Synthesis, Biological Evaluation and Reversal of Sulfonated Di‐ and Triblock Copolymers as Novel Parenteral Anticoagulants

Despite targeting different coagulation cascade sites, all Food and Drug Administration‐approved anticoagulants present an elevated risk of bleeding, including potentially life‐threatening intracranial hemorrhage. Existing studies have not thoroughly investigated the efficacy and safety of sulfonate polymers in animal models and fully elucidate the precise mechanisms by which these polymers act. The activity and safety of sulfonated di‐ and triblock copolymers containing poly(sodium styrenesulfonate) (PSSS), poly(sodium 2‐acrylamido‐2‐methylpropanesulfonate) (PAMPS), poly(ethylene glycol) (PEG), poly(sodium methacrylate) (PMAAS), poly(acrylic acid) (PAA), and poly(sodium 11‐acrylamidoundecanoate) (PAaU) blocks are synthesized and assessed. PSSS‐based copolymers exhibit greater anticoagulant activity than PAMPS‐based ones. Their activity is mainly affected by the total concentration of sulfonate groups and molecular weight. PEG‐containing copolymers demonstrate a better safety profile than PAA‐containing ones. The selected copolymer PEG47‐PSSS32 exhibits potent anticoagulant activity in rodents after subcutaneous and intravenous administration. Heparin Binding Copolymer (HBC) completely reverses the anticoagulant activity of polymer in rat and human plasma. No interaction with platelets is observed. Selected copolymer targets mainly factor XII and fibrinogen, and to a lesser extent factors X, IX, VIII, and II, suggesting potential application in blood‐contacting biomaterials for anticoagulation purposes. Further studies are needed to explore its therapeutic applications fully. This study evaluates sulfonate‐based copolymers for anticoagulant therapy. It highlights the efficacy and safety of poly(ethylene glycol)47‐poly(sodium styrenesulfonate)32 which demonstrates high anticoagulant activity with a favorable safety profile. This copolymer shows the reversible anticoagulant effect, mainly targets factor XII and fibrinogen, and has the potential for both intravenous and subcutaneous administration. This novel copolymer offers promise in thrombotic disorder treatment.