CN112274657B - 一种t1-t2双模态超高场磁共振造影剂及其制备方法和应用 - Google Patents
一种t1-t2双模态超高场磁共振造影剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种T1‑T2双模态超高场磁共振造影剂,包括磁性纳米粒子,修饰在其表面的水溶性配体以及通过化学偶联修饰在其表面的水溶性高分子。该造影剂在体内呈现良好的超高场磁共振造影效果,可以通过T1‑T2双模态磁共振成像对肿瘤血管通透性进行准确、灵敏度高的评估。本发明还涉及T1‑T2双模态超高场磁共振造影剂的制备方法及其在制备磁共振纳米造影剂中的应用。其制备方法的反应条件可控,产物尺寸均一,形貌良好,产物生物安全性高,具有良好的临床转化可能性。
Description
技术领域
本发明涉及无机纳米材料的合成,具体涉及一种T1-T2双模态超高场磁共振造影剂及其制备方法和应用。
背景技术
在当前各种疾病中,心血管疾病和肿瘤致死率分别居于第一位和第二位。肿瘤和心血管疾病的发生发展往往伴随着血管结构与功能的改变,如恶性肿瘤中异常的血管生成、心脑血管疾病中的血管变化等,因此通过血管成像来评估血管的结构与功能对于肿瘤和心脑血管疾病的精确诊断与治疗指导具有重要的临床意义。
磁共振成像(MRI)作为一种非侵入性的医学影像学手段,在软组织成像方面极具优势,并发展出多种技术可用于分析血管结构与功能。相比目前临床上常用的低场MRI(≤3T),超高场MRI(≥7T)能够提供更高的分辨率和信噪比,因而在血管成像方面具有十分可观的应用前景。
超高场MRI需要引入造影剂来提高其灵敏度。在MRI中,通常使用分子量较低的钆剂作为T1造影剂,但因其循环时间短、在超高场下T1对比效果减弱等问题而不适用于高场下的血管成像。此外,基于超顺磁性氧化铁纳米粒子(SPION)的T2造影剂在T2加权成像模式中使图像变暗,但所产生的磁化率伪影在超高场下更为显著,同样不利于高场下的血管成像。而T1-T2双模态MRI可以提供互补的T1加权图像和T2加权图像,获得更加精确的诊断信息。因此,需要设计T1-T2双模态造影剂以实现准确、灵敏度高的超高场磁共振血管成像。
常见的T1-T2双模态造影剂的设计策略之一是在T2造影剂SPION的表面直接吸附顺磁性的T1造影剂,但SPION在超高场下T2效应较强,且可能会干扰T1造影剂的弛豫过程,从而显著降低T1信号;同时,掺杂的顺磁性物质中通常含有Gd、Mn、Co等元素,存在一定毒副作用。
发明内容
本发明的目的在于提供一种T1-T2双模态超高场磁共振造影剂及其制备方法和应用,该造影剂呈现良好的超高场磁共振造影效果,可以通过T1-T2双模态磁共振成像对肿瘤血管通透性进行准确、灵敏度高的评估。
本发明所提供的技术方案为:
一种T1-T2双模态超高场磁共振造影剂,包括磁性纳米粒子,修饰在磁性纳米粒子表面的水溶性配体以及通过与水溶性配体化学偶联修饰在磁性纳米粒子表面的水溶性高分子。
上述的技术方案中,T1-T2双模态超高场造影剂是通过在尺寸超小的磁性纳米粒子表面修饰水溶性的配体和水溶性的高分子形成的。该造影剂超小的尺寸及表面修饰的小分子亲水性配体(如柠檬酸等)有助于纳米粒子表面的Fe3+离子与水质子的作用,缩短周围环境中水质子的的纵向弛豫时间,从而使得该造影剂在超高场下具有较好的T1对比效果;相较于较低强度的磁场,磁性纳米粒子(如超小氧化铁纳米粒子等)在超高场下表现出更高的磁化强度,因此T2对比效果增强。因此该造影剂在体内呈现出良好的超高场磁共振造影剂效果,可以通过T1-T2双模态磁共振成像对肿瘤血管通透性进行准确、灵敏度高的评估。
优选的,所述磁性纳米粒子的粒径小于5nm。
优选的,所述磁性纳米粒子选自氧化铁纳米粒子、四氟化钆钠纳米粒子、氧化钴纳米粒子或氧化锰纳米粒子;所述水溶性配体选自柠檬酸、多巴胺、精氨酸、多巴胺磺酸盐、琥珀酰肝素或半乳糖酸中的一种或几种;所述水溶性高分子配体选自聚乙二醇、葡聚糖、壳聚糖、聚丙烯酸、白蛋白、聚乙烯亚胺、聚乳酸、聚多巴胺、聚丙烯酰胺、多聚赖氨酸或聚乳酸-羟基乙酸共聚物中的一种或几种。磁性纳米粒子可以采用现有技术中的制备方法制得,磁性纳米粒子具有T1造影效果,例如2.2nmγ-Fe2O3(Kim B H,Lee N,Kim H,et al.Large-scale synthesis of uniform and extremely small-sized iron oxide nanoparticlesfor high-resolution T 1magnetic resonance imaging contrast agents.Journal ofthe American Chemical Society,2011,133(32):12624-12631)。
本发明还提供一种上述T1-T2双模态超高场磁共振造影剂的制备方法,包括如下步骤:
(1)使用水溶性配体对磁性纳米粒子进行配体交换;
(2)使用水溶性高分子通过化学偶联对配体交换后的磁性纳米粒子进行表面修饰;
所述步骤1)中使用水溶性配体对磁性纳米粒子进行配体交换主要是为了实现磁性纳米粒子的相转换,使得磁性纳米粒子从分散于油相转换成分散于水相;此外,配体交换时还可以引入功能基团例如羧基、氨基、磺酸基团等,便于后续进行聚乙二醇等水溶性高分子的表面修饰。
优选的,选用柠檬酸进行配体交换时,使得磁性纳米粒子从分散于油相转换成分散于水相,同时使其表面修饰了功能基团羧基。相应地选择末端氨基修饰的聚乙二醇通过化学偶联对其进行表面修饰。
优选的,选用多巴胺或多巴胺磺酸盐等进行配体交换,可引入氨基、磺酸基团等功能基团。
优选的,当水溶性配体为柠檬酸、水溶性高分子配体为聚乙二醇时,T1-T2双模态超高场磁共振造影剂的制备方法,包括如下步骤:
1)油酸包覆的超小氧化铁纳米粒子选用柠檬酸进行配体交换,得到羧基修饰的超小氧化铁纳米粒子;
2)使用聚乙二醇-氨基通过与柠檬酸的化学偶联进行表面修饰,得到聚乙二醇修饰的超小氧化铁纳米粒子。
优选的,所述步骤1)中羧基修饰的超小氧化铁纳米粒子的制备方法包括:
1.1)将三氯化铁六水合物、油酸钠分散于无水乙醇、正己烷和去离子水的混合物中,升温搅拌反应,经萃取旋蒸干燥后得到油酸铁复合物;
1.2)将油酸铁复合物溶解于二苯醚和油醇的混合液中,升温搅拌反应,经不良溶剂沉淀,得到油酸包覆的超小氧化铁纳米粒子;
1.3)将油酸包覆的超小氧化铁纳米粒子分散于邻二氯苯和N,N-二甲基甲酰胺的混合液中,加入柠檬酸,升温搅拌反应,经不良溶剂沉淀,得到羧基修饰的超小氧化铁纳米粒子。
优选的,所述步骤1.1)中油酸钠与三氯化铁六水合物的投料摩尔比为2-4:1。进一步优选为3:1。
优选的,所述步骤1.1)中无水乙醇、正己烷和去离子水的体积比为3-5:6-8:3。进一步优选为4:7:3。
优选的,所述步骤1.1)中将油酸钠和三氯化铁六水合物溶解在无水乙醇、正己烷和去离子水的混合物中,60-80℃油浴搅拌3-5h,反应的混合物产物使用去离子水萃取多次后,保留深色的有机相,通过旋蒸除去残余的液体并加热干燥,最终得到深红色蜡状固体形式的油酸铁复合物。
优选的,所述步骤1.2)中油酸铁复合物和油醇的摩尔投料比为1:4-8。进一步优选为1:6。
优选的,所述步骤1.2)中将油酸铁复合物溶解于油醇和二苯醚的混合物中,升温至80-100℃,真空环境下除水除氧后通入氩气作为保护气体,加热至240-260℃,在该温度下反应20-40min;反应结束后使用石油醚快速降温,反应后的液体经不良溶剂如乙醇或丙酮沉淀,得到油酸包覆的超小氧化铁纳米粒子,将其分散于三氯甲烷中待用。
优选的,所述步骤1.3)中油酸包覆的超小氧化铁纳米粒子与柠檬酸的质量投料比为1-4:1,分散于邻二氯苯和N,N-二甲基甲酰胺的混合液中,80-120℃加热反应24小时;反应结束后,待混合物冷却至室温,加入乙醚或丙酮沉淀产物数次,通过离心分离去除上清液,得到深色沉淀,即为羧基修饰的超小氧化铁纳米粒子。进一步优选,油酸包覆的超小氧化铁纳米粒子与柠檬酸的质量投料比为6:5。
优选的,所述步骤2)中羧基修饰的氧化铁纳米粒子与聚乙二醇-氨基的质量投料比为1:2-5。进一步优选为1:2。
本发明还提供一种如上述的T1-T2双模态超高场磁共振造影剂在制备磁共振纳米造影剂中的应用。
同现有技术相比,本发明的有益效果体现在:
(1)本发明所提供的T1-T2双模态超高场磁共振造影剂在体内呈现良好的超高场磁共振造影效果,可以通过T1-T2双模态磁共振成像对肿瘤血管通透性进行准确、灵敏度高的评估。
(2)本发明所提供的制备方法的反应条件可控,产物尺寸均一,形貌良好,具有良好的临床转化可能性。
(3)本发明所提供的T1-T2双模态超高场磁共振造影剂,由于氧化铁纳米粒子、柠檬酸以及聚乙二醇都具有很高的生物相容性,使得该造影剂对人体有很高的生物安全性。
附图说明
图1为实施例1制备的超小氧化铁纳米粒子的TEM图;
图2为实施例3制备的聚乙二醇修饰配体交换后的超小氧化铁纳米粒子的TEM图;
图3为柠檬酸配体交换后的超小氧化铁纳米粒子、聚乙二醇修饰的超小氧化铁纳米粒子的动态光散射粒度分布图和Zeta电位图;
图4为应用例1中T1-T2双模态超高场磁共振造影剂的T1加权像和T2加权像图;
图5为应用例2中T1-T2双模态超高场磁共振造影剂的纵向弛豫率和横向弛豫率图;
图6为应用例3中T1-T2双模态超高场磁共振造影剂用于评估大鼠原位脑胶质瘤血管通透性。
具体实施方式
下面结合具体实施例和说明书附图对本发明作进一步说明。
实施例1:超小氧化铁纳米粒子的制备
准确称取10.8g三氯化铁六水合物(FeCl3·6H2O,40mmol)和36.5g油酸钠(120mmol),置于500mL圆底烧瓶中,再使用量筒量取80mL无水乙醇、60mL去离子水、140mL正己烷加入圆底烧瓶中,混合物置于油浴锅中70℃油浴,搅拌反应4小时。反应结束,将混合物转移至分液漏斗中,加入30mL蒸馏水进行萃取,弃去下层透明液体,重复操作三次。萃取完毕,得到深色液体,通过旋转蒸发除去液体,再真空加热干燥,最终得到蜡状固体形式的油酸铁复合物。
准确称取0.9g(1mmol)油酸铁复合物置于50mL三颈烧瓶中,再加入1.61g(6mmol)油醇,加入5g二苯醚作为反应溶剂,90℃除水除氧2小时后,通入氩气作为保护气体,以10℃/min的恒定加热速率从90℃加热到250℃,反应30分钟后,停止加热,用石油醚将反应溶液迅速冷却至室温,将反应液转移至离心管中,加入30mL丙酮沉淀,离心去上清,沉淀再用无水乙醇洗涤两次,最终所得黑色固体分散于三氯甲烷中待用。
对氧化铁纳米粒子用透射电镜进行形貌表征,如图1所示,粒径约为2.2nm。
实施例2:使用柠檬酸对超小氧化铁纳米粒子配体交换
取含有120mg超小氧化铁纳米粒子的三氯甲烷溶液,加入丙酮沉淀,离心后将黑色固体重新分散于邻二氯苯溶液中,置于50mL圆底烧瓶中,准确称取柠檬酸0.1g加入烧瓶中,再加入邻二氯苯和N,N-二甲基甲酰胺,使得液体总体积为15mL,且邻二氯苯和N,N-二甲基甲酰胺的体积比为1:1。将烧瓶置于油浴锅中100℃油浴搅拌24小时。反应结束后,待冷却至室温,加入乙醚沉淀,再用乙醚和丙酮分别洗涤沉淀两次,经柠檬酸配体交换后的超小氧化铁纳米粒子分散于去离子水中待用。
实施例3:聚乙二醇修饰配体交换后的超小氧化铁纳米粒子
柠檬酸配体交换后的超小氧化铁纳米粒子表面存在羧基,可以选择末端修饰氨基的聚乙二醇,利用羧基和氨基之间的缩合反应将聚乙二醇修饰到超小氧化铁粒子表面,得到T1-T2双模态超高场造影剂。
(1)取50mg柠檬酸配体交换后的超小氧化铁纳米粒子溶液分散于10mL去离子水中,加入50mg聚乙二醇-氨基(上海子起生物有限公司),0.05g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,0.06g N-羟基琥珀酰亚胺,常温搅拌过夜,调整溶液pH值至9,室温下搅拌24小时后,转移至透析袋中,在去离子水中透析48小时,得到聚乙二醇修饰的超小氧化铁纳米粒子,其可以作为T1-T2双模态超高场造影剂。
(3)表征实验
使用透射电镜对得到的T1-T2双模态超高场造影剂进行形貌表征,如图2所示,这种聚乙二醇修饰的超小氧化铁纳米粒子在水中依然保持单分散。
利用动态光散射分析配体交换后的超小氧化铁纳米粒子(C-UDIOC)、聚乙二醇修饰的超小氧化铁纳米粒子(P-UDIOC)的粒度分布(图3中的A)和Zeta电位变化(图3中的B),结果如图3所示。图3中的A显示超小氧化铁纳米粒子在柠檬酸配体交换、聚乙二醇修饰后粒径逐渐增加。图3中的B显示超小氧化铁纳米粒子在柠檬酸配体交换、聚乙二醇修饰后Zeta电位逐渐增加。
应用例1:T1-T2双模态超高场造影剂用于超高场磁共振成像
实验步骤如下:将实施例3中制备好的T1-T2双模态超高场造影剂水溶液进行稀释,最终得到铁浓度为1mmol/L、0.5mmol/L、0.25mmol/L、0.13mmol/L、0.06mmol/L,0mmol/L的一组溶液。
使用外磁场强度为7T的磁共振成像仪进行扫描,分别得到T1加权像和T2加权像,如图4所示。在超高场下,随着样品中铁的浓度的增高,T1加权像越来越亮,即T1对比成像效果越来越好;T2加权像越来越暗,即T2对比成像效果越来越好。因此在超高场下,聚乙二醇修饰的超小氧化铁纳米粒子同时具有T1和T2对比成像效果,可以作为T1-T2双模态超高场造影剂。
这是因为超小氧化铁纳米粒子极小的尺寸使其具有较大的比表面积,表面暴露大量Fe3+离子,Fe3+离子最外层有5个未配对电子,可以有效缩短水质子的纵向弛豫时间,且表面修饰的小分子亲水性配体柠檬酸有助于纳米粒子表面的Fe3+离子与水质子的作用,缩短周围环境中水质子的的纵向弛豫时间,从而使得该造影剂在超高场下具有较好的T1对比效果。。
另外,磁化强度随着外磁场强度的增加而增加,且与水质子的T2弛豫时间成反比。相较于较低强度的磁场,超小氧化铁纳米粒子在超高场下表现出更高的磁化强度,因此T2对比效果增强。因此聚乙二醇修饰的超小氧化铁纳米粒子在超高场下可以作为T1-T2双模态造影剂。
应用例2:T1-T2双模态超高场造影剂弛豫率的测定
将制备好的T1-T2双模态超高场造影剂水溶液进行稀释,最终得到铁浓度为1mmol/L、0.5mmol/L、0.25mmol/L、0.13mmol/L、0.06mmol/L,0mmol/L的一组溶液。
纵向弛豫率r1的测量:用反转恢复法(Inversion-Recovery)法测量样品的纵向弛豫时间T1,外磁场强度为7T。根据等式:(1/T1)obs=(1/T1)d+r1[M],其中(1/T1)obs和(1/T1)d分别为样品溶液和纯溶剂中质子的纵向弛豫速率,即纵向弛豫时间的倒数,[M]为溶液中铁的摩尔浓度,由于铁的浓度已知,只要测量出(1/T1)obs和((1/T1)d即可得到r1的值。
横向弛豫率r2的测量:利用自旋回波序列(spin echo)测量样品的横向弛豫时间T2,外磁场强度为7T。根据等式:(1/T2)obs=(1/T2)d+r2[M],其中(1/T2)obs和(1/T2)d分别为样品溶液和纯溶剂中质子的横向弛豫速率,即横向弛豫时间的倒数,[M]为溶液中铁的摩尔浓度,由于铁的浓度已知,只要测量出(1/T12)obs和((1/T2)d即可得到r2的值。
如图5中的A和B所示的T1-T2双模态超高场造影剂纵向弛豫率r1以及横向弛豫率r2。图中直线的斜率即为弛豫率。其r1为1.37mM-1s-1,r2为7.53mM-1s-1,r2/r1为5.50,比值适中,说明其可以在超高场下作为T1-T2双模态造影剂。
应用例3:T1-T2双模态超高场磁共振造影剂用于评估大鼠原位脑胶质瘤血管通透性
取已种植原位脑胶质瘤的大鼠一只,将已制备好的T1-T2双模态超高场磁共振造影剂分散在pH为7.4的PBS缓冲液中,以5mg/kg的浓度通过尾静脉注射进入大鼠体内,使用2D多梯度回波序列(MGE)进行动态对比增强磁共振成像(DCE-MRI)扫描,外磁场强度为7T,获得大鼠脑部T1加权DCE-MRI和T2加权DCE-MRI半定量分析图(CNR of AUC-M0,CNR ofAUC-R2)。
如图6所示,图6中的A表明注射造影剂后,在T1加权DCE-MRI成像模式下,DCE-MRI半定量分析图(CNR of AUC-M0)中肿瘤部位变亮;图6中的B表示注射造影剂后,在T1加权DCE-MRI成像模式下,DCE-MRI半定量分析图(CNR of AUC-R2)中肿瘤部位变亮。这是因为肿瘤组织相比正常组织,其血管具有较高的通透性,造影剂从通透性高的肿瘤血管渗透进入肿瘤组织,因为其在超高场下具有T1和T2对比成像效果,T1-T2双模态DCE-MRI半定量分析图中肿瘤组织都表现出信号增强。图6中的C表示将图6中的A和图6中的B的结果进行交叉验证,得到双重验证图像(DCP image),可以观察到T1和T2加权的半定量分析图可以进行交叉验证,得到的结果能准备反映血管通透性高的部位为肿瘤组织,因此T1-T2双模态超高场造影剂能通过超高场T1-T2双模态DCE-MRI准备评估肿瘤组织血管通透性。
Claims (3)
1.一种T1-T2双模态超高场磁共振造影剂,其特征在于,包括磁性纳米粒子氧化铁纳米粒子,修饰在磁性纳米粒子表面的水溶性配体柠檬酸以及通过与水溶性配体柠檬酸化学偶联修饰在磁性纳米粒子表面的水溶性高分子聚乙二醇;
制备方法包括如下步骤:
1)油酸包覆的超小氧化铁纳米粒子选用柠檬酸进行配体交换,得到羧基修饰的超小氧化铁纳米粒子;
所述步骤1)中的羧基修饰的超小氧化铁纳米粒子的制备方法包括:
1.1)将三氯化铁六水合物、油酸钠分散于无水乙醇、正己烷和去离子水的混合物中,升温搅拌反应,经萃取后旋蒸干燥得到油酸铁复合物;
1.2)将油酸铁复合物溶解于二苯醚和油醇的混合液中,升温搅拌反应,经不良溶剂沉淀,得到油酸包覆的超小氧化铁纳米粒子;
1.3)将油酸包覆的超小氧化铁纳米粒子分散于邻二氯苯和N,N-二甲基甲酰胺的混合液中,加入柠檬酸,升温搅拌反应,经不良溶剂沉淀,得到羧基修饰的超小氧化铁纳米粒子;
所述步骤1.1)中油酸钠与三氯化铁六水合物的投料摩尔比为2-4:1;所述步骤1.2)中油酸铁复合物和油醇的摩尔投料比为1:4-8;所述步骤1.3)中油酸包覆的超小氧化铁纳米粒子与柠檬酸的质量投料比为1-4:1;
2)使用聚乙二醇-氨基通过与柠檬酸的化学偶联进行表面修饰,得到聚乙二醇修饰的超小氧化铁纳米粒子;
所述步骤2)中羧基修饰的超小氧化铁纳米粒子与聚乙二醇-氨基的质量投料比为1:2-5。
2.根据权利要求1所述的T1-T2双模态超高场磁共振造影剂,其特征在于,所述磁性纳米粒子的粒径小于5nm。
3.一种如权利要求1~2任一所述的T1-T2双模态超高场磁共振造影剂在制备磁共振纳米造影剂中的应用。
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