymeric matrix with the aim to obtain a new polymeric material appropriate for the design and realization of filters or membranes able to effectively remove heparin from blood. In this way, also the side effects connected to systemic administration of heparin antagonists are avoided. Besides the synthesis, preliminary results on the neutralization capacity towards heparin, both in physiological solution and in blood, are reported.

Targeting heparin and heparan sulfate protein interactions

“…91 A subsequent study showed these molecules, immobilized onto polymer matrix filters, were able to remove heparin from blood, therefore minimizing side effects associated with administration of heparin reversal agents. 92 …”

Modified Diatomaceous Earth in Heparin Recovery from Porcine Intestinal Mucosa

“…Typically, a positively charged polymer or biomolecule binds with the negative sulfate and carboxylate sites of heparin via electrostatic interactions (Scheme 1) [36][37][38][39]. The extraction of heparin using this method has been widely utilized in various applications [35,37,40,41], such as an FDA-approved antidote for heparin to substitute protamine, for the production of label-free sensors for heparin monitoring on molecularly imprinted resin, and to regulate bacterial activity [38,39,[42][43][44][45][46]. Therefore, in this research, we have functionalized DE with quaternary ammonium functional groups containing side chains (Scheme 2) and utilized them for heparin extraction from the porcine intestinal mucosa.…”

One-Pot Synthesis of Cross-Linked Polymer Networks as a Hydrophilic Super-Adsorbent for Efficient Recovery of Heparin

“…In this method, typically a cationic biomolecule or polymer is used to bind heparin via electrostatic interactions of the negative sites of heparin molecule (Scheme ) with the positive charges of the adsorbent. This methodology has been used extensively in different applications and technologies associated with the purification of heparin, − the synthesis of heparin binders as an antidote for heparin to substitute protamine (the only clinically and Food and Drug Administration (FDA)) approved antidote for heparin), − for heparin monitoring and removal, the fabrication of label-free sensors for heparin based on molecularly imprinted resin, and for the control of bacterial activity . For all of these applications, it is crucial to prepare pure heparin, which is free of impurities to engineer the best performance.…”