Frontiers in Bioengineering and Biotechnology
·
2020
·
IF 3.644
Wu Haitao,Su Manlin,Jin Hui,Li Xinyu,Wang Puyu,Chen Jingxiao,Chen Jinghua
In this paper, we fabricated rutin-loaded silver nanoparticles (Rutin@AgNPs) as the nano-anticoagulant with antithrombotic function. The serum stability, anticoagulation activity, and bleeding risk of Rutin@AgNPs were evaluated. The results showed Rutin@AgNPs had good serum stability, hemocompatibility, and cytocompatibility. The anticoagulation activity of rutin was maintained, and its stability and aqueous solubility were improved. The Rutin@AgNPs could provide a sustained release to prolong the half-life of rutin. The results of the coagulation parameter assay and thrombus formation test in mice model showed that the activated partial thromboplastin time and prothrombin time were prolonged, and Rutin@AgNPs inhibited the thrombosis in the 48 h period. Moreover, the limited bleeding time indicated that the Rutin@AgNPs significantly minimized the hemorrhage risk of rutin. This Rutin@AgNPs is a potential anticoagulant for antithrombotic therapy.
研究领域:
纳米医学
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药理学
·
生物材料科学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Ning Yu,Rui Fang,Zhao Ding,Xi Xu,Jianfa Zhang
Heparins are sulfated polysaccharides with a heterogeneous mixture derived from animal tissues, subject to supply limitations and the risk of animal virus residues. Patients using heparin also face the risks of spontaneous bleeding and thrombocytopenia. Here we reported an efficient riclinoctaose-based approach for rapid chemical synthesis of a structurally defined heparin-like anticoagulant sulfated octasaccharide (SRO). We used sulfur trioxide-pyridine, sulfur trioxide-trimethylamine, and sulfur trioxide-triethylamine complexes as solvents for one-pot O-sulfation and determined the optimal conditions for synthesizing SRO. Sulfur trioxide-trimethylamine provided reasonable control over the degree of substitution between 1.85 and 1.88, revealing a single molecule with a theoretical molecular weight of 2952.96 g/mol. The structural features of the SRO were carried out by Fourier transform infrared spectroscopy and one- and two- dimensional 1 H and 13 C NMR analysis, revealing sulfation repeatedly present at the fixed positions of C-6/C-2/C-3 and reducing terminals. The anticoagulant activity of SRO was demonstrated by efficiently blocking coagulation in the blood of mice and human. SRO dose-dependently decreased ferric chloride-induced experimental thrombosis in mice. Like heparin, SRO specifically inhibits coagulation factor Xa, but significantly reduces the risk of bleeding compared to heparin. Therefore, we named it octaparin. These results support that octaparin is expected to replace animal-sourced heparin.
研究领域:
药理学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2025
·
IF 4.9
Wentao Ma,Shiwen Gong,Xianbiao He,Die Hu,Bo Cheng,Jing Yang,Binbin Li,Xinyu Wang
Thrombosis is a critical marker of cardiovascular diseases such as stroke and myocardial infarction. Timely diagnosis and dissolution of thrombi can significantly reduce patient mortality risk. Theranostic nanoparticles with targeting capabilities offer a promising solution to this issue. We developed fucoidan-modified PLGA nanoparticles loaded with indocyanine green (ICG) and lumbrokinase (LK) (FCP-ICG@LK NPs) to achieve integrated diagnosis and treatment of thrombotic diseases while minimizing hemorrhagic risks. Targeting experiments demonstrated the affinity of fucoidan for P-selectin. In a mouse model of carotid thrombosis, FCP-ICG@LK NPs demonstrated excellent diagnostic and monitoring capabilities while effectively dissolving thrombi under near-infrared light. Compared with free LK, FCP-ICG@LK NPs showed better thrombolysis effects at the same dose. Furthermore, bleeding risk assessment experiments indicated that FCP-ICG@LK NPs do not induce hemorrhagic risks. FCP-ICG@LK NPs showed no significant cytotoxicity or hemolysis. These results indicate that fucoidan-modified PLGA drug-loaded nanoparticles are a promising thrombus-targeted theranostic agent.
研究领域:
生物医学工程
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药剂学
·
心血管疾病研究
✓ 已验证
产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2023
·
IF 4.6
Boyu Fang,Shasha Jin,Wandi Du,Weimin Cai
Background Recent studies have reported a higher risk of bleeding among patients that are co-administrated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and anticoagulant, which raises our concern about the possible TKIs-warfarin pharmacokinetic and pharmacodynamic interaction that could be life-threatening to tumor patients who take warfarin for preventing deep vein thrombosis (DVT). Methods Influences of anlotinib and fruquintinib on the pharmacokinetic and dynamic behavior of warfarin were estimated. Influence on the activity of cytochrome P450 (CYP450) enzymes was detected in vitro through rat liver microsomes. Quantitative analysis of blood concentration in rats was finished by a validated UHPLC-MS/MS method. Furthermore, pharmacodynamic interactions were studied in rats by monitoring prothrombin time (PT) and activated partial thromboplastin time (APTT), while Inferior vena cava (IVC) stenosis-induced DVT model was built to further investigate the antithrombotic effect after co-administration. Results Anlotinib inhibited the activity of cyp2c6, cyp3a1/2 and cyp1a2 in rat liver microsomes in a dose-dependent manner, meanwhile enhanced the AUC 0∼t and AUC 0∼∞ of R-warfarin. However, fruquintinib showed no effects on pharmacokinetics of warfarin. Anlotinib and fruquintinib co-administrated with warfarin was found to exert more significant increase on PT and APTT values than that taking warfarin alone. In IVC stenosis-induced DVT model rats, the co-administration groups significantly reduced the length of thrombus compared with the single warfarin group. Conclusions Anlotinib and fruquintinib enhanced the anticoagulated and antithrombotic effect of warfarin. The anlotinib-induced interaction may due to the inhibition of the metabolism of warfarin. The mechanism of the pharmacodynamic interaction between fruquintinib and warfarin should be further investigated.
研究领域:
肿瘤学
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药理学
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血液学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Meng Huang,Yuda Zhu,Guang Xin,Yilan Wang,Fan Li,Shiyi Li,Yuman Dong,Kun Zhang,Lijuan Feng,Li Tang,Boli Zhang,Wen Huang
Intravenous injection of thrombolytic drugs is the most feasible strategy for the clinical treatment of thrombotic diseases, however, its applications are yet limited by narrow therapeutic index, short half-life, and hemorrhagic risk. Inspired by the excessive ROS and inflammatory factors at the thrombus site, we manufactured a thrombus microenvironment-modulated nanosystem , which achieved the targeted delivery of thrombolytic drugs and ROS scavenging agents. Ir monomers (Ir-PVP) with enzyme-mimetic activity were prepared and then wrapped with lumbrokinase (LK) by HA materials of thrombo-inflammatory affinity, forming multifunctional thrombolytic agents [email protected] [email protected] could prolong the biological half-life of LK and target the thrombus site to release LK with reduced bleeding risk. Moreover, Ir-NPs, as both CT imaging contrast agent and ROS scavenger, not only allowed us to observe the progression of thrombolytic treatment through CT imaging in real time, but also played an important role in elimination of excessive ROS at thrombus site. Taken together, the in vitro and in vivo experiments illustrated that [email protected] with CT function displayed an excellent efficiency in thrombolysis, anti-inflammation and ROS scavenging. Our work may encourage further exploration of thrombus microenvironment-modulated theranostic platforms.
研究领域:
纳米医学
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诊疗学
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药学
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生物医学工程
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产品关联
DOI
高影响因子
PHARMACOLOGICAL RESEARCH
·
2025
·
IF 10.5
Ning Yu,Shule Zhang,Rui Fang,Yingxin Zhang,Xi Xu,Lijuan Cao,Jianfa Zhang
Clinically approved thrombolytic agents carry significant bleeding risks due to systemic plasminogen activation. Heparin analogs prevent thrombus formation but lack direct thrombolytic activity. Here, we report a previously unrecognized thrombolytic mechanism of octaparin, a synthetic heparin analog. Studies demonstrated that octaparin exhibits potent anticoagulant and thrombolytic activity both in vitro and in vivo , with a lower bleeding risk compared to conventional heparin-based agents. Octaparin directly binds fibrin monomers, altering their secondary conformation to inhibit polymerization and destabilize preformed thrombi, while preserving tissue factor-driven coagulation. In murine models of pulmonary embolism and inferior vena cava thrombosis, octaparin both prevented and dose-dependently dissolved established clots without compromising hemostatic integrity, sharply contrasting with conventional thrombolytics that induce hemorrhage. Further analyses using molecular docking, microscale thermophoresis, and spectroscopy confirmed that octaparin induces changes in fibrin monomer folding that compromise fibrin network stability. In human systems, octaparin selectively prolonged intrinsic coagulation time, reduced clot retraction, did not induce platelet activation, and its effects were reversible with protamine sulfate. This study establishes targeted fibrin destabilization as a viable therapeutic strategy, revealing a previously unrecognized thrombolytic mechanism achievable through heparin-based molecular design.
研究领域:
药理学
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血液学
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分子医学
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血管生物学
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抗凝治疗
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2025
·Vol. 11
·期 3
·
IF 12.5
Lang Li,Hao Tian,Liulin Wu,Na Chen,Qiao Zhang,Lin Chen,Kai Zhu,Lin Lin,Xi Chen,Lang He,Min Liu,Wenyan Zhao,Yang Su,Juan Yan,Xingli Zhao,Xin Zhou,Zhenhua Zhou,Wen Zeng
The body weight–based thrombolytic medication strategy in clinical trials shows critical defects in recanalization rate and post-thrombolysis hemorrhage. Methods for perceiving thrombi heterogeneity of thrombolysis resistance is urgently needed for precise thrombolysis. Here, we revealed the relationship between the thrombin heterogeneity and the thrombolysis resistance in thrombi and created an artificial biomarker-based nano-patrol system with robotic functional logic to perceive and report the thrombolysis resistance of thrombi. The nano-patrols are contrallable and are able to accomplish thrombolysis resistance-matched personalized and precise therapy according to the feedback signal from artificial biomarkers. This nano-patrol system depicted more enhanced thrombolytic efficiency (elevated by 25%) than alteplase for mini pig model and clinical thrombi and achieved recanalization in thrombotic model where alteplase encountered failure. Moreover, the nano-patrol remarkably reduced the infarct volume and the hemorrhagic transformation risk (0.12-fold of alteplase) of cerebral thrombosis. Therefore, we developed a unique tool for diagnosing thrombolysis resistance and achieving personalized and precise thrombolysis.
研究领域:
医学
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药理学
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生物医学工程
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Xiaoyu Cheng,Chunling Wang,Junchao Xu,Yubiao Huang,Zhuo Chen,Liyue Zhong,Chong Du,Guangjun Nie,Yinlong Zhang
Antithrombotic drugs are widely used to prevent thrombotic events in patients with cardiovascular diseases. However, they all carry varying degrees of bleeding risk. Currently, there are no approved reversal agents for antiplatelet medications, which limits their further clinical application and poses challenges in managing bleeding complications. In this proof-of-concept study, we explore the feasibility of a reversal agent system using ticagrelor and a corresponding liposome-based antidote. Specifically, we developed an azide-functionalized ticagrelor derivative (Tic-N 3 ) and a clickable DBCO-modified liposome (Lipo-DBCO) to enable controlled reversal of antiplatelet activity. Our findings demonstrate that the azide modification does not compromise the antiplatelet efficacy and biocompatibility of ticagrelor. The antiplatelet effects of Tic-N 3 were successfully reversed by Lipo-DBCO, as validated through platelet aggregation assays and in vivo mouse models of tail bleeding and liver injury. Additionally, we investigated the thiol-maleimide pairing as an alternative system, enhancing the versatility of our approach. This strategy reveals the possibility and clinical application prospects of antiplatelet drug reversal agents, offering a promising solution for the safe management of bleeding risks associated with antiplatelet therapy.
研究领域:
药理学
·
药物递送系统
·
血栓与止血
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
·
2018
·
IF 6.5
Zeliang Wei,Guang Xin,Haibo Wang,Huajie Zheng,Chengjie Ji,Jun Gu,Limei Ma,Chaoyi Qin,Zhihua Xing,Hai Niu,Wen Huang
Thrombosis is the leading cause of death in patients with cardiovascular disease in the world. Current antithrombotic agent aspirin has serious side effects such as higher bleeding risk and serious gastrointestinal ulcers . Diosgenin reported in clinical research could prevent thrombosis without side effects. However, poor bioavailability and low knowledge on its molecular targets limit its clinical application. A novel prodrug with antithrombotic effect was prepared based on conjugating diosgenin derivatives to PEG with Schiff-base bond. The prodrug with long blood circulation time and satisfying safety could self-assemble into micelles in water. The prodrug micelles with pH-responsibility could targetedly release diosgenin in position of thrombus in vivo . The results indicate that the prodrug micelles without bleeding risk and histological damages prevent thrombosis by inhibiting platelet activation and apoptosis . Our studies demonstrate that the prodrug micelles could obviously enhance the efficacy in the prevention of arterial thrombus and venous thrombus than aspirin.
研究领域:
药剂学
·
心血管疾病
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药物递送系统
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2020
·
IF 7.242
Ying Wang,Xiaowen Xu,Xuan Zhao,Zongning Yin
Pathological thrombosis within a vessel hampers blood flow and is the mainspring of numerous fatal cardiovascular complications. In order to specifically image and dissolve a thrombus, we rationally designed a functionalized polymeric hybrid micelle (PHM) system self-assembled from amphiphilic polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethylene glycol (PCL-PEG). Based on a biological component of thrombi, activated coagulation factor XIII (FXIIIa), which is responsible for fibrin crosslinking, we further developed FXIIIa-targeted near infrared imaging and thrombolytic nanoparticles , termed IR780/FPHM/LK NPs, through chemical conjugation of peptides to the system. In a ferric chloride (FeCl 3 )-induced mouse carotid thrombosis model, IR780/FPHM/LK NPs specifically targeted the thrombus and significantly enhanced the photoacoustic signal for an accurate diagnosis. When loaded with the fibrinolytic drug lumbrokinase (LK), FPHM remarkably dissociated the thrombus accompanied by an increase in the d -dimer level, a fibrin degradation product , and alleviation of fatal nonspecific hemorrhagic risk. Given its thrombus-specific imaging along with potent therapeutic activities, IR780/FPHM/LK NPs hold promise for developing nanotheranostic agents in preclinical thrombotic vascular disease models.
研究领域:
纳米技术
·
诊疗学
·
心血管疾病
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药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）