CN109503770B - 一种具有高弛豫率的水溶性交联纳米聚合物及其合成方法和用途 - Google Patents
一种具有高弛豫率的水溶性交联纳米聚合物及其合成方法和用途 Download PDFInfo
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Abstract
本发明公开了一种具有高弛豫率的水溶性交联纳米聚合物及其合成方法和用途,其中具有高弛豫率的水溶性交联纳米聚合物的结构通式如下:其中x、y、z的数值区间分别为1‑500,w的数值区间为0.5‑100,n的数值区间为1‑100。本发明通过可逆加成‑断裂链转移聚合(RAFT聚合)的方法设计制备得到线性纳米聚合物,该方法制备得到的线性纳米聚合物既分子量可控,又继承了聚乙二醇甲基丙烯酸酯的优良的水溶性性能,还引入了DO3A的大环结构,为下一步的螯合Gd3+提供螯合位点。本发明最终得到的目标产物具有更高的弛豫率,测量值达到16.48mM‑1*S‑1,是市售Gd‑DO3A弛豫率(3.5mM‑1*S‑1)的将近4.7倍,具有更好的造影效果。
Description
技术领域
本发明涉及一种具有高弛豫率的水溶性交联纳米聚合物及其合成方法和用途。
背景技术
恶性疾病如癌症的早期有效诊断和治疗对挽救病人生命,提高生存质量至关重要。目前早期临床影像诊断以磁共振成像(MRI),正电子发射计算机断层扫描(PET),单光子发射计算机断层成像(SPECT)为代表。其中MRI也是一种发射断层成像,它对任意成像平面的识别力,对软组织的解析度和空间断层成像的分辨率均达到很高水平。成像过程无需用放射性同位素,因而更加安全。
MRI的基本原理是,通过测试调整体内水质子的纵向(自旋-点阵或纵向驰豫时间,longitudinalrelaxation time,T1)及横向(自旋-自旋或横向弛豫时间,transverserelaxation time,T2)弛豫时间,得到多种物理参数,如质子密度、T1、T2、扩散系数、磁化系数、化学位移等,然后重建人体信息。与CT、超声、PET等成像相比,MRI得到信息更加丰富,是医学影像中一个热门的研究方向。由于MRI对细胞的恶化过程中的代谢及病理变化的敏感度不高,需要联用外在造影剂(contrast agent)以提高诊断图像解析度和对比度,以区别正常细胞和病变细胞,所以新型高效造影剂的特性将直接影响MRI诊断图像的准确度和分别率。
基于T1机理的钆(Gadolinium,Gd)螯合物造影剂的研究是医学影像学中的前沿和热点。大多数T1造影剂均为小分子Gd螯合物,代表性的如已获FDA批准的Gd(DTPA)和Gd(DOTA)。虽然小分子有利于进入细胞内部实施准确诊断,但多数小分子T1造影剂尚有很多不完善之处,如敏感度不高(靶向性不好),对比度不理想,毒性较高,细胞组织内停留时间较短,体内排除较快等,因而药代动力学特征不理想,最终导致诊断成像窗期缩短。
水溶性交联纳米聚合物造影剂被越来越多地用于诊断和药物运载,很重要的原因是其可以模拟细胞环境的高亲和性和多价的相互作用。目前以聚合物纳米颗粒为主体的T1MRI造影剂的研究和临床应用已经越来越受到重视。聚合物纳米T1MRI造影剂具有较好的物理和化学稳定性,可以有效提高药代动力学,延长细胞组织停留时间,抵御体内酶降解,同时能降低肾小球和滑膜过滤以减少背景吸收。聚合物纳米诊断颗粒还具备别的优势,如可集多种影像手段于一身,实现多种图像诊断的联用;在纳米材料中可引入相应的治疗药物,在影像同时实现治疗药物的输送和释放,是一种用于核磁共振仪器探测人体内的肿瘤细胞及其他病变细胞的新型有机造影剂。该造影剂是由有机合成的纳米级球形聚合物,其表面有与人体内癌细胞及其他病变细胞相互作用的官能团,从而实现在仪器中显现人体病变细胞的造影图像。
发明内容
本发明旨在提供一种具有高弛豫率的水溶性交联纳米聚合物及其合成方法和用途,所要解决的技术问题是通过分子设计手段,合成一种具有高弛豫率的水溶性交联纳米聚合物,以作为磁共振成像造影剂使用。
本发明具有高弛豫率的水溶性交联纳米聚合物,其结构通式如下所示:
其中x、y、z的数值区间分别为1-500,w的数值区间为0.5-100,n的数值区间为1-100。
本发明具有高弛豫率的水溶性交联纳米聚合物的制备方法,是以聚乙二醇甲基丙烯酸酯(OEGMA-300)、甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯(HEMA-2BA-DO3A)、4-氰基-4-(硫代苯甲酰)戊酸为原料,以偶氮二异丁腈(AIBN)为引发剂,首先合成了亲水段的线性纳米聚合物;再以此亲水段的线性纳米聚合物、乙二醇二甲基丙烯酸酯(EGDMA)和甲基丙烯酸二乙氨基乙酯(DEAEMA)为原料,合成得到水溶性交联纳米聚合物;最后再对得到水溶性交联纳米聚合物在二氯甲烷(DCM)和三氟乙酸(TFA)条件下切断,异丙醇(IPA)和水的条件下,加入GdCl3·6H2O,进行Gd的螯合,透析后得到目标产物。
本发明,一方面,可以得到尺寸小于100nm的水溶性聚合物,另一方面,聚合物中Gd的引入,提高了整体聚合物的弛豫率,该纳米聚合物的弛豫率达到16.48mM-1·S-1,是市售Gd-DO3A弛豫率(3.5mM-1·S-1)的将近4.7倍。
本发明具有高弛豫率的水溶性交联纳米聚合物的制备方法,包括如下步骤:
步骤1:在氮气保护下,将聚乙二醇甲基丙烯酸酯、甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯(HEMA-2BA-DO3A)和4-氰基-4-(硫代苯甲酰)戊酸加入置有有机溶剂的配有聚合装置的聚合瓶中,同时加入偶氮二异丁腈作为引发剂,充氮冷冻除空气多次以除去聚合瓶中的氧气,然后升温至50-100℃搅拌反应2-48小时,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于20-80℃真空干燥后得到亲水段的线性纳米聚合物;
步骤2:以步骤1获得的线性纳米聚合物为原料,在配有聚合装置的聚合瓶中加入DEAEMA和EGDMA,再加入有机溶剂,充氮冷冻除空气多次,然后升温至50-100℃反应时间2-48h,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于20-80℃真空干燥后得到水溶性交联纳米聚合物;
步骤3:将步骤2得到的0.5-3g水溶性交联纳米聚合物在5-50ml的二氯甲烷(DCM)和1-20ml的三氟乙酸(TFA)条件下切断,以异丙醇(IPA)和水为混合溶剂,加入1-10gGdCl3·6H2O进行Gd的螯合,透析后得到目标产物。
步骤1中,所述有机溶剂选自四氢呋喃、氯仿或二氧六烷。
步骤1中,聚乙二醇甲基丙烯酸酯、甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯、4-氰基-4-(硫代苯甲酰)戊酸和偶氮二异丁腈的摩尔比为20-200:10-100:0.5-10:0.1-1。
步骤2中,DEAEMA和EGDMA的摩尔比为20-200:0.5-10。
步骤2中,有机溶剂选自四氢呋喃、N,N-二甲基甲酰胺或二氧六烷。
步骤3中,混合溶剂中IPA和水的体积百分比为90-50:10-50。
步骤3中,透析时使用1000D-12000D的透析袋。
本发明反应过程如下:
步骤1中,线性纳米聚合物的合成过程如下:
步骤2中,水溶性交联纳米聚合物的合成过程如下:
步骤3中,水溶性交联纳米聚合物的羧化和Gd3+的螯合过程如下:
本发明具有高弛豫率的水溶性交联纳米聚合物的用途,是作为核磁共振成像造影剂的应用。
与已有技术相比,本发明的有益效果体现在:
1、本发明通过可逆加成-断裂链转移聚合(RAFT聚合)的方法设计制备得到线性纳米聚合物,该方法制备得到的线性纳米聚合物既分子量可控,又继承了聚乙二醇甲基丙烯酸酯的优良的水溶性性能,还引入了DO3A的大环结构,为下一步的螯合Gd3+提供螯合位点。
2、本发明制备过程使用的原料及溶剂都比较环保,没有使用对环境污染大的材料,合成的纳米聚合物的后处理也简单容易,且溶剂可以重复使用,是一种环境友好型材料。
3、本发明制备工艺简单,成本低廉,收率超过80%。得到的目标产物粒径为10-200nm,能够在水中稳定分布和存在。
4、本发明最终得到的目标产物具有更高的弛豫率,测量值达到16.48mM-1*S-1,是市售Gd-DO3A弛豫率(3.5mM-1*S-1)的将近4.7倍,具有更好的造影效果。
附图说明
图1是本发明目标产物的结构模拟图。
图2是本发明目标产物在透射电子显微镜(TEM)下的透射电镜图,标尺为100nm,由图2可以看出,水溶性交联纳米聚合物的分布均匀,大小较为规整,尺寸大小约为40nm。
图3是本发明目标产物在动态光散射(DLS)中的粒径分布图。由图3可以看出,水溶性交联纳米聚合物的粒径分布较好,尺寸大小约为40nm。
图4是本发明目标产物的弛豫率图。由图4可以看出,水溶性交联纳米聚合物的弛豫率测量分布规整,线性拟合度较好,斜率大小代表其弛豫率,弛豫率大小达到了16.48mM-1*S-1,是市售Gd-DO3A弛豫率(3.5mM-1*S-1)的将近4.7倍。
具体实施方式
实施例1:
1、氮气保护下,将6g(0.02mol)聚乙二醇甲基丙烯酸酯、2.72g(0.004mol)甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯(HEMA-2BA-DO3A)和56mg(0.0002mol)的4-氰基-4-(硫代苯甲酰)戊酸加入史莱克管中,加入20ml二氧六烷作溶剂,同时加入3.28mg(0.00002mol)偶氮二异丁腈作为引发剂,油泵抽气-液氮冷冻-氮气充气三个循环,每个循环做10次;循环结束后升温至70℃搅拌反应12小时,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于80℃真空干燥后得到线性纳米聚合物,产率90%。
2、以4.37g步骤1获得的线性纳米聚合物为原料,在配有双排管、搅拌磁子的史莱克管中加入15.8mg(0.000018mol)EGDMA、1.64g(0.01mol)DEAEMA和溶剂二氧六烷,抽气-冷冻-充气三个循环,每个循环做10次;循环结束后,升温至70℃反应12h,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于80℃真空干燥后得到水溶性交联纳米聚合物,产率72%。
3、将步骤2获得的水溶性交联纳米聚合物在20ml二氯甲烷(DCM)和10ml三氟乙酸(TFA)条件下切断,旋转蒸发,干燥后得到产物,产率92%;将得到的产物溶解在14ml异丙醇(IPA)和6ml水的条件下,加入3.71g(0.01mol)GdCl3*6H2O,进行Gd的螯合,透析得到目标产物,产率82%。
实施例2:
1、氮气保护下,将3g(0.01mol)聚乙二醇甲基丙烯酸酯、1.36g(0.002mol)甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯(HEMA-2BA-DO3A)和28mg(0.0002mol)的4-氰基-4-(硫代苯甲酰)戊酸加入史莱克管中,加入10ml二氧六烷作溶剂,同时加入3.28mg(0.00004mol)偶氮二异丁腈作为引发剂,油泵抽气-液氮冷冻-氮气充气三个循环,每个循环做10次;循环结束后,升温至80℃搅拌反应12小时,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于80℃真空干燥后得到线性纳米聚合物,产率92%。
2、以2.68g步骤1获得的线性纳米聚合物为原料,在配有双排管、搅拌磁子的史莱克管中加入7.9mg(0.000009mol)EGDMA和0.82g(0.005mol)的DEAEMA,并加入二氧六烷作溶剂,抽气-冷冻-充气三个循环,每个循环做10次;循环结束后,升温至80℃反应12h,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于80℃真空干燥后得到水溶性交联纳米聚合物,产率76%。
3、将步骤2获得的水溶性交联纳米聚合物在10ml二氯甲烷(DCM)和5ml三氟乙酸(TFA)条件下切断,旋转蒸发,干燥后得到产物,产率92%;将得到的产物溶解在16ml异丙醇(IPA)和4ml水的条件下,加入1.85g(0.005mol)GdCl3*6H2O,进行Gd的螯合,透析得到目标产物,产率83%。
实施例3:
1、氮气保护下,将6g(0.02mol)聚乙二醇甲基丙烯酸酯、2.72g(0.004mol)甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯(HEMA-2BA-DO3A)和56mg(0.0002mol)的4-氰基-4-(硫代苯甲酰)戊酸加入史莱克管中,加入20ml N,N-二甲基甲酰胺作溶剂,同时加入3.28mg(0.00002mol)偶氮二异丁腈作为引发剂,油泵抽气-液氮冷冻-氮气充气三个循环,每个循环做10次;循环结束后,升温至80℃搅拌反应10小时,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于80℃真空干燥后得到线性纳米聚合物,产率92%。
2、以4.37g步骤1获得的线性纳米聚合物为原料,在配有双排管、搅拌磁子的史莱克管中加入15.8mg(0.000018mol)EGDMA、1.64g(0.01mol)DEAEMA,并加入10ml的N,N-二甲基甲酰胺作溶剂,抽气-冷冻-充气三个循环,每个循环做10次;循环结束后,升温至80℃反应12h,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于80℃真空干燥后得到水溶性交联纳米聚合物,产率75%。
3、将步骤2获得的水溶性交联纳米聚合物在20ml二氯甲烷(DCM)和10ml三氟乙酸(TFA)条件下切断,旋转蒸发,干燥后得到产物,产率90%;将得到的产物溶解在18ml异丙醇(IPA)和2ml水的条件下,加入3.71g(0.01mol)GdCl3*6H2O,进行Gd的螯合,透析得到目标产物,产率86%。
Claims (10)
2.一种权利要求1所述的具有高弛豫率的水溶性交联纳米聚合物的合成方法,其特征在于:
以聚乙二醇甲基丙烯酸酯、甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯、4-氰基-4-(硫代苯甲酰)戊酸为原料,以偶氮二异丁腈为引发剂,首先合成了亲水段的线性纳米聚合物;再以此亲水段的线性纳米聚合物、乙二醇二甲基丙烯酸酯和甲基丙烯酸二乙氨基乙酯为原料,合成得到水溶性交联纳米聚合物;最后再对得到水溶性交联纳米聚合物在二氯甲烷和三氟乙酸条件下切断,异丙醇和水的条件下,加入GdCl3·6H2O,进行Gd的螯合,透析后得到目标产物。
3.根据权利要求2所述的合成方法,其特征在于包括如下步骤:
步骤1:在氮气保护下,将聚乙二醇甲基丙烯酸酯、甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯和4-氰基-4-(硫代苯甲酰)戊酸加入置有有机溶剂的配有聚合装置的聚合瓶中,同时加入偶氮二异丁腈作为引发剂,充氮冷冻除空气多次以除去聚合瓶中的氧气,然后升温至50-100℃搅拌反应2-48小时,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于20-80℃真空干燥后得到亲水段的线性纳米聚合物;
步骤2:以步骤1获得的线性纳米聚合物为原料,在配有聚合装置的聚合瓶中加入DEAEMA和EGDMA,再加入有机溶剂,充氮冷冻除空气多次,然后升温至50-100℃反应时间2-48h,反应结束后在0℃的正己烷中沉降,过滤收集沉淀物,于20-80℃真空干燥后得到水溶性交联纳米聚合物;
步骤3:将步骤2得到的0.5-3g水溶性交联纳米聚合物在5-50ml的二氯甲烷和1-20ml的三氟乙酸条件下切断,以异丙醇和水为混合溶剂,加入1-10g GdCl3·6H2O进行Gd的螯合,透析后得到目标产物。
4.根据权利要求3所述的合成方法,其特征在于:
步骤1中,所述有机溶剂选自四氢呋喃、氯仿或二氧六烷。
5.根据权利要求3所述的合成方法,其特征在于:
步骤1中,聚乙二醇甲基丙烯酸酯、甲基丙烯酸羟基乙基乙酸-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸三叔丁酯、4-氰基-4-(硫代苯甲酰)戊酸和偶氮二异丁腈的摩尔比为20-200:10-100:0.5-10:0.1-1。
6.根据权利要求3所述的合成方法,其特征在于:
步骤2中,有机溶剂选自四氢呋喃、N,N-二甲基甲酰胺或二氧六烷。
7.根据权利要求3所述的合成方法,其特征在于:
步骤2中,DEAEMA和EGDMA的摩尔比为20-200:0.5-10。
8.根据权利要求3所述的合成方法,其特征在于:
步骤3中,混合溶剂中IPA和水的体积百分比为90-50:10-50。
9.根据权利要求3所述的合成方法,其特征在于:
步骤3中,透析时使用1000D-12000D的透析袋。
10.一种权利要求1所述的具有高弛豫率的水溶性交联纳米聚合物的用途,其特征在于:所述水溶性交联纳米聚合物在制备核磁共振成像造影剂中的应用。
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