Carbonization of quercetin into nanogels: a leap in anticoagulant development

Han-Wei Chu; Wan-Jyun Chen; Ko-Hsin Liu; Ju-Yi Mao; Scott G Harroun; Binesh Unnikrishnan; Han-Jia Lin; Yunn-Hwa Ma; Huan-Tsung Chang; Chih-Ching Huang

doi:10.1039/d4tb00228h

Carbonization of quercetin into nanogels: a leap in anticoagulant development

J Mater Chem B. 2024 May 8. doi: 10.1039/d4tb00228h. Online ahead of print.

Authors

Han-Wei Chu¹, Wan-Jyun Chen², Ko-Hsin Liu³, Ju-Yi Mao², Scott G Harroun⁴, Binesh Unnikrishnan², Han-Jia Lin^{2

5}, Yunn-Hwa Ma^{3

6}, Huan-Tsung Chang^{1

7

8

9}, Chih-Ching Huang^{2

5

10}

Affiliations

¹ Department of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan.
² Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202301, Taiwan. huanging@ntou.edu.tw.
³ Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan. yhma@mail.cgu.edu.tw.
⁴ Department of Engineering Physics, Polytechnique Montréal, Montréal, Québec H3T 1J4, Canada.
⁵ Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 202301, Taiwan.
⁶ Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
⁷ Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan 33302, Taiwan.
⁸ Center for Advanced Biomaterials and Technology Innovation, Chang Gung University, Taoyuan 33302, Taiwan.
⁹ Division of Breast Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Taoyuan 33305, Taiwan.
¹⁰ School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

PMID: 38716492
DOI: 10.1039/d4tb00228h

Abstract

Quercetin, a flavonoid abundantly found in onions, fruits, and vegetables, is recognized for its pharmacological potential, especially for its anticoagulant properties that work by inhibiting thrombin and coagulation factor Xa. However, its clinical application is limited due to poor water solubility and bioavailability. To address these limitations, we engineered carbonized nanogels derived from quercetin (CNGs_Qur) using controlled pyrolysis and polymerization techniques. This led to substantial improvements in its anticoagulation efficacy, water solubility, and biocompatibility. We generated a range of CNGs_Qur by subjecting quercetin to varying pyrolytic temperatures and then assessed their anticoagulation capacities both in vitro and in vivo. Coagulation metrics, including thrombin clotting time (TCT), activated partial thromboplastin time (aPTT), and prothrombin time (PT), along with a rat tail bleeding assay, were utilized to gauge the efficacy. CNGs_Qur showed a pronounced extension of coagulation time compared to uncarbonized quercetin. Specifically, CNGs_Qur synthesized at 270 °C (CNGs_Qur270) exhibited the most significant enhancement in TCT, with a binding affinity to thrombin exceeding 400 times that of quercetin. Moreover, variants synthesized at 310 °C (CNGs_Qur310) and 290 °C (CNGs_Qur290) showed the most substantial delays in PT and aPTT, respectively. Our findings indicate that the degree of carbonization significantly influences the transformation of quercetin into various CNGs_Qur forms, each affecting distinct coagulation pathways. Additionally, both intravenous and oral administrations of CNGs_Qur were found to extend rat tail bleeding times by up to fivefold. Our studies also demonstrate that CNGs_Qur270 effectively delays and even prevents FeCl₃-induced vascular occlusion in a dose-dependent manner in mice. Thus, controlled pyrolysis offers an innovative approach for generating quercetin-derived CNGs with enhanced anticoagulation properties and water solubility, revealing the potential for synthesizing self-functional carbonized nanomaterials from other flavonoids for diverse biomedical applications.