A Novel Series of Synthetic Heparin‐Mimetics–Itaconic Acid‐Containing Copolymers for Targeting Tumor Cell Coagulability and Metastasis

Thromboses are potentially fatal complication in malignant tumor diseases. Today, oral anticoagulants are considered equivalent alternatives to low molecular weight heparin (LMWH) in guideline-based treatments of cancer-associated thromboses. Nevertheless, debates on potential antitumorigenic heparin activities beyond anticoagulation are still highly relevant. However, disclosure of heparin targeted activities is complicated by the heterogeneous structure of this glycosaminoglycan of natural origin. Therefore, synthetic polymers appear promising as heparin mimetics to interfere with different steps in tumor metastatic spread. Here, the synthesis of noncarbohydrate copolymers of itaconic acid is described with either potassium-3-sulfopropylmethacrylate (SPMA), sodium 4-styrenesulfonate (SS), or 2-acrylamido-2-methyl-1-propanesulfonate (AMPS) via reversible addition-fragmentation-chain-transfer (RAFT) polymerization. The copolymers, characterized by GPC, display high efficiencies to inhibit heparanase enzymatic activity, exceeding the potency of the clinical candidate PG545. The SS-copolymers (poly(SS-co-IA)) outperform the other copolymers and LMWH in blocking tumor cell-induced platelet activation (TCIPA), thus platelet degranulation or aggregation as key issues in metastasis by reducing thrombin formation. The cytotoxicity of poly(SS-co-IA) is very low. Notably, poly(SS-co-IA) copolymers displayed a thousand-fold lower binding affinity to platelet factor-4 (PF4) than unfractionated heparin (UFH), suggesting a lower risk for HIT II susceptibility. The indicated polymers represent promising heparin mimetics with superior activities in oncology for metastatic control.