CN108144071B - 原发性肝癌磁共振双靶点特异性分子探针及其制备方法 - Google Patents
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Abstract
本发明公开了一种原发性肝癌MR双靶点特异性分子探针及其制备方法，包括载体，所述载体末端分别连接有两种能够与原发肝癌细胞特异性结合抗体：Anti‑AFP和Anti‑GPC3。所述载体选自超顺磁性氧化铁（SPIO）或超小超顺磁性氧化铁（USPIO）。对所述载体末端修饰后增加羧基，通过所述羧基分别连接Anti‑AFP和Anti‑GPC3。本发明有益效果：在一个分子探针上连接连个双靶点特异性抗体，可以显著提高对肝癌病灶，以及肝癌末血管侵犯病灶(MVI)检出率。同时也便于对原发性肝癌体外和活体分子成像研究。
Description
技术领域
本发明属于医疗及分子影像学技术领域，具体地说，本发明涉及一种原发性肝癌磁共振(MR)双靶点特异性分子探针及其制备方法。
背景技术
磁共振检查具有软组织分辨率高、无电离辐射，能够提供多参数、多对比度图像等特点，已经成为肝脏占位病变临床影像学检查最重要的检查方法。但是，目前使用的或用于临床前期研究原发肝癌MR特异性分子探针均为甲胎蛋白(Alpha-fetoprotein,AFP)或磷脂酰肌醇蛋白聚糖3(Glypican-3,GPC3)单分子靶点的分子探针，这些单靶点特异性分子探针存在检测灵敏度低，对于AFP或GPC3低表达得原发性肝癌就无法检测到，更是无法检测到小的肝癌病灶。
原发性肝癌(Hepatocellular carcinoma，HCC)是多种因素造成的多基因累积、多步骤和多阶段的过程，属于一种多基因复杂性状疾病。在其发生和发展过程涉及到不同的基因和不同表达形式。所以，单靶点的分子探针无法提高探测的灵敏度，致使无法检测到小的病灶，特别是肝癌微血管侵犯(microvascular invasion,MVI)病灶。肝细胞肝癌小病灶和MVI检出对于肝细胞肝癌治疗效果至关重要。
AFP和GPC3在原发性肝癌肝细胞呈现出高表达，但是有些肝癌细胞AFP表达并不高，有文献报道在AFP低表达的肝癌细胞GPC3呈现高的表达。AFP和GPC3在原发性肝癌检出中具有很好的互补性，原发性肝癌诊疗规范(2017年版)也将这两个生物标志物纳入诊疗规范中。
为了解决检测小的肝癌病灶和提高对MVI检出率。我们先前工作的基础上，制备出原发性肝癌MR双靶点(AFP和GPC3)特异性分子探针。
发明内容
针对相关技术中的上述技术问题，本发明提出一种对原发性肝癌MR双靶点特异性分子探针及其制备方法。
为实现上述技术目的，本发明的技术方案是这样实现的：
一种原发性肝癌MR双靶点特异性分子探针，包括载体，所述载体末端分别连接有两种能够与原发肝癌细胞特异性结合抗体：Anti-AFP和Anti-GPC3。
其中，所述载体为MR非特异性对比剂，所述载体选自超顺磁性氧化铁(SPIO)或超小超顺磁性氧化铁(USPIO)。对所述载体末端修饰后增加羧基，通过所述羧基分别连接Anti-AFP和Anti-GPC3。
进一步的，Anti-AFP与所述载体连接的分子数量多于Anti-GPC3与所述载体连接的分子数量，Anti-AFP与Anti-GPC3优选比例为3：2或3：1。
本发明提供一种原发性肝癌MR双靶点特异性分子探针，其分子结构如下所示：
本发明还提供一种原发性肝癌MR双靶点特异性分子探针的制备方法，采用一锅法制备，具体包括以下步骤：
S1选择载体，所述载体为超顺磁性氧化铁SPIO或超小超顺磁性氧化铁USPIO，对其末端修饰后增加羧基；
S2利用羧基连接两个能够与原发肝癌细胞特异性结合抗体：Anti-AFP和Anti-GPC3；
S3采用离心机离心方法或磁性分离方法分离最后产物。
进一步的，Anti-AFP与所述载体结合分子数量多于Anti-GPC3与所述载体结合分子数量。
优选的，Anti-AFP与所述载体结合分子数量和Anti-GPC3与所述载体结合分子数量的比例为3:2或3:1。
本发明的有益效果：在一个分子探针上连接连个双靶点特异性抗体，可以显著提高对肝癌病灶，以及MVI检出率。同时也便于对原发性肝癌体外和活体分子成像研究。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1和图2是根据本发明实施例的一种原发肝癌双靶点USPIO纳米载体双靶点特异性分子探针分子结构；
图3和图4是两种羧基末端修饰的载体与Anti-AFP-NH2/Anti-GPC3-NH2的酰胺反应式；
图5是三种特异性肝癌MR分子探针与人肝癌细胞BEL-7402结合图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
基于纳米USPIO或SPIO为载体，对其末端修饰后增加羧基。
采用一锅法，将N-乙基-N'-(3-二甲胺基丙基)碳二亚胺盐酸盐(N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride,EDC)1mg和N-羟基硫代琥珀酰亚胺(sulfo-NHS)2mg溶解到0.5mL磷酸盐缓冲液(phosphate-buffered saline,PBS)中，PH＝7.4。将缓冲液PH调至5.0。加入末端修饰后带有羧基USPIO或SPIO 1ml或5mg后反应3小时；然后，加入磷脂酰肌醇蛋白聚糖3(Glypican3,GPC3)抗体(anti-GPC3)反应1小时后，加入甲胎蛋白(Alpha-Fetoprotein,AFP)抗体(anti-AFP)再继续反应3小时。将反应液中的PH值调至7.0。然后再反应30分钟。反应过程进行缓慢搅拌。将反应液离心(5000rpm/min,5min)分离探针。或采用磁性分离技术分离探针。
本发明实施例所有试剂均从Sigma-Aldrich公司购得，SPIO或USPIO的比重均为2.6g/cm3，SPIO的颗粒大小大于50nm，USPIO的颗粒大小小于50nm。质量控制：直接用电镜检测，流式细胞鉴定或荧光显微镜。
在EDC/NHS的活化作用下，Anti-AFP/Anti-GPC3与纳米分子或MR对比剂连接化学反应式如下式1和式2，其中，式1中，Anti-AFP与所述载体结合分子数量与Anti-GPC3与所述载体结合分子数量比例为3：2(图1)；式2中，Anti-AFP与所述载体结合分子数量与Anti-GPC3与所述载体结合分子数量比例为3：1(图2)。
测量T1/T2(USPIO 0.125mg)
图5所示，是三种特异性肝癌MR分子探针(USPIO-antiAFP，USPIO-antiGPC3及antiAFP-USPIO-antiGPC3与人肝癌细胞BEL-7402结合图，表明双靶点分子探针(antiAFP-USPIO-antiGPC3)明显提高细胞摄取率，半定量计算累积光密度值提高25％以上。
Claims (4)
1.一种原发性肝癌MR双靶点特异性分子探针，包括载体，其特征在于，所述载体末端分别连接有两种能够与原发肝癌细胞特异性结合抗体：Anti-AFP和Anti-GPC3，所述载体选自超顺磁性氧化铁或超小超顺磁性氧化铁，Anti-AFP与所述载体结合的分子数量和Anti-GPC3与所述载体结合的分子数量的比例为3:2或3:1，所述超顺磁性氧化铁的颗粒大小大于50nm，所述超小超顺磁性氧化铁的颗粒大小小于50nm。
2.根据权利要求1所述的原发性肝癌MR双靶点特异性分子探针，其特征在于，对所述载体末端修饰后增加羧基，通过所述羧基分别连接Anti-AFP和Anti-GPC3。
3.一种如权利要求1所述的原发性肝癌MR双靶点特异性分子探针的制备方法，其特征在于，采用一锅法制备，具体包括以下步骤：
S1选择载体，所述载体为超顺磁性氧化铁或超小超顺磁性氧化铁，对其末端修饰后增加羧基；
S2利用羧基连接两个能够与原发肝癌细胞特异性结合抗体：Anti-AFP和Anti-GPC3，采用一锅法，将N-乙基-N'-（3-二甲胺基丙基）碳二亚胺盐酸盐和N-羟基硫代琥珀酰亚胺溶解到磷酸盐缓冲液中，调节缓冲液pH至5.0，加入末端修饰后带有羧基的超小超顺磁性氧化铁或超顺磁性氧化铁进行反应，然后加入Anti-GPC3进行反应，加入Anti-AFP再继续反应后，调节反应液的pH值至7.0再进行反应。
4.根据权利要求3所述的原发性肝癌MR双靶点特异性分子探针的制备方法，其特征在于，进一步包括以下步骤：
S3采用离心机离心方法或磁性分离方法分离最后产物。
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| CN103784979A (zh) * | 2014-01-17 | 2014-05-14 | 福州市传染病医院 | 用于肝癌光热治疗和核磁影像的antiGPC3-PB NPs及其制备和应用 |
| CN106075440A (zh) * | 2015-07-01 | 2016-11-09 | 哈尔滨医科大学 | 一种肝癌靶向光热治疗剂及其制备方法与应用 |
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