[1]邹卫娟,郝俊年,吴建荣,等.氧化铱纳米载药复合物的制备及其用于肿瘤声动力-化疗协同治疗的研究[J].陆军军医大学学报(原第三军医大学学报),2021,43(22):2395-2406.
 ZOU Weijuan,HAO Junnian,WU Jianrong,et al.Preparation of drug-loaded iridium oxidenanocomposites and its application in synergetic sonodynamic/chemotherapeutic therapy against cancer[J].J Amry Med Univ (J Third Mil Med Univ),2021,43(22):2395-2406.
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氧化铱纳米载药复合物的制备及其用于肿瘤声动力-化疗协同治疗的研究(/HTML )
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陆军军医大学学报(原第三军医大学学报)[ISSN:1000-5404/CN:51-1095/R]

卷:
43卷
期数:
2021年第22期
页码:
2395-2406
栏目:
基础医学
出版日期:
2021-11-30

文章信息/Info

Title:
Preparation of drug-loaded iridium oxidenanocomposites and its application in synergetic sonodynamic/chemotherapeutic therapy against cancer
作者:
邹卫娟郝俊年吴建荣郑元义
重庆医科大学超声分子影像重庆市重点实验室;上海交通大学附属第六人民医院,上海超声医学研究所
Author(s):
ZOU Weijuan HAO Junnian WU Jianrong ZHENG Yuanyi
Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing Medical University, Chongqing, 400010; 2Shanghai Institute of Ultrasound Medicine, Sixth People’s Hospital affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
 
关键词:
氧化铱声动力治疗化疗协同治疗肿瘤
Keywords:
iridium oxide sonodynamic therapy chemotherapy synergistic therapy tumor
分类号:
R454.3; R730.58; R944.9
文献标志码:
A
摘要:

目的制备氧化铱(iridium oxide,IrOX)作为纳米声敏剂,用以负载化疗药物阿霉素(doxorubicin,DOX)后得到具有pH和超声辐照双响应的纳米载药复合物(IrOX@DOX),验证其用于肿瘤声动力治疗(sonodynamic therapy,SDT)-化疗协同治疗肿瘤的效果。方法采用热水解法制备IrOX纳米颗粒,并负载DOX。采用透射电子显微镜(transmission electron microscope, TEM)、X射线光电子能谱(X-ray photoelectron spectroscopy, XPS)、紫外-可见分光光度计(ultraviolet-visible spectrophotometer, UV-vis)、Zeta 电位分析仪等手段对纳米颗粒的形貌及理化性质进行相关表征;采用UV-Vis和酶标仪考察载药量及药物释放行为;用电子顺磁共振波谱仪(lectron spin-resonance spectroscopy, ESR)定性评价其活性氧产生性能;激光共聚焦显微镜评价IrOX@DOX在超声辐照下的细胞摄取行为;荧光显微镜和流式细胞仪探究细胞内活性氧产生;CCK-8法及流式凋亡检测评价IrOX@DOX的声动力治疗-化疗协同治疗效果。建立 Hepa1-6肝癌裸鼠皮下移植瘤模型,并分为生理盐水组、IrOX组、IrOX+US组、IrOX@DOX组、IrOX@DOX+US组(n=3),观察各组荷瘤鼠肿瘤的体积、超声造影成像结果与病理学变化,计算肿瘤体积抑制率评价其体内协同治疗效果。结果 成功制备IrOX纳米颗粒,粒径大约为5 nm。当IrOX与DOX的比值为4.0时,载药量可达18.7%;IrOX@DOX在pH =7.4时释放的DOX量不足10%,证实了其良好的稳定性;pH=5.5 时, DOX的累积释放量可达39.9%。在超声辐照下释放量进一步增加达69.9 %;ESR 和 UV-Vis 实验结果表明活性氧产量与辐照功率和时间呈正相关;激光共聚焦结果显示超声能促进细胞对IrOX@DOX的摄取;细胞毒性实验表明,与单纯化疗组相比,协同治疗组存活率降至19.4%,证明IrOX@DOX在超声辐照下可以实现良好的SDT-化疗协同治疗效果。动物实验表明与生理盐水组相比,IrOX+US组、IrOX@DOX组和IrOX @DOX+US组的肿瘤抑制率分别为27%、57%及76%,差异具有统计学意义(P<0.05)。这与超声造影和HE染色结果一致。结论 成功制备了具有pH和超声辐照双重刺激响应的IrOX@DOX纳米复合物,在超声辐照下可以实现SDT-化疗协同治疗。

Abstract:

ObjectiveTo prepare iridium oxide (IrOX) as a nano-sonosensitizer to load chemotherapy drug doxorubicin (DOX) in order to obtain nanocomposites IrOX@DOX with dual response of pH/ultrasound (US) irradiation, and to verify its efficacy in sonodynamic therapy (SDT)-chemotherapy for tumor treatment. MethodsIrOX nanoparticles were prepared by thermal hydrolysis and then loaded with DOX. The morphological, chemical and physical properties of the nanoparticles were characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), ultraviolet-visible spectrophotometer (UV-Vis) and Zeta potential analyzer. The drug loading efficiency and drug release behavior were determined with UV-vis spectrometry and ELISA. The generation of reactive oxygen species (ROS) by IrOX@DOX nanoparticles was evaluated usingelectron spin-resonance spectroscopy (ESR). The uptake of IrOX@DOX by 4T1 cells under ultrasonic irradiation was evaluated with laser confocal scanning microscopy (LCSM), and the level of intracellular ROS was investigated using fluorescence microscopy and flow cytometry. The synergistic efficacy of IrOX@DOX in SDT-chemotherapy against 4T1 cells was evaluated by CCK-8 assay and flow cytometry. In addition, the Hepa1-6 xenograft tumor model in nude mice was built and divided into 5 groups (n=3 in each group) as follows: saline, IrOX, IrOX+US, IrOX@DOX, and IrOX @DOX+US. The tumor volume, contrast-enhanced US imaging and pathological changes of each group were observed, and the inhibitory rate of tumor volume was calculated to evaluate the effect of synergistic therapy in vivo. Results IrOX nanoparticles were successfully prepared, at a diameter of about 5.0 nm, and when the ratio of IrOX to DOX was 4.0, the drug loading reached 18.7%. Prepared IrOX@DOX released less than 10% of DOX at pH 7.4, which confirmed its good stability, while the cumulative release of DOX reached 39.9% at pH 5.5, and further increased to 69.9% under US irradiation. Both ESR and UV-vis experiments demonstrated that ROS production was positively correlated with irradiation power and time. Meanwhile, LCSM showed that US promoted the uptake of IrOX@DOX by tumor cells. In vitro cytotoxicity experiments indicated the survival rate of tumor cells in the synergistic treatment group (IrOX @DOX+US) was reduced to 19.4%, significantly lower than that of the chemotherapy group alone (P<0.05), which proved that IrOX@DOX nanocomposites achieved an excellent synergistic effect of SDT-chemotherapy under ultrasound irradiation. Furthermore, in vivo experiments showed that as compared with saline group, the tumor-inhibiting rate of IrOX+US, IrOX@DOX and IrOX@DOX+US groups were 27%, 57% and 76%, respectively, indicating significant difference (P<0.05), and this was consistent with contrast US imaging and H&E staining results. Conclusion IrOX@DOX nanocomposites with dual stimulation response of pH and US irradiation are successfully developed, and the synergistic treatment of SDT-chemotherapy can be achieved under US irradiation.

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更新日期/Last Update: 2021-11-23