H 2 O 2 /PFP-loaded acoustic phase-change lipid nanoparticles enhancing thrombolysis in artificial vessel for simulation of coronary circulation: an  in-vitro  study by low intensity focused ultrasound irradiation

Jiang Nan; Hu Bo; Cao Sheng; Deng Qing; Zhou Zhen; Zhu Min; Zhou Qing; Guo Ruiqiang

doi:10.3760/cma.j.issn.1004-4477.2019.01.015

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• 实验研究 •

低强度聚焦超声联合载过氧化氢相变纳米粒靶向助溶模拟冠状动脉循环的人工血管血栓栓塞

中华超声影像学杂志, 2019,28(1) : 71-76. DOI: 10.3760/cma.j.issn.1004-4477.2019.01.015

摘要

目的

制备可释氧的载过氧化氢(H₂O₂)相变纳米粒，联合低强度聚焦超声(LIFU)靶向溶解人工血管内血栓，探讨其在急性心肌梗死(AMI)冠状动脉溶栓治疗中的价值。

方法

采用薄膜水化和双乳化法制备包载H₂O₂和液态氟碳(PFP)的脂质相变型纳米粒。取家兔颈总动脉血50 ml制备成质量约400～800 mg的血栓块。本实验分为4组：PBS对照组(A组)、SonoVue微泡组(B组)、PFP相变纳米粒组(C组)和载H₂O₂相变纳米粒组(D组)。每组血栓样本均置入体外溶栓模拟循环装置的人工血管中联合LIFU辐照。称量各组溶栓前后血栓重量并观察比较各组溶栓后HE染色切片；溶氧仪检测溶栓后循环液中纳米粒释氧量。

结果

载H₂O₂相变纳米粒粒径大小为(456.7±31.2)nm；荧光显微镜示纳米粒液体相时结构稳定，大小均一。溶栓后四组血栓重量损失及损失率分别为A组(52.2±11.5)mg、(9.7±3.5)%，B组(110.0±21.9)mg、(19.4±2.4)%，C组(239.6±46.3)mg、(39.7±6.3)%，D组(309.8±44.8)mg、(54.2±6.6)%，C组和D组溶栓前后的重量损失及损失率明显大于A、B两组，差异有统计学意义(均P<0.01)；C组、D组间差异无统计学意义(P>0.05)。溶氧仪检测纳米粒释氧量随着H₂O₂浓度的增加而逐渐增高。

结论

载H₂O₂相变纳米粒可高效溶解人工血管血栓栓塞，并通过释氧改善组织缺氧，为AMI患者冠状动脉血栓栓塞提供潜在的治疗新方式。

引用本文: 姜楠, 胡波, 曹省, 等. 低强度聚焦超声联合载过氧化氢相变纳米粒靶向助溶模拟冠状动脉循环的人工血管血栓栓塞 [J] . 中华超声影像学杂志,2019,28 (1): 71-76. DOI: 10.3760/cma.j.issn.1004-4477.2019.01.015

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未经授权，不得转载、摘编本刊文章，不得使用本刊的版式设计。

除非特别声明，本刊刊出的所有文章不代表中华医学会和本刊编委会的观点。

急性心肌梗死(acute myocardial infarction，AMI)是严重危及人类健康的心血管疾病，发病率及致死率均较高。AMI发病原因主要由冠状动脉阻塞引起供血不足或中断，从而导致心肌细胞出现严重的急性缺血性坏死。目前临床常用的治疗措施为介入治疗、手术和药物溶栓等^[1,2,3]。近年来，超声联合微泡治疗血栓栓塞性疾病一直是研究的热点，而其中聚焦超声以其热效应、机械效应、空化效应等多种机制和定位精准的优势成为一种新兴的无创治疗技术^[4,5]。因此，本研究在联合低强度聚焦超声的基础上，模拟体外循环条件，探索制备了一种包裹过氧化氢/液态氟碳(H₂O₂/PFP)的相变纳米粒，探究其在体外溶栓的有效性和安全性，从而为AMI的无创治疗提供新的临床思路。

贡献者信息

姜楠

武汉大学人民医院超声影像科　430060

胡波

武汉大学人民医院超声影像科　430060

曹省

武汉大学人民医院超声影像科　430060

邓倾

武汉大学人民医院超声影像科　430060

周桢

武汉大学人民医院心血管外科　430060

朱敏

武汉大学人民医院超声影像科　430060

周青

武汉大学人民医院超声影像科　430060

郭瑞强

武汉大学人民医院超声影像科　430060

通信作者

胡波

武汉大学人民医院超声影像科　430060

Email：krishu@whu.edu.cn

关键词

超声检查; 微气泡; 过氧化氢; 血栓溶解疗法;

基金项目

国家自然科学基金青年项目（81501495）

武汉大学自主科研资助项目（2042018kf0056）

利益冲突

利益冲突　所有作者均声明不存在利益冲突

历史

出版日期：2019-01-25

收稿日期：2018-06-14

Experimental Research

H₂O₂/PFP-loaded acoustic phase-change lipid nanoparticles enhancing thrombolysis in artificial vessel for simulation of coronary circulation: an in-vitro study by low intensity focused ultrasound irradiation

Jiang Nan, Hu Bo, Cao Sheng, Deng Qing, Zhou Zhen, Zhu Min, Zhou Qing, Guo Ruiqiang

Published 2019-01-25

Cite as Chin J Ultrasonogr, 2019,28(1): 71-76. DOI: 10.3760/cma.j.issn.1004-4477.2019.01.015

Abstract

Objective

To prepare a novel H₂O₂-loaded and phase-change nanoparticles, combined with low intensity focused ultrasound (LIFU) to dissolve intravascular thrombosis for the evaluation of its value in the treatment of coronary artery thrombolysis in the patients with acute myocardial infarction (AMI).

Methods

H₂O₂-loaded and phase-change nanoparticles were prepared by membrane hydration method. 50 ml arterial blood was collected from rabbit carotid artery and made into 400-800 mg thrombus blocks. They were divided into four groups randomly: poly butylene succinate buffer (PBS) solution as blank control (group A), SonoVue microbubbles group(group B), PFP phase-change nanoparticles group (group C), H₂O₂-loaded and phase-change nanoparticles group (group D). Each group of thrombus samples were placed into the artificial blood vessels of the extracorporeal thrombolysis simulation cycle device and combined with LIFU irradiation. The weights and pathological presentations were compared before and after thrombolysis. The volume of O₂ in the vascular system was inspected using Dissolved Oxygen Detector (DOD) after LIFU exposure.

Results

The average size of H₂O₂-loaded nano-droplets was (456.7±31.2)nm. Fluorescence microscopy showed that the structure of nanoparticles was stable and uniform in size. The weight loss and rates of thrombus in the four groups after thrombolysis were: group A (52.2±11.5)mg, (9.7±3.5)%; group B (110.0±21.9)mg, (19.4±2.4)%; group C (239.6±46.3)mg, (39.7±6.3)% and group D (309.8±44.8)mg, (54.2±6.6)%, respectively. The weight loss and rates of thrombus in group C and D were higher than those in group A and B (all P<0.01), but there was no significant difference between group C and D (P>0.05). The DOD showed that along with the increase of H₂O₂ concentration, O₂ release was rising.

Conclusions

H₂O₂/PFP nanoparticles with LIFU performs efficient thrombolysis and provides O₂ to improve hypoxia, which provides a potential novel treatment method for AMI patients with coronary embolism.

Key words:

Ultrasonography; Microbubbles; Hydrogen peroxide; Thrombolytic therapy

Contributor Information

Jiang Nan