College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou, China.
Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York, United States.
Thromb Haemost. 2021 Jan;121(1):15-26. doi: 10.1055/s-0040-1714738. Epub 2020 Aug 30.
Fucosylated chondroitin sulfate (FCS) polysaccharide isolated from sea cucumber has potent anticoagulant activity. Based on its resistance to the enzymes present in vertebrates, it may serve as an anticoagulant and shows antithrombotic effects when delivered through gastro-resistant (GR) tablets. However, due to the multiple plasma targets of FCS polysaccharide in the coagulation pathway, bleeding can occur after its oral administration. In the current study, we used FCS oligomers, in particular a mixture of oligosaccharides having 6 to 18 saccharide units, as the active ingredient in GR microcapsules for oral anticoagulation. In a Caco-2 model, the FCS oligomers showed higher absorption than native FCS polysaccharides. Oral administration of FCS oligomer-GR microcapsules provided a dose-dependent, prolonged anticoagulant effect with a selective inhibition of the intrinsic coagulation pathway when compared with administration of FCS oligomers or oral administration of unformulated FCS oligomers or native FCS-GR microspheres. Continued oral administration of FCS oligomer-GR microcapsules did not result in the accumulation of oligosaccharides in the plasma. Venous thrombosis animal models demonstrated that FCS oligomers delivered via GR microcapsules produced a potent antithrombotic effect dependent on their anticoagulant properties in the plasma, while oral administration of unformulated FCS oligomers at the same dose exhibited a weaker antithrombotic effect than the formulated version. Oral administration of FCS oligomer-GR microcapsules resulted in no bleeding, while oral administration of native FCS-GR microcapsules resulted in bleeding ( < 0.05). Our present results suggest that a FCS oligomer-GR microcapsule formulation represents an effective and safe oral anticoagulant for potential clinical applications.
岩藻依聚糖硫酸酯（FCS）多糖从海参中分离出来，具有很强的抗凝活性。基于其对脊椎动物中存在的酶的抗性，它可用作抗凝剂，并且当通过耐胃（GR）片剂给药时显示出抗血栓作用。然而，由于 FCS 多糖在凝血途径中的多个血浆靶标，口服给药后可能会发生出血。在本研究中，我们使用 FCS 低聚物，特别是具有 6 至 18 个糖单位的低聚糖混合物，作为 GR 微胶囊的活性成分用于口服抗凝。在 Caco-2 模型中，FCS 低聚物的吸收高于天然 FCS 多糖。与口服 FCS 低聚物或口服未形成 FCS 低聚物或天然 FCS-GR 微球相比，口服 FCS 低聚物-GR 微胶囊给药可提供剂量依赖性，延长的抗凝作用，并选择性抑制内源性凝血途径。持续口服 FCS 低聚物-GR 微胶囊不会导致血浆中寡糖的积累。静脉血栓形成动物模型表明，通过 GR 微胶囊递送的 FCS 低聚物产生了依赖于其在血浆中抗凝特性的强大抗血栓作用，而以相同剂量口服未形成 FCS 低聚物的抗血栓作用比配方版本弱。口服 FCS 低聚物-GR 微胶囊给药不会导致出血，而口服天然 FCS-GR 微胶囊给药会导致出血（<0.05）。我们目前的结果表明，FCS 低聚物-GR 微胶囊制剂代表了一种有效的、安全的口服抗凝剂，具有潜在的临床应用前景。
