摘要
目的:采用177Lu标记超支化聚合物(HG)修饰的液态金属纳米液滴(LMND)@HG,探索其在乳腺癌治疗中的放疗增敏效应。方法:使用超声破碎法制备LMND@HG,再通过合金化作用进行177Lu标记,得到177Lu-LMND@HG,检测其标记率、血浆稳定性和细胞毒性。构建小鼠乳腺癌移植瘤模型,瘤体注射177Lu-LMND@HG进行肿瘤抑制实验,采用小动物活体光学成像系统观察肿瘤生长情况。使用免疫组织化学与免疫荧光实验对其抑瘤机制进行初步验证。采用单因素方差分析、重复测量方差分析、最小显著差异t检验分析数据。结果:成功采用177Lu标记LMND@HG,标记率95%以上,产物不需后续纯化,且5 d后血浆中放化纯仍>95%。细胞毒性实验显示888 kBq(40 mg/L)177Lu-LMND@HG对4T1细胞具有明显的毒性,细胞存活率[(16.48±7.81)%]明显低于相同剂量177LuCl 3[(85.77±8.87)%;F=77.81,t=11.73,P<0.001]与40 mg/L LMND@HG[(46.53±5.75)%;t=6.20,P<0.001]处理后的细胞存活率。生物分布实验表明,瘤体注射后5 d 177Lu-LMND@HG仍主要分布于肿瘤组织。肿瘤抑制实验结果表明,1.48 MBq 177Lu-LMND@HG较177LuCl 3可明显抑制肿瘤生长[肿瘤体积:(222.66±97.70)与(789.13±245.04)mm 3;F=18.55,t=4.29,P=0.005]。小动物活体光学成像显示,1.48 MBq与3.70 MBq 177Lu-LMND@HG均明显抑制肿瘤生长。免疫荧光与免疫组织化学实验表明177Lu-LMND@HG可造成双链DNA的断裂,同时通过抑制肿瘤细胞增殖能力与血管新生能力达到抑制肿瘤的效果。结论:本研究成功制备了一种新型的177Lu-液态金属基活性氧(ROS)放疗增敏剂,制备方法高效便捷,产物稳定性高、在小鼠乳腺癌移植瘤模型中显示出明显的放疗增敏效果。
Objective To radiolabel hyperbranched polymer(HG)-modified liquid metal nanodroplet(LMND)@HG with 177Lu,and explore the radiotherapy sensitization effect on anti-breast cancer therapy.Methods The ultrasonication method was used to prepare LMND@HG,and then 177LuCl3 was mixed with LMND@HG to label 177Lu by alloying reactions.The labeling rate,plasma stability and cytotoxicity of 177Lu-LMND@HG were detected.Xenograft mouse model of breast cancer was constructed,and the tumor inhibition test was performed by an intratumoral injection.The tumor progression was monitored by in vivo imaging system.The mechanism of tumor inhibition was verified by immunohistochemistry and immunofluorescence assays.One-way analysis of variance,repeated measures analysis of variance,and the least significant difference t test were used to analyze the data.Results 177Lu was successfully labeled to LMND@HG with a high labeling efficiency>95%.The product did not require further purification and the plasma radiochemical purity was still higher than 95%after 5 d.The cytotoxicity test showed that a dose of 888 kBq(40 mg/L)177Lu-LMND@HG had obvious toxicity to 4T1 cells,which was significantly lower than 177LuCl3(cell viabilities:(16.48±7.81)%vs(85.77±8.87)%;F=77.81,t=11.73,P<0.001)and LMND@HG((46.53±5.75)%;t=6.20,P<0.001).The biological distribution results showed that 177Lu-LMND@HG was mainly distributed in tumor tissue 5 d after intratumoral injection.The results of the tumor inhibition experiment showed that 1.48 MBq 177Lu-LMND@HG could significantly inhibit the tumor growth compared with the 177LuCl3(tumor volume:(222.66±97.70)vs(789.13±245.04)mm3;F=18.55,t=4.29,P=0.005).In vivo optical imaging of small animals showed that 1.48 MBq and 3.70 MBq 177Lu-LMND@HG both significantly inhibited the tumor growth.Immunofluorescence and immunohistochemical results showed that 177Lu-LMND@HG caused double-stranded DNA break,and suppressed the tumor growth by inhibiting cell proliferation and angiogenesis.Conclusions A novel 177Lu-liquid metal-based reactive oxygen species(ROS)radiation sensitizer is successfully prepared in this study.The preparation method is efficient and convenient,and the product has high stability.177Lu-LMND@HG shows an obvious radiotherapy sensitization effect on breast tumor-bearing mice.
作者
严骏杰
宿晨
林剑涵
王辛宇
潘栋辉
徐宇平
王立振
陈重阳
杨敏
Yan Junjie;Su Chen;Lin Jianhan;Wang Xinyu;Pan Donghui;Xu Yuping;Wang Lizhen;Chen Chongyang;Yang Min(NHC Key Laboratory of Nuclear Medicine,Jiangsu Key Laboratory of Molecular Nuclear Medicine,Jiangsu Institute of Nuclear Medicine,Wuxi 214063,China)
出处
《中华核医学与分子影像杂志》
CAS
CSCD
北大核心
2024年第6期343-348,共6页
Chinese Journal of Nuclear Medicine and Molecular Imaging
基金
国家自然科学基金(22075114,31971316)
江苏省自然科学基金(BK20211034)。
关键词
乳腺肿瘤
同位素标记
镥
放射疗法
活性氧
肿瘤细胞
培养的
小鼠
裸
光学成像
Breast neoplasms
Isotope labeling
Lutetium
Radiotherapy
Reactive oxygen species
Tumor cells,cultured
Mice,nude
Optical imaging
