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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
Preparation of drug-loaded iridium oxidenanocomposites and its application in synergetic sonodynamic/chemotherapeutic therapy against cancer
- 第三军医大学学报 2021年43卷第22期 页码：2395-2406
- 作者机构：
1.400010 重庆，医科大学超声分子影像重庆市重点实验室
2.200233 上海，上海交通大学附属第六人民医院，上海超声医学研究所
- 作者简介：
[ 郑元义，E-mail：zhengyuanyi@163.com ZHENG Yuanyi, E-mail: zhengyuanyi@163.com
- 基金信息：国家自然科学基金国际(地区)合作与交流项目(81720108023);国家自然科学基金重点项目(82030050);癌基因及相关基因国家重点实验室开放项目(KF2104-93#)
DOI：10.16016/j.1000-5404.202105108
中图分类号： R454.3;R730.58;R944.9收稿：2021-05-24，
修回：2021-07-27，
纸质出版：2021-11-30
- 稿件说明：
移动端阅览
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]. 第三军医大学学报, 2021,43(22):2395-2406.
Weijuan ZOU, Junnian HAO, Jianrong WU, et al. Preparation of drug-loaded iridium oxidenanocomposites and its application in synergetic sonodynamic/chemotherapeutic therapy against cancer[J]. Journal of Third Military Medical University, 2021, 43(22): 2395-2406.
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]. 第三军医大学学报, 2021,43(22):2395-2406. DOI： 10.16016/j.1000-5404.202105108.
Weijuan ZOU, Junnian HAO, Jianrong WU, et al. Preparation of drug-loaded iridium oxidenanocomposites and its application in synergetic sonodynamic/chemotherapeutic therapy against cancer[J]. Journal of Third Military Medical University, 2021, 43(22): 2395-2406. DOI： 10.16016/j.1000-5404.202105108.
摘要
目的
2
制备氧化铱（iridium oxide，IrO
X
）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（IrO
X
@ 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
2
采用热水解法制备IrO
X
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IrO
X
@ 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IrO
X
@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、IrO
X
组、IrO
X
+US组、IrO
X
@DOX组、IrO
X
@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
2
成功制备IrO
X
纳米颗粒，粒径大约为5 nm。当IrO
X
与DOX的比值为4.0时，载药量可达18.7%；IrO
X
@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IrO
X
@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IrO
X
@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，IrO
X
+US组、IrO
X
@DOX组和IrO
X
@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
2
成功制备了具有pH和超声辐照双重刺激响应的IrO
X
@DOX纳米复合物，在超声辐照下可以实现SDT-化疗协同治疗。
Abstract
Objective
2
To prepare iridium oxide (IrO
X
) as a nano-sonosensitizer to load chemotherapy drug doxorubicin (DOX) in order to obtain nanocomposites IrO
X
@DOX with dual response of pH/ultrasound (US) irradiation
and to verify its efficacy in sonodynamic therapy (SDT)-chemotherapy for tumor treatment.
Methods
2
IrO
X
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 IrO
X
@DOX nanoparticles was evaluated usingelectron spin-resonance spectroscopy (ESR). The uptake of IrO
X
@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 IrO
X
@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 follo
ws: saline
IrO
X
IrO
X
+US
IrO
X
@DOX
and IrO
X
@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
2
IrO
X
nanoparticles were successfully prepared
at a diameter of about 5.0 nm
and when the ratio of IrO
X
to DOX was 4.0
the drug loading reached 18.7%. Prepared IrO
X
@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 IrO
X
@DOX by tumor cells.
In vitro
cytotoxicity experiments indicated the survival rate of tumor cells in the synergistic treatment group (IrO
X
@DOX+US) was reduced to 19.4%
significantly lower than that of the chemotherapy group alone (
P
<
0.05)
which proved that IrO
X
@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 IrO
X
+US
IrO
X
@DOX and IrO
X
@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
2
IrO
X
@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.
关键词
Keywords
references
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