超声可视化的肿瘤原位液固相变生物磁铁聚集磁性脂质体的实验研究  

Tumor-specific aggregation of magnetic liposome nanoparticles in tumor-bearing mice after ultrasound-guided intratumor injection of liquid-solid phase-change biomagnetic material

作　　者：郝俊年 汪蓉晖 冉海涛[1] 王志刚[1] 郑元义[1,3,4] HAO Junnian;WANG Ronghui;RAN Haitao;WANG Zhigang;ZHENG Yuanyi(Institute of Ultrasound Imaging,Chongqing Key Laboratory of Ultrasound Molecular Imaging,Chongqing Medical University,Chongqing,400016;Department of Ultrasonography,Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine,Shanghai,200025;Department of Ultrasonography,the Second Affiliated Hospital of Chongqing Medical University,Chongqing,400010;Department of Ultrasonography,Shanghai Institute of Ultrasound Medicine,Sixth People's Hospital Affiliated to Shanghai Jiaotong University,Shanghai,200233,China)

机构地区：[1]重庆医科大学超声影像学研究所超声分子影像重庆市重点实验室,重庆400016 [2]上海交通大学医学院附属瑞金医院超声科,上海200025 [3]重庆医科大学第二附属医院超声科,重庆400016 [4]上海交通大学附属第六人民医院超声科上海超声医学研究所,上海200233

出　　处：《第三军医大学学报》2020年第20期1995-2002,共8页Journal of Third Military Medical University

基　　金：国家自然科学基金国际(地区)合作与交流项目(81720108023);国家自然科学基金青年科学基金(81801699)。

摘　　要：目的构建超声监控下肿瘤原位液固相变钕铁硼生物磁铁(NdFeB/Fe3O4/PLGA,NFP),研究静脉注射型磁性脂质体纳米粒(magnetic liposome nanoparticles,MLPs)在肿瘤内富集的可行性及效率。方法制备液固相变NFP生物磁铁,对其液固相变能力、形态和充磁磁化能力等进行表征。同时制备包载超顺磁性Fe3O4的脂质体纳米粒,表征其形态、大小及粒径等一般性能。通过细胞毒性增殖实验检测NFP生物磁铁和MLPs的细胞生物安全性。通过体外循环模拟捕获实验检测在微循环的流速下NFP对血管中MLPs的捕获效率。通过建立4T1乳腺癌荷瘤小鼠模型,探索超声监控下注射NFP可磁化的生物磁铁植入体作为体内生物磁铁靶向吸引尾静脉注射连接荧光染料的MLPs的能力。结果扫描电镜与元素分析结果显示相变后的植入体各元素分布均匀。体外充磁实验证实NFP生物磁铁充磁后被赋予磁性,25、50、75、100μL NFP生物磁铁的磁力分别为(350.14±23.89)、(493.47±19.54)、(679.39±34.23)、(812.36±27.99)Gs,结果显示NFP生物磁铁的磁性随体积增大而增强。成功制备磁性脂质体纳米粒,透射电镜观察呈球形,大小较均匀,粒径为(373.658±50.000)nm,电位为(-24.8±1.4)mV。细胞毒性实验显示NFP生物磁铁和MLPs对肿瘤细胞和正常细胞均未见明显的生长抑制作用。体内的荧光成像结果显示NFP生物磁铁与MLPs联合使用组肿瘤部位的荧光明显增强,其余各组肿瘤部位未见明显增强。结论成功制备了超声可视化液固相变植入体NFP及生物安全性较好的MLPs,该植入体磁化后可在肿瘤原位产生磁场,吸引经尾静脉注射的MLPs特异性地富集于肿瘤。Objective To prepare ultrasound-guided intratumor injection of liquid-solid phase-transition biomagnetic material(NdFeB/Fe3O4/PLGA,NFP)and investigate its feasibility and efficiency of aggregating for targeted aggregation of intravenously injected magnetic liposome nanoparticles(MLPs).Methods The biomagnetic material NFP was prepared and its liquid-solid phase transition ability,morphology and magnetization performances were assessed;the form,particle size and diameter of MLPs were also characterized.The biocompatibility of NFP and MLPs were evaluated by cytotoxic proliferation experiments,and the efficiency of MLP capture by NFP was determined using an in vitro model of extracorporeal circulation.A 4 T1 mouse model bearing breast cancer xenograft was established,in which NFP was injected in the tumor under ultrasound guidance and MLPs conjugated with a fluorescent dye was injected intravenously by tail vein.The efficiency of NFP implant for capturing the MLPs for targeted aggregation of the latter in the xenograft was evaluated using in vivo fluorescence imaging.Results The biomagnetic material NFP capable of liquid-solid phase transition was successfully prepared.Scanning electron microscopy and elemental mapping results showed a homogeneous distribution of the elements in NFP after phase transition.The NFP implant could be efficiently magnetized in vitro,and the magnetic forces of NFP was positively correlated with its volume(350.14±23.89,493.47±19.54,679.39±34.23,and 812.36±27.99 Gs for 25,50,75,and 100μL of NFP,respectively).The prepared MBLs had a uniform particle size of 373.658±50.000 nm with a zeta potential of-24.8±2.5 mV.Cytotoxicity experiments with tumor cells and normal cells showed no obvious cytotoxicity of either NFP or MLPs.in vivo fluorescence imaging showed that following intravenous MLB injection and intratumor NFP implantation,the fluorescence intensity was significantly enhanced in the xenografts in the tumor-bearing mice.Conclusion The prepared liquid-solid phase-change biomagnetic

关 键 词：生物磁铁 磁靶向 靶向药物递送 磁性脂质体 超声可视化 纳米粒 

分 类 号：R445.1[医药卫生—影像医学与核医学] R737.9[医药卫生—诊断学]