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靶向肿瘤新生血管的顺磁性纳米脂质体在MRI诊断肺癌中的研究
         
Study on angiogenesis-targeting paramagnetic nanoliposomes in MRI for diagnosis of pulmonary carcinoma

摘    要
目的:构建以肿瘤新生血管为靶向的顺磁性纳米脂质体,通过对荷瘤裸鼠模型行MRI以观察其在探查微小肿瘤病灶方面的应用价值.方法:靶向多肽-脂肪酸接枝物采用9-芴甲氧羰基(fluorenylmethoxy carbony, Fmoc)固相合成法获得,薄膜超声法制备靶向纳米脂质体,超滤离心法测定钆双胺(Gd-DPTA-BMA)包封率;激光粒度分析仪测定平均粒径;偶氮氯膦 Ⅲ 比色法测定钆含量;对肺腺癌A549裸鼠移植瘤模型行MRI,评价靶向纳米脂质体对肿瘤特异性MRI信号增强作用.结果:分别制备获得以整合素αVβ3、血管内皮生长因子受体(vascular endothelial growth factor receptor, VEGFR)-1、VEGFR-2为靶点的及不同连接方式的靶向纳米脂质体,包封率为55.5%~60.1%;平均粒径为109~128nm,其中以整合素受体αVβ3和VEGFR-2为靶点分子的顺磁性纳米脂质体在裸鼠移植瘤模型中显示出良好的肿瘤特异性MRI成像信号增强作用,尤以整合素受体为佳;其中连接臂又以采用疏水性连接臂6-氨基己酸效果最好.MRI T1加权像上肿瘤信号强度明显增强,可达对照的1.8~2.8倍,并清晰显示直径为2~5mm的微小肿瘤病灶;体内生物分布测定表明,肿瘤部位Gd3+浓度高于心脏、肺、肝脏、肌肉等器官,也略高于脾脏和肾脏.结论:构建的靶向顺磁性纳米脂质体具有肿瘤特异性,肿瘤部位持续时间长,MRI信号强度高,可清晰显示直径2~5mm微小肿瘤病灶,有可能发展成为新的肿瘤特异性磁共振对比剂.
标    签 肺肿瘤   磁共振成像   新生血管化, 病理性   纳米技术   顺磁性   Lung neoplasms   Magnetic resonance imaging   Neovascularization, pathologic   Nanotechnology   Paramagnetic  
 
Abstract
Objectives: To construct tumor angiogenesis-targeting paramagnetic liposomes and investigate their potential value as a magnetic resonance imaging(MRI) to detect minute tumor foci in tumor-bearing nude mice.Methods: Peptide-palmitic acid conjugate was prepared using fluorenylmethoxy carbony(Fmoc) solid-phase synthetic method.Angiogenesis-targeting paramagnetic liposome particles were prepared by the thin film dispersion-sonication method.Entrapped efficiency of Gd-DPTA-BMA was determined by centrifugal ultrafiltration.The average size of liposome particles was determined by laser particle sizing analysis.Gd3+ concentration was determined by chlorophosphonazo Ⅲ colorimetry.The signal enhancement ratio of targeted paramagnetic liposome particles was evaluated by MRI in human lung adenocarcinoma implanted in nude mice.Results: Five paramagnetic liposome particles which targeted αVβ3, vascular endothelial growth factor receptor(VEGFR)-1 and-2 and had different conjugation forms were prepared.Entrapped efficiency of the five prepared paramagnetic liposome particles was from 55.5% to 60.1%, and average particle size was from 109-128 nm.Integrin αⅤβ3 and VEGFR-2-targeted paramagnetic liposome particles showed good tumor-specific MRI signal enhancement in xenograft of the nude mice, especially for Integrin αVβ3 receptor.Spacer 6-aminohexanoic acid demonstrated the better signal enhancement than the other two linkages.Tumor relative signal intensity was increased 1.8-2.8 folds than control in T1 weighted MR imaging.Minute tumor nodules(2-5mm) were clearly identified.Biodistribution analysis showed that the Gd3+ concentration in tumor was significantly higher than that in the heart, lung, liver, and muscle, and slightly higher than that in the spleen and kidney.Conclusion: Angiogenesis-targeting paramagnetic liposome particles were tumor-specific and lasted for a long time.MRI signal enhancement was higher and minute tumor foci(2-5mm) were clearly identified.It can be developed as a potential tumor-specific MRI contrast agent for the early diagnosis of cancer and metastases.

中图分类号 R730.4   DOI 10.3781/.jissn.1000-7431.2008.06.009

 
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所属栏目 技术与方法

基金项目 上海市自然科学基金资助项目(编号:072R14124);上海市纳米专项基金资助项目(编号:0752nm018)

收稿日期 2008/2/29

修改稿日期 2008/4/9

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备注粟波(1969-),男(汉族),副研究员

引用该论文: SU Bo,XU Qing-hua,ZHOU Song-wen,SUN Xi-wen,WU Qiu-fang,ZHOU Cai-cun. Study on angiogenesis-targeting paramagnetic nanoliposomes in MRI for diagnosis of pulmonary carcinoma[J]. Tumor, 2008, 28(6): 494~497
粟波,徐清华,周崧雯,孙希文,吴秋芳,周彩存. 靶向肿瘤新生血管的顺磁性纳米脂质体在MRI诊断肺癌中的研究[J]. 肿瘤, 2008, 28(6): 494~497


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