Journal of Biomedical Nanotechnology
·
2021
·Vol. 17
·期 9
·1711-1725
·
IF 4.099
Zhang Ru,Luo Shang,Hao Lin-Kun,Jiang Yun-Ying,Gao Ying,Zhang Ning-Ning,Zhang Xue-Cheng,Song Yi-Min
In order to improve the therapeutic effect, prolong the action time and reduce the side effects of the first generation thrombolytic drug urokinase (UK), a novel UK/multi-walled carbon nanotubes (MWCNTs)-chitosan (CS)-arginine-glycine-aspartic acid (Arg-Gly-Asp) (RGD) drug delivery
system was synthesized by chemical bonding/non covalent bond modification/ultrasonic dispersion. The results showed that the diameter of the UK/MWCNTs-CS-RGD drug delivery system was about 30–40 nm, there was a layer of UK was attached to the surface of the tube wall, and the distribution
was relatively uniform. The average encapsulation efficiency was 83.10%, and the average drug loading was 12.81%. Interestingly, it also had a certain sustained-release effect, and its release law was best fitted by first-order kinetic equation. Moreover, the accelerated and long-term stability
test results show that it had good stability. Compared with free UK, UK/MWCNTs-CS-RGD had thrombolytic effect in vitro. In addition, MTT experiment showed that the prepared MWCNTs-CS-RGD nanomaterials had good biocompatibility. A rabbit model of carotid artery thrombosis was used to
conduct targeted thrombolysis experiments in vivo. Compared with free UK, UK/MWCNTs-CS-RGD could be enriched in the thrombosis site to achieve thrombus targeting. UK/MWCNTs-CS-RGD drug delivery system was expected to become an effective thrombolytic drug for targeted therapy of thrombosis.
研究领域:
药理学
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生物医学工程
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纳米医学
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2022
·
IF 14.903
Songli Wang,Ruifeng Wang,Nana Meng,Linwei Lu,Jun Wang,Jianfen Zhou,Jiasheng Lu,Qianzhu Xu,Cao Xie,Changyou Zhan,Yao Li,Yang Yu,Weiyue Lu,Min Liu
Thrombolytic agents have thus far yielded limited therapeutic benefits in the treatment of thrombotic disease due to their short half-life, low targeting ability, and association with serious adverse reactions, such as bleeding complications. Inspired by the natural roles of platelets during thrombus formation, we fabricated a platelet-based delivery system (NO@uPA/PLTs) comprising urokinase (uPA) and arginine (Arg) for targeted thrombolysis and inhibition of re-embolism. The anchoring of uPA to the platelet surface by lipid insertion increased the thrombotic targeting and in vivo circulation duration of uPA without disturbing platelet functions. Nitric oxide (NO) generated by the loaded Arg inhibited platelet aggregation and activation at the damaged blood vessel, thereby inhibiting re-embolism. NO@uPA/PLTs effectively accumulated at the thrombi in pulmonary embolism and carotid artery thrombosis model mice and exerted superior thrombolytic efficacy. In addition, the platelet delivery system showed excellent thrombus recurrence prevention ability in a mouse model of secondary carotid artery injury. The coagulation indicators in vivo showed that the platelet-based uPA and NO co-delivery system possessed a low hemorrhagic risk, providing a promising tool for rapid thrombolysis and efficient inhibition of posttreatment re-embolism.
研究领域:
药学
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生物医学工程
·
血液学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Yina Su,Linjie Huang,Guizhen Xu,Simin Chen,Jiaqiong Wu,Siyu Wang,Yichao Zhang,Xiahui Lin
Traditional antithrombotic therapeutic strategies encounter challenges including heightened bleeding risks, short circulation times, low targeting ability, and inferior thrombus penetration. Therefore, a novel thrombolysis nanodrug (APBUL) is designed that incorporates urokinase (UK) loaded onto the surface of bowl-shaped nanomotors (APBs) encapsulated within fibrin peptide (CREKA)-modified thermosensitive liposomes, presenting an innovative therapeutic platform for thrombolysis. APBUL leverages CREKA's targeting ability for thrombus accumulation. Subsequently, under the irradiation of near-infrared light, the thermosensitive liposomal shell undergoes controlled disruption, releasing internal APBs and UK. Then, the APBs move directionally though thermophoresis effect, facilitating photothermal therapy and deep thrombus penetration, and synergistically enhancing UK release and diffusion to optimize thrombolysis. Moreover, the APBUL possesses a catalase-like activity, catalyzing hydrogen peroxide into oxygen to alleviate oxidative stress and inflammatory factors at the thrombus site, thereby lowering the recurrence risk. Combined with the ability of APBUL's photoacoustic imaging, this new strategy is expected to provide an inspiring idea for the integrated use of clinical thrombolytic therapy in diagnosis, imaging, and treatment.
研究领域:
生物医学工程
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纳米医学
·
药剂学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 16
·4656-4666
·
IF 7.59
Dongya Wang,Qianqian Zhao,Jingcan Qin,Yuanyuan Guo,Chuan Zhang,Yuehua Li
Ischemic stroke often causes devastating damage to human life and health. Excess production of reactive oxygen species (ROS) during thrombolysis will paradoxically result in neuronal injury. Neuroprotection from reperfusion injury must overcome the challenge of crossing the blood–brain barrier (BBB). A strategy including thrombolysis and ROS scavenging accompanied by BBB penetration is highly desirable for improving combination therapies in ischemic stroke. Herein, urokinase plasminogen activator (uPA) loaded on black phosphorus nanosheets (BPNs) is tested as a nanodrug for sequential thrombolysis and neuroprotection. The in vitro thrombolysis shows that the uPA-loaded BPNs can efficiently deliver uPA for thrombus dissolution. The residual BPNs after uPA release exhibit ROS scavenging effects, especially for the most common H2O2 and ˙OH species. Moreover, in vivo studies show that the BPNs can cross the BBB with the assistance of laser irradiation, owing to their good photothermal properties. Further experiments show the effectiveness of BPNs for attenuating reperfusion injury and achieving neuroprotection. These results highlight the promising potential of the present BPN-based nanodrugs for the treatment of ROS-related diseases.
研究领域:
神经科学
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纳米医学
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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
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Haoyuan Li,Zhipeng Yang,Qisheng Tang,Zhifeng Shi,Ying Mao
Stroke models are vital tools in neuropharmacology and rehabilitation research. However, a classic and widely used model—the suture occlusion model—is not suitable for all research approaches, especially regarding thrombolysis. For embolic stroke models in thrombolytic research, the surgical procedures of thrombin injection in the middle cerebral artery or clot injection in the carotid artery involved are too sophisticated. Here, we report a new stroke model in mice that uses magnetic nanoparticle (MNP) cross-linked with thrombin to embolize. Briefly, after the magnet was positioned in the common carotid artery, MNP@Thrombin was injected from the tail vein. Within several minutes postinjection, the MNP@Thrombin accumulated in the carotid artery and induced thrombus formation. These complex clots were flushed into and subsequently blocked the cerebral artery. Collectively, these results suggested that this new method was a quick and easy stroke model that blocked hemisphere blood flow and damaged neural function. Importantly, this model had an excellent response to thrombolytic drugs. After urokinase injection, cerebral blood flow was restored and symptom scores were enhanced by nearly one. This method, including a quick synthesis of MNP and thrombin, provided an easy and minimally invasive process for a new stroke model that is usable in both pharmacological and rehabilitative research.
研究领域:
神经药理学
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康复研究
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中风模型
·
溶栓
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Songzhi Xie,Chuanfei Mo,Wenxiong Cao,Shuang Xie,Shang Li,Zhanlin Zhang,Xiaohong Li
Effective thrombolysis is critical to rapidly rebuild blood flow for thrombosis patients. Drug delivery systems have been developed to address inadequate pharmacokinetics of thrombolytic agents, but challenges still remain in the timely removal of blood clots regarding the dense fibrin networks. Herein, rod-shaped tubular micromotors were developed to achieve efficient penetration and thorough destruction of thrombi. By using electrospun fiber fragments as the template, urokinase (uPA)-loaded polydopamine (PDA) microtubes with surface decorated fucoidan ( Fu PDA uPA ) were prepared at the aspect ratio of around 2. One E. coli Nissle 1917 (EcN) was assembled into one microtube to construct a Fu PDA uPA @EcN hybrid micromotor through PDA adhesion and L-aspartate induction. The pharmacokinetic analysis indicates that the encapsulation of uPA into micromotors extends the half-life from 0.4 to 5.6 h and increases the bioavailability over 10 times. EcN-propelled motion elevates adsorption capacities of Fu PDA uPA @EcN for more than four times compared with that of Fu PDA uPA . The fucoidan-mediated targeting causes 2-fold higher thrombolysis capacity in vitro and over 10-fold higher uPA accumulation in thrombi in vivo . In the treatment of venous thrombi at mouse hindlimbs, intravenous administration of Fu PDA uPA @EcN completely removed blood clots with almost full recovery of blood flows and apparently alleviated tail bleeding. It should be noted that Fu PDA uPA @EcN treatment at a reduced uPA dose caused no significant difference in the blood flow rate compared with those of Fu PDA uPA . The synergistic action of fucoidan-induced targeting and EcN-driven motion provides a prerequisite for promoting thrombolytic efficacy and reducing uPA dose and bleeding side effect. Statement of significance The standard treatment to thrombosis patient is intravenous infusion of thrombolytic agents, but the associated bleeding complications and impairment of normal haemostasis greatly offset the therapeutic benefits. Drug delivery systems have been developed to address the limitations of inadequate pharmacokinetics of thrombolytic agents, but challenges still exist in less efficient penetration into dense networks for thorough destruction of thrombi. Up to now only few attempts have been made to construct nano-/micromotors for combating thrombosis and there is no single case that antithrombosis is assisted by bacteria or cells-propelled motors. Herein, bacteria-propelled microtubes were developed to carry urokinase for efficient penetration into blood clots and effective thrombolysis. The synergistic action of bacteria-driven motion and specific ligand-induced targeting holds a promising treatment strategy for life-threatening cardiovascular diseases such as thrombosis and atherosclerosis.
研究领域:
生物医学工程
·
药理学
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心血管疾病
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Minglin Ji,Qinying Tang,Olanrewaju Yaasir Olatunji,Rufei Ge,Yue Ying,Jianwei Pan,Khaydar E. Yunusov,Guohua Jiang
Thrombus treatment remains a significant challenge, primarily due to factors such as the short half-life of thrombolytic agents, suboptimal drug utilization, and limited therapeutic efficacy. In this study, we developed a platelet membrane-camouflaged bioactive glass nanoparticles (BGs) as drug carriers to load thrombolytic agent urokinase (UK) and anticoagulant drug tirofiban (TF). UK and TF were firstly incorporated onto BGs, and followed by a camouflage of polydopamine (PDA) and platelet membrane (PM) to form composite nano-formulation (TUBGs@PP). This composite nano-formulation leverages the PM camouflage to enhance its biocompatibility, prolong circulation time in vivo , and extend the half-life of drugs. Additionally, as-fabricated TUBGs@PP composite nano-formulation can circumvent immune system-mediated clearance, thereby facilitating targeted drug delivery to the thrombus sites and enhancing the thrombolytic efficacy. In vivo results demonstrated that the TUBGs@PP composite nano-formulations not only prolonged circulation time but also effectively unclogged blood vessels at the site of thrombosis, while reducing recurrence of thrombosis and drug side effects. Statement of Significance The platelet membrane-camouflaged bioactive glass nanoparticles as drug carriers for the synergistic co-delivery of urokinase and tirofiban have been developed (TUBGs@PP) for the treatment of acute arterial thrombosis. This cutting-edge therapeutic strategy addresses several critical limitations inherent in current thrombolytic treatments, including the transient half-life of thrombolytic agents, suboptimal drug bioavailability, and limited therapeutic efficacy. In vivo studies demonstrate that TUBGs@PP not only achieves sustained circulation but also effectively restores vascular patency at thrombotic loci, concurrently reducing the risk of thrombotic recurrence and minimizing adverse drug effects. This study highlights the paradigm-shifting potential of TUBGs@PP in thrombolytic therapy, offering a transformative solution to existing challenges and promising to markedly improve clinical outcomes for patients.
研究领域:
药剂学
·
生物医学工程
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Ying Li,Qi Xiang,Yan Zhang,Fuxue Luo,Yunfang Wu,Haitao Ran,Yang Cao
Arterial thrombosis is a severe cardiovascular condition associated with high mortality and disability rates. Traditional pharmacological thrombolytic therapies, however, are limited by a narrow therapeutic window, short drug half-lives, restricted therapeutic effectiveness, and the risk of hemorrhagic complications. Moreover, the unique biological microenvironment of arterial thrombosis is characterized by high shear stress and an inflammatory milieu rich in reactive oxygen species (ROS), resulting in a relatively high recurrence rate. To address these challenges, a mechanical biomimetic nanocomposite MPB-NO-UK@PM is developed by doping sodium nitroprusside, a nitric oxide (NO) donor, into mesoporous Prussian blue (MPB) nanoparticles to form MPB-NO, which is then loaded with urokinase (UK) and coated with platelet membranes (PM). The nanocomposite exhibits excellent thrombus-targeting ability and enhances thrombolytic efficacy through synergistic photothermal and pharmacological, while simultaneously reducing the risk of bleeding. The released NO induces antiplatelet aggregation effects, while Prussian blue effectively scavenges ROS and inflammatory cytokines, thereby preventing thrombus recurrence. Additionally, the nanocomposite possesses superior photoacoustic imaging capabilities, enabling visualization of thrombus diagnosis and treatment. This therapeutic approach represents a novel pathway for the multidimensional and efficient management of arterial thrombosis.
研究领域:
生物医学工程
·
心血管病学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2025
·
IF 4.8
Yu-Ming Huang,Cheng-Rang Liu,Yi-Qi Xu,Chao Cao,Zhen-Gan Huang,Hong-Wen Fei,Yue-Shan Huang
Objective: This study aimed to develop a poly (lactic-co-glycolic acid) (PLGA)-based magnetic loaded iron oxide (Fe3O4) and single-chain urokinase-type plasminogen activator (proUK) for enhancing thrombolysis under a controlled rotating magnetic field, specifically targeting acute lower limb venous thrombosis.Background: Acute thrombotic disorders are significant health threats, however, the exploration of magnetic actuation as a treatment for acute thrombosis has been limited.Methods: Magnetic microbubbles were prepared using a double emulsion method, loaded with Fe3O4 nanoparticles and proUK. The microbubble characteristics were analyzed through chemical, physical, and biological related technologies.Results: Fe3O4 nanoparticle loading was confirmed by X-ray diffraction, and the encapsulation efficiency of the magnetic microbubbles was determined using an ELISA kit and colorimetric assay, reaching a maximum of 56.65% at a proUK concentration of 7.5 mg/mL. Thrombolysis efficiency was significantly enhanced under a rotating magnetic field of 1.5 mT and 6 Hz frequency, achieving up to 25% lysis rate in vitro, markedly higher than control conditions. Furthermore, in vivo experiments using a rabbit model of hindlimb venous thrombosis validated the efficacy of this approach, with Color Doppler Flow Imaging showing restored blood flow and elevated D-dimer levels indicating effective thrombus dissolution.Conclusion: This novel magnetic drug delivery system, combined with a rotating magnetic field, demonstrates excellent thrombolysis efficiency and presents a promising and safe therapeutic strategy for acute venous thrombosis.
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Dingfu Wang,Dan Li,Xiaolin Liu,Shixin Wang,Yile Fan,Ling Lu,Chuanbin Shen,Chunxia Li
Thrombolytic therapy for cardiovascular and cerebrovascular diseases is significantly limited by the short half-life, inadequate targeting specificity, and hemorrhagic complications of conventional therapeutic agents. To overcome these challenges, we developed a dual-functional nanogel (PGS-SP@UK) that integrates P-selectin-mediated thrombus targeting with ROS-responsive drug release. Taking advantage of the P-selectin targeting capability of polyguluronate sulfate (PGS), we synthesized the sulfated polysaccharide with selenocystamine and pinacol phenylboronate (PBAP) to construct an amphiphilic copolymer capable of encapsulating urokinase (UK). Notably, this nanogel exhibited H 2 O 2 -triggered UK release (85.79%) while maintaining great stability under physiological conditions. In vitro studies confirmed its neuroprotective effects through modulation of the ferroptosis signaling pathway in an OGD/R-induced model. In vivo studies revealed efficient blood-brain barrier penetration and thrombus-specific accumulation, achieving 84.3% recovery in cerebral infarct area through synergistic thrombolysis and oxidative stress mitigation. Our study presents an innovative drug delivery system with significant potential for clinical ischemic stroke treatment. Statement of Significance Conventional thrombolytic agents suffer from poor targeting specificity and severe bleeding complications, limiting their clinical efficacy in ischemic stroke treatment. We designed a dual-functional nanogel (PGS-SP@UK) that uniquely integrates P-selectin-mediated active targeting with ROS-responsive drug release mechanisms. This innovative design represents a system to combine polyguluronate sulfate-based thrombus recognition with oxidative stress-triggered urokinase liberation. Our nanogel achieves unprecedented selectivity through dual targeting: bioactive targeting via P-selectin binding and microenvironmental responsiveness to pathological ROS levels. In vivo validation demonstrated exceptional therapeutic outcomes with 84.3% cerebral infarct recovery while eliminating systemic hemorrhagic risks. This breakthrough establishes a new therapeutic paradigm that transcends current limitations through synergistic thrombolysis and neuroprotection, offering transformative potential for precision medicine in thrombotic disorders.
研究领域:
生物材料
·
纳米医学
·
脑血管病学
·
药物递送系统
·
氧化应激
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神经保护
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血栓靶向
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 47
·10854-10866
·
IF 5.344
Cuifu Fang,Zhiwei Zhong,Teng Zhang,Shuang Jia,Xingwei Ding,Weimin Zhou,Xiaolei Wang
Problems such as massive hemorrhage caused by uncontrolled drug dosage are the main significant obstacles in clinical thrombolytic therapy, which are prominently due to the lack of targeting and controlled release ability of efficient thrombolytic drug systems. In recent years, our team demonstrated that the photothermal effect can facilitate the thrombolytic effect of urokinase plasminogen activator (uPA). However, conventional photothermal agents are relatively expensive or contain heavy metals. If drug delivery systems with low toxicity, minimized heavy metal elements and easy accessibility (preferably provided by human self) can be developed, they will be of value in the future related applications. Herein, uPA-loaded human black hair derived nanoparticles with gelatin capsules (uPA@HBHNP@GNCs) were applied for the first time as a thrombolytic system. Upon irradiation by near-infrared I window (NIR-I) laser or II window (NIR-II) laser, the photothermal effect of HBHNP was triggered to promote the melting of the gelatin encapsulated around the outer layer, thereby realizing the targeted release of uPA. The in vitro and in vivo experiments demonstrated that the deep response to NIR (especially II window) of this system exhibited a satisfactory thrombolytic effect with ideal biosafety. Briefly, the proposed hair derived drug delivery system has the characteristics of human source, low cost, minimum heavy metal components, deep response to NIR (II window) laser, and good biocompatibility, which is expected to be expanded to the treatment for some diseases, even in deep tissue areas.
研究领域:
药学
·
生物医学工程
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2024
·Vol. 14
·期 10
·7195-7205
·
IF 3.9
Shun Xiao,Xiaozhi Sun,Chong Wang,Jianlie Wu,Kun Zhang,Mingjin Guo,Bing Liu
Deep vein thrombosis (DVT) is a venous return disorder caused by abnormal clotting of blood in deep veins. After thrombosis, most of the thrombus will spread to the deep vein trunk throughout the limb. If DVT is not treated in time, most of them will develop into thrombosis sequelae and even threaten life. Intravenous thrombolytic drugs are the most promising strategy for treating DVT, but current drugs used for thrombolysis suffer from short half-lives and narrow therapeutic indexes. To effectively manage DVT, it is necessary to develop a novel multifunctional drug-loading system to effectively prolong the treatment time and improve the therapeutic efficacy. In this study, a urokinase-loaded protocatechuic aldehyde-modified chitosan microsphere drug-loading platform was constructed for the treatment of DVT. This microsphere adsorbed urokinase well through electrostatic interaction, and the introduction of bovine serum albumin conferred stability to the microspheres. Therefore, the microsphere drug delivery system could achieve slow drug release to effectively dissolve blood fibrin. In addition, chitosan grafted with protocatechuic aldehyde imparted excellent antioxidant activity to the system to reduce free radicals in the blood vessels. Effective management of oxidative stress could avoid abnormal platelet activation and new thrombus formation. The experimental results showed that this microsphere had good biocompatibility, anti-inflammatory properties, and considerable thrombolytic activity. In conclusion, this study provided a new direction and developed a novel multi-functional nano microsphere drug delivery platform for the treatment of DVT.
研究领域:
药剂学
·
药理学
·
生物医学工程
·
材料科学
·
治疗学
✓ 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）