PMID- 35499202 OWN - NLM STAT- MEDLINE DCOM- 20220610 LR - 20220610 IS - 1521-4095 (Electronic) IS - 0935-9648 (Linking) VI - 34 IP - 23 DP - 2022 Jun TI - Porous Polymers as Universal Reversal Agents for Heparin Anticoagulants through an Inclusion-Sequestration Mechanism. PG - e2200549 LID - 10.1002/adma.202200549 [doi] AB - Heparins are widely used anticoagulants for surgical procedures and extracorporeal therapies. However, all of them have bleeding risks. Protamine sulfate, the only clinically approved antidote for unfractionated heparin (UFH), has adverse effects. Moreover, protamine can only partially neutralize low-molecular-weight heparins (LMWHs) and is not effective for fondaparinux. Here, an inclusion-sequestration strategy for efficient neutralization of heparin anticoagulants by cationic porous supramolecular organic frameworks (SOFs) and porous organic polymers (POPs) is reported. Isothermal titration calorimetric and fluorescence experiments show strong binding affinities of these porous polymers toward heparins, whereas dynamic light scattering and zeta potential analysis confirm that the heparin sequences are adsorbed into the interior of the porous hosts. Activated partial thromboplastin time, anti-FXa, and thromboelastography assays indicate that their neutralization efficacies are higher than or as high as that of protamine for UFH and generally superior to protamine for LMWHs and fondaparinux, which is further confirmed by tail-transection model in mice and ex vivo aPTT or anti-FXa analysis in rats. Acute toxicity evaluations reveal that one of the SOFs displays outstanding biocompatibility. This work suggests that porous polymers can supply safe and rapid reversal of clinically used heparins, as protamine surrogates, providing an improved approach for their neutralization. CI - (c) 2022 Wiley-VCH GmbH. FAU - Lin, Furong AU - Lin F AUID- ORCID: 0000-0001-5732-6253 AD - Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China. FAU - Yu, Shang-Bo AU - Yu SB AUID- ORCID: 0000-0001-7186-367X AD - Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China. FAU - Liu, Yue-Yang AU - Liu YY AD - Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai, 200438, P. R. China. FAU - Liu, Chuan-Zhi AU - Liu CZ AD - Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai, 200438, P. R. China. FAU - Lu, Shuai AU - Lu S AD - College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518055, P. R. China. FAU - Cao, Jin AU - Cao J AD - Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China. FAU - Qi, Qiao-Yan AU - Qi QY AD - Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China. FAU - Zhou, Wei AU - Zhou W AD - Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai, 200438, P. R. China. FAU - Li, Xiaopeng AU - Li X AD - College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518055, P. R. China. FAU - Liu, Yi AU - Liu Y AD - The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA. FAU - Tian, Jia AU - Tian J AD - Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China. FAU - Li, Zhan-Ting AU - Li ZT AUID- ORCID: 0000-0003-3954-0015 AD - Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China. AD - Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai, 200438, P. R. China. LA - eng GR - 21890732/National Natural Science Foundation of China/ GR - 21890730/National Natural Science Foundation of China/ GR - 21921003/National Natural Science Foundation of China/ GR - 20ZR1408100/Natural Science Foundation of Shanghai/ GR - 2021M693278/Chinese Postdoctoral Science Foundation/ GR - 2020513/Shanghai Post-doctoral Excellence Program/ GR - 22YF1458300/Shanghai Sailing Program/ GR - Office of Science/ GR - DE-AC02-05CH11231/U.S. Department of Energy/ GR - Shanghai Blood Center/ GR - Shanghai Synchrotron Radiation Facility/ GR - GM124169-01/DOE BER Integrated Diffraction Analysis Technologies/ GR - 22YF1458300/Science and Technology Commission of Shanghai Municipality/ GR - DE-AC02-05CH11231/Lawrence Berkeley National Laboratory/ GR - 2020513/Shanghai Municipal Human Resources and Social Security Bureau/ GR - 2021M693278/Postdoctoral Research Foundation of China/ PT - Journal Article DEP - 20220502 PL - Germany TA - Adv Mater JT - Advanced materials (Deerfield Beach, Fla.) JID - 9885358 RN - 0 (Anticoagulants) RN - 0 (Polymers) RN - 0 (Protamines) RN - 9005-49-6 (Heparin) RN - J177FOW5JL (Fondaparinux) SB - IM MH - Animals MH - *Anticoagulants/chemistry/pharmacology/therapeutic use MH - Fondaparinux MH - *Heparin/chemistry/pharmacology MH - Mice MH - Polymers MH - Porosity MH - Protamines/pharmacology MH - Rats OTO - NOTNLM OT - antidotes OT - heparin anticoagulants OT - inclusion-based neutralization OT - porous organic polymers OT - supramolecular organic frameworks EDAT- 2022/05/03 06:00 MHDA- 2022/06/11 06:00 CRDT- 2022/05/02 07:30 PHST- 2022/03/22 00:00 [revised] PHST- 2022/01/18 00:00 [received] PHST- 2022/05/03 06:00 [pubmed] PHST- 2022/06/11 06:00 [medline] PHST- 2022/05/02 07:30 [entrez] AID - 10.1002/adma.202200549 [doi] PST - ppublish SO - Adv Mater. 2022 Jun;34(23):e2200549. doi: 10.1002/adma.202200549. Epub 2022 May 2.