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Thromb Haemost 2021; 121(01): 015-026
DOI: 10.1055/s-0040-1714738
Coagulation and Fibrinolysis

Oral Administration of Fucosylated Chondroitin Sulfate Oligomers in Gastro-Resistant Microcapsules Exhibits a Safe Antithrombotic Activity

Lufeng Yan
1   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
2   Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York, United States
,
Mengshan Zhu
3   Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Uji, Japan
,
Danli Wang
1   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
,
Wenyang Tao
1   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
,
Donghong Liu
1   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
,
Fuming Zhang
2   Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York, United States
,
Robert J. Linhardt
2   Center for Biotechnology and Interdisciplinary Studies, Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York, United States
,
Xingqian Ye
1   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
,
Shiguo Chen
1   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
› Author Affiliations Funding The authors are grateful to the National Key R&D Program of China (2018YFD0901101); the National Natural Science Foundation of China (31871815), and 2018 Zhejiang University Academic Award (11513022) for Outstanding Doctoral Candidates.
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Abstract

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 subcutaneous 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 (p < 0.05). Our present results suggest that a FCS oligomer-GR microcapsule formulation represents an effective and safe oral anticoagulant for potential clinical applications.

Keywords

fucosylated chondroitin sulfate oligomers - gastro-resistant microcapsules - oral administration - anticoagulant and antithrombotic activities - bleeding tendency

Authors' Contributions

L.Y., M.Z., D.W., and W.T. performed the experiments; L.Y., X.Y., and F.Z. analyzed the results; and L.Y., R.J.L., and S.C. wrote the manuscript.


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Publication History

Received: 18 April 2020

Accepted: 25 July 2020

Article published online:
30 August 2020

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