BME Frontiers
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2024
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IF 5
Jian Tang,Huiting Xu,Mingxi Li,Yang Liu,Fang Yang
Objective: The objective of this work is to design and fabricate a novel multifunctional nanocarrier combining thrombus-targeted imaging and ultrasound-mediated drug delivery for the theranostics of thrombotic diseases. Impact Statement: This study develops a new technology that can accurately visualize the thrombus and deliver drugs with controllable properties to diagnose and treat thrombotic diseases. Introduction: Thrombotic diseases are a serious threat to human life and health. The diagnosis and treatment of thrombotic diseases have always been a challenge. In recent years, nanomedicine has brought new ideas and new methods for the theranostics of thrombotic diseases. However, there are also many problems need to be solved, such as biosafety and stability of nanocarriers, early diagnosis, and timely treatment of thrombotic diseases, difficulty in clinical translation. Methods: The S1P@CD-PLGA-rtPA nanobubbles (NBs) were prepared by integrating sulfur hexafluoride (SF6)-loaded poly (D, L-lactide-co-glycolide) (PLGA) NBs, cyclodextrin (CD), sphingosine-1-phosphate (S1P), and recombinant tissue plasminogen activator (rtPA). Results: S1P@CD-PLGA-rtPA NBs had rapid and excellent thrombosis targeting imaging performance based on the specific interaction of S1P–S1PR1 (sphingosine-1-phosphate receptor 1). Furthermore, S1P@CD-PLGA-rtPA NBs that specifically targeting to the thrombosis regions could also respond to external ultrasound to achieve accurate and efficient delivery of rtPA to enhance the thrombolysis effectiveness and efficiency. Conclusion: This study proposes a new idea and strategy of targeting thrombus in rats via the specific interaction of S1P–S1PR1. On this basis, the acoustic response properties of bubble carriers could be fully utilized by combining thrombus-specific targeted imaging and ultrasound-mediated drug delivery for effective thrombolysis, which is expected to be applied in targeted diagnosis and treatment of thrombotic diseases in the future.
研究领域:
纳米医学
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治疗诊断学
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生物医学工程
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药学
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医学成像
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产品关联
DOI
PubMed
高影响因子
Neurotherapeutics
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2024
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IF 5.6
Zhiyuan Shen,Yuxuan Lu,Yingying Ren,Zhaoxia Wang,Jianwen Deng,Ding Nan,Jingjing Jia,Weiwei Yu,Yunyi Jin,Wei Sun,Yining Huang,Xiaozhong Qu,Haiqiang Jin
The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into the infarcted core, remain uncertain. This study employed an invasive fiber-optic oxygen meter and a newly developed oxygen-responsive probe called RuA 3 -Cy5-rtPA (RC-rtPA) based on recombinant tissue-type plasminogen activator (rtPA) to examine the oxygen content thresholds. A mouse model of middle cerebral artery occlusion was generated and animals were randomly divided into a sham, 24-h reperfusion after 3-h ischemia (IR 3-h), and IR 6-h groups, all of which were sacrificed following reperfusion. Stroke severity was evaluated based on the infarction area, neurological symptoms, microcirculation perfusion, and microemboli in microcirculation. OCIDP was characterized based on its extent and distribution, whereas OCCM was measured using RC-rtPA. During ischemia, stroke severity escalation manifested as increasing infarction area, severe neurologic symptoms, and poorer microcirculation perfusion with more microthrombi depositions. OCIDP presented rapid decline following artery occlusion along with a gradual increase in the hypoxic area. Within 3 h following ischemia induction, the ischemic tissue that experienced hypoxia could be rescued, and this reversibility would disappear after 6 h. Within 6 h, OCCM continued to decrease. A significant decrease in oxygen content in cortical venules and cortical parenchyma was observed. These findings assist in establishing the extent of the ischemic penumbra at the microcirculation level and offer a foundation for assessing the ischemic penumbra that could respond positively to reperfusion therapy beyond the typical time window.
研究领域:
神经科学
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中风
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微循环
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氧测量
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动物模型
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产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
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2017
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IF 5.012
Mei-Xue Dong,Chen-Meng Li,Peng Shen,Qing-Chuan Hu,You-Dong Wei,Yi-Fei Ren,Jia Yu,Si-Wen Gui,Yi-Yun Liu,Jun-Xi Pan,Peng Xie
Objectives Recombinant tissue plasminogen activator (rtPA) is widely used for patients with thromboembolic disease , and increasing evidence indicates that it can directly induce neurotoxicity independent of its thrombolysis property. Here, we aimed to confirm the long-term effect of rtPA on animal's behavior , and investigate the underlying pathogenesis. Methods and results Male Sprague-Dawley rats randomly received a dose of rtPA (10 mg/kg) or sterile saline. Three months later, the animals receiving rtPA displayed anxiety-like behaviors in the open field and novelty-suppressed feeding tests. To investigate the possible pathogenesis, gas chromatography-mass spectrometry-based metabolomics analysis was performed, with 18 differential metabolites identified in the hippocampus 24 h after the treatments. Based upon these differential metabolites, a metabolite-protein integrated network was generated, which indicated that ERK1/2-glutamic acid decarboxylase (GAD) 1-γ aminobutyric acid (GABA) cascade may be related to long-term anxiety-like behaviors. The GABA levels in hippocampus were decreased 24 h post-treatment and three months later, confirmed by a high performance liquid chromatography method. We also examined the expression of GAD1 and GAD2 using western blotting or immunohistochemical staining . Levels of GAD1 were persistently decreased after treatment, while GAD2 levels, GAD1-immunoreactive, and GAD2-immunoreactive neurons showed no significant differences. The underlying pathogenesis also involved activation of ERK1/2, confirmed by increased phospho-ERK1/2 24 h post-treatment. Conclusions RtPA can induce long-term anxiety-like behaviors after a clinical injected dose. The underlying pathogenesis involves the ERK1/2-GAD1-GABA cascade in the hippocampus. This pharmacological side effect of rtPA may further exacerbate post-stroke anxiety disorder for stroke patients.
研究领域:
神经科学
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药理学
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行为科学
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产品关联
DOI
PubMed
高影响因子
Small
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2022
·Vol. 18
·期 34
·2202848
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IF 15.153
Xiuzhen Tang,Laliphat Manamanchaiyaporn,Qi Zhou,Chenyang Huang,Lihuang Li,Ziqiao Li,Longchen Wang,Jienan Wang,Lei Ren,Tiantian Xu,Xiaohui Yan,Yuanyi Zheng
Magnetic micro-/nanoparticles are extensively explored over the past decade as active diagnostic/therapeutic agents for minimally invasive medicine. However, sufficient function integration on these miniaturized bodies toward practical applications remains challenging. This work proposes a synergistic strategy via integrating particle functionalization and bioinspired swarming, demonstrated by recombinant tissue plasminogen activator modified magnetite nanoparticles (rtPA-Fe 3 O 4 NPs) for fast thrombolysis in vivo with low drug dosage. The synthesized rtPA-Fe 3 O 4 NPs exhibit superior magnetic performance, high biocompatibility, and thrombolytic enzyme activity. Benefiting from a customized magnetic operation system designed for animal experiments and preclinical development, these agglomeration-free NPs can assemble into micro-/milli-scale swarms capable of robust maneuver and reconfigurable transformation for on-demand tasks in complex biofluids. Specifically, the spinning mode of the swarm exerts focused fluid shear stresses while rubbing on the thrombus surface, constituting a mechanical force for clot breakdown. The synergy of the NPs’ inherent enzymatic effect and swarming-triggered fluid forces enables amplified efficacy of thrombolysis in an in vivo occlusion model of rabbit carotid artery, using lower drug concentration than clinical dosage. Furthermore, swarming-enhanced ultrasound signals aid in imaging-guided treatment. Therefore, the pharmacomechanical NP swarms herein represent an injectable thrombolytic tool joining advantages of intravenous drug therapy and robotic intervention.
研究领域:
纳米技术
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药理学
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生物医学工程
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治疗学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Wenli Zhang,Maoyuan Sun,Yun Liu,Yu Zhang,Lian Xu,Ying Luo,Qianying Du,Jie Xu,Jia Liu,Jun Zhou,Haitao Ran,Zhigang Wang,Junrui Wang,Dajing Guo
Thrombotic diseases cause significant risks of disability and death worldwide. However, conventional thrombolytic drugs have short half-lives, poor targeting capabilities, limited therapeutic effects， and narrow therapeutic windows. Moreover, most basic studies focus only on thrombolytic efficiency and ignore the inflammatory factors that promote thrombosis progression, such as reactive oxygen species (ROS)-mediated oxidative stress. Therefore, to achieve comprehensive and effective thrombolytic management, both targeted thrombolytic therapy and the elimination of inflammatory factors must be achieved. In this study, we developed a platelet membrane (PM)-functionalized hollow mesoporous Prussian blue nanomedicine (HMPB-rtPA@PM), which was innovatively coassembled from two FDA-approved drugs (Prussian blue (PB) and alteplase (rtPA)) and showed marked advantages in both thrombi targeting and photothermal/pharmacological synergistic fibrinolysis. Moreover, HMPB-rtPA@PM exhibited the potential to inhibit platelet aggregation and regulate the inflammatory microenvironment by scavenging ROS. As expected, this nanomedicine not only achieved more efficient thrombolysis in both thrombus models but also delayed thrombosis progression through therapeutic visualization in the black tail model. Such rational therapeutic principle provides a broad platform for the comprehensive management of thrombotic diseases.
研究领域:
药学
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纳米医学
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血栓研究
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药物递送系统
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）