Properties of Heparinoids Premixed with Tumor-Derived Extracellular Vesicles

Tumor-derived exosomes are bound and internalized to organ-specific cells, affecting metastasis. Heparan sulfate proteoglycans mediate the interaction between cells and exosomes. Exosome transfer to the recipient cell can be competitively blocked by heparinoids, because heparin is structurally similar to heparan sulfate. It is hypothesized that there may be structural requirements of heparinoids to attenuate the cellular uptake and metastatic activity of tumor-derived exosomes. Here, we compared the properties of unfractionated heparin (UFH), glycol-split UFH, low-molecular-weight heparin (LMWH), glycol-split LMWH, and ultra-LMWH premixed with A549-derived exosomes. Uptake of A549-derived exosomes (0.1 mg/mL) into BEAS-2B cells was significantly blocked by 0.4 mg/mL of heparinoids. Heparinoids attenuated migration of BEAS-2B cells stimulated by A549-derived exosomes. Glycol-split LMWH with no antifactor Xa activity exhibited the strongest antimigratory effects than other heparinoids. Thus, heparinoids with proper molecular weight and structure can inhibit tumor-derived exosomes, not proportionally to the anticoagulant activity.