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钆-乙二胺二乙酸-肼基烟酰胺-多肽螯合物MR分子探针的构建及在体肿瘤显像实验研究

Preliminary study of molecular imaging of human hepatoceilular carcinoma xenoggaft with Gd-based MR probe containiug arginine-glycine-aspartic acid chelate

摘要:

目的 构建一种含有精氨酸、甘氨酸、天冬氨酸(RGD)基序多肽的钆(Gd)类小分子MR分子探针,以特异性显示高表达整合素avβ3受体的肿瘤.方法 肼基烟酰胺(HYNIC)-RGD在乙二胺二乙酸(EDDA)存在的情况下,用三氯化钆(GdCl3)进行标记,用固相萃取(SPE)方法进行分离,得到分子探针Gd-EDDA-HYNIC-RGD.对分子探针进行紫外和MRI信号检测,测量弛豫率.进行3-(4,5-二甲基噻唑)-2,5-二苯基四氮唑溴盐(MTT)细胞毒性实验,将分子探针稀释成0.40、0.20、0.10、0.05 μmol/ml 4个浓度梯度,每个浓度20μl加入到含有人肝癌细胞的培养板内,测量吸光度值,并与未加分子探针的对照组吸光度值进行独立样本t检验.用逆转录聚合酶链反应(RT-PCR)检测BEL-7402人肝癌细胞系和肿瘤组织avβ3受体表达,用免疫荧光观察受体-配体结合情况.建立裸鼠肿瘤模型,将荷瘤裸鼠分为3组,分别由尾静脉注射0.2 ml分子探针、钆喷替酸葡甲胺(Gd-DTPA)和生理盐水,平扫加注药后即刻、30、60和90 min以及24 h分别进行图像采集,对0和90 min信号变化数据进行配对资料t检验.结果 Gd-EDDA-HYNIC-RGD分子探针被成功分离,MR T1 WI信号较强;分子探针弛豫率为3.31 mmoL/s;分子探针浓度在0.1 μmoL/ml以下比较安全;BEL-7402人肝癌细胞系和肿瘤组织表达avβ3受体;受体-配体在体外可以特异性结合;体内实验表明,肿瘤部位平扫和增强90 rain后的平均信号强度分别为2247.6±39.0和2820.9±35.2,增强25%,差异有统计学意义(t=-38.031,P<0.05);肌肉部位则为1824.2±32.8和1845.8±27.2,信号变化无统计学意义(t=-1.424,P>0.05);肿瘤信号与肌肉信号两者差值(423.4±56.7和975.1±32.1)有统计学意义(t=-24.650,P<0.05).肿瘤在注射分子探针、Gd-DTPA和生理盐水后具有不同的增强特点:分子探针组在0~90 min内逐步增强,在90 min信号最强;Gd-DTPA在注药后30 min信号最强,其后迅速减低;生理盐水组基本无增强;组织学检查显示,肿瘤为典型的恶性形态,血管丰富,可见大量坏死灶.结论 Gd-EDDA-HYNIC-RGD有望成为一种新的MR分子探针,显示高表达avβ3受体肿瘤,为临床提供一种早期诊断和鉴别诊断的可能手段.

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abstracts:

Objective To develop a Gd-based MR probe containing arginine-glyeine-aspartic acid (RGD)motif to reveal integrin avβ3 receptor-expressed tumor.Methods Commercially available HYNICRGD conjugate with co-ligand EDDA was labeled with GdCl3,and the mixture was isolated and purified by solid phase extract(SPE)to get the entire probe Gd-EDDA-HYNIC-RGD.Human HCC cell line BEL-7402 was cultured and the cells harvested and suspended then subcutaneously inoculated into athymic nude mice for tumor growth.In vitro cell binding assay to integrin avβ3 receptor and cell viability experiments were conducted.Then in vivo,imaging of the three arms of xenografts were performed by MR scan with a dedicated animal coil at baseline and time points of 0.30,60,90 mninutes and 24 hour post-intravenous injection(P.i.) via the tail vein.Three arms of nude mice then were sacrificed for histological examination to confirm the imaging results.Results Gd-EDDA-HYNIC-RGD was successfully isolated by SPE and validity was verifled on signal enhancement througll in vitro and in vivo experiments.The T1 relaxation rate of the probe is 3.31 mmol/s:It is well tolerated to living cells when the concentration of the probe is below 0.1 μmol/ml;both BEL-7402 Hunlan Hepatocellular Carcinoma cell Iine and the tumor expressed avβ3receptor;The RGD-iigand was observed specificly binding with avβ3 receptor in vitro;The nude mice model bearing HHCC was well estabhshed.The signal intensity(SI)at the tumor site were 2247.6±39.0 at baseline and 2820.9±35.2 at 90 min p.i.respectively,the SI at 90min increased less than 25%of baseline,which is statistically different(t=-38.031,P<0.05);while the SI at muscle site were 1824.2±32.8 and 1845.8±27.2 respectively,which is not statistically different(t=-1.424,P>0.05);The signal to time curve for probe-administrated group is straightforward over time in the span of 0 to 90 minute p.i.while the control arms do not show such tendency.Conclusion Gd-EDDA-HYNIC-RGD has the potential to used as an MR probe detecting integrin avβ3 receptor-expressed tumor.This work may offer possibility of early detection and differentiation of specific tumors.

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作者: 霍天龙 [1] 杜湘珂 [1] 张森 [1] 李绪斌 [1] 刘霞 [1]
期刊: 《中华放射学杂志》2008年42卷10期 1095-1100页 MEDLINEISTICPKUCSCD
分类号: R9
栏目名称: 实验研究
DOI: 10.3321/j.issn:1005-1201.2008.10.020
发布时间: 2008-12-15
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