CN114870037A - 一种叶酸受体靶向的大分子钆肿瘤磁共振造影剂及其制备方法与应用 - Google Patents
一种叶酸受体靶向的大分子钆肿瘤磁共振造影剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供了一种叶酸受体靶向的大分子钆肿瘤磁共振造影剂及其制备方法与应用。所述的叶酸受体靶向的大分子钆肿瘤磁共振造影剂由叶酸‑壳聚糖复合物与壳聚糖‑Gd‑DTPA复合物交联形成的纳米粒组成。其中叶酸可靶向作用于过度表达叶酸受体的肿瘤细胞,壳聚糖做为大分子可增加造影剂在肿瘤细胞内的滞留时间,两者结合可特异靶向肿瘤细胞,减少对正常组织的损害并明显增强造影效果,提高滞留时间。本发明还提供了本发明所述的叶酸受体靶向的大分子钆肿瘤磁共振造影剂的制备方法,所述方法操作简单、污染小、效率高。
Description
技术领域
本发明属于磁共振成像技术领域,涉及一种磁共振造影剂及其制备和应用,具体涉及一种叶酸受体靶向的大分子钆肿瘤磁共振造影剂及其制备和应用。
背景技术
目前,医学影像学在临床中被广泛应用于疾病的诊断,常用的成像技术包括磁共振成像(MRI)、X射线断层成像(CT)、正电子发射断层成像(PET)、放射性同位素成像(SPECT)、超声成像等。其中,磁共振成像(MRI)技术是一种革命性的医学诊断工具,具有无辐射损伤的安全性,能够高分辨率地将人体特定组织或器官可视化,广泛应用于炎症、梗塞和肿瘤等的诊断。磁共振造影剂作为磁共振影像检查的重要补充手段,其作用原理是与体内局部组织中水质子相互作用,改变其弛豫时间,从增强肿瘤组织和周边正常组织间的对比度,有效提高肿瘤诊断效率和精准度。
目前临床上常用的磁共振造影剂主要为含钆的小分子配合物,如二乙基三胺五乙酸(DTPA)-Gd和1,4,7,10-四氮杂环十二烷-1,4,7,10-四羧酸(DOTA)-Gd等,这些造影剂仍存在较多的局限性,如对肿瘤细胞的选择性较差,对成像质量的提高幅度不大;在体内的循环时间较短、易代谢;对肾功能不全的患者使用钆基造影剂可能会诱发严重的疾病,即肾源性全身性纤维化。因此,迫切需要开发更具有肿瘤靶向特异性的灵敏度高的核磁共振造影剂,以降低毒副作用、提高临床肿瘤诊断的效率和精准度。
发明内容
本发明的首要目的是为了克服现有磁共振造影剂的缺点与不足,提供一种叶酸受体靶向的大分子钆肿瘤磁共振造影剂。本发明通过叶酸偶联壳聚糖与壳聚糖偶联DTPA-Gd形成纳米粒,构建一种具有叶酸受体靶向性的纳米载体递送系统,可主动靶向至过度表达叶酸受体的肿瘤组织实现功能化。
本发明的另一目的在于提供所述的叶酸受体靶向的大分子钆肿瘤磁共振造影剂和应用。
为了实现上述目的,本发明通过以下技术方案实现。本发明提供一种叶酸受体靶向的大分子钆肿瘤磁共振造影剂,其组成为叶酸受体靶向分子叶酸(FA)、纳米材料壳聚糖(CS)、磁共振成像离子Gd3+、磁共振成像离子螯合分子二乙基三胺五乙酸(DTPA)和荧光素。
本发明的目的通过下述技术方案实现:
(1)所述靶向分子叶酸经羧基活化试剂活化后与酸性溶液中质子化的纳米材料壳聚糖通过羧基与氨基反应偶联形成FA-CS复合物;
(2)所述磁共振成像离子Gd3+与磁共振成像离子螯合分子DTPA通过配位键结合,形成DTPA-Gd复合物;
(3)DTPA与纳米材料壳聚糖同样通过氨基与羧基偶联,再与Gd3+结合,形成CS-DTPA-Gd复合物;所述CS-DTPA-Gd复合物与荧光素如FITC连接,形成荧光素标记的CS-DTPA-Gd复合物;
(4)所述荧光素标记的CS-DTPA-Gd复合物单独或与FA-CS复合物混合通过离子交联,分别形成荧光素标记的CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒。
所述的FA-CS复合物通过如下方法制备得到:
叶酸与羧基活化试剂在室温搅拌1h,使叶酸活化;活化后的叶酸缓慢滴加到pH在3.5-4.5范围的壳聚糖醋酸溶液,室温避光反应24h,调pH至9.0;经透析、离心及冷冻干燥制得所述的FA-CS复合物。
所述羧基活化试剂为碳化二亚胺盐酸盐和N-羟基琥珀酰亚胺。
所述的DTPA-Gd复合物通过如下方法制备得到:
磁共振成像离子螯合分子DTPA和顺磁金属盐氯化钆于水中回流搅拌过夜,经丙酮沉淀、过滤及干燥制得所述的DTPA-Gd复合物。
所述荧光素标记的CS-DTPA-Gd复合物通过如下方法制得:
磁共振成像离子螯合分子DTPA室温下与羧基活化试剂反应2h,使DTPA活化;活化后的叶酸缓慢滴加到pH在3.5-4.5范围的壳聚糖醋酸溶液,室温反应72h;随后加入顺磁金属盐氯化钆,继续反应30min,经透析、离心及冷冻干燥制得所述的CS-DTPA-Gd复合物。所述的CS-DTPA-Gd复合物与荧光素FITC混合反应,经离心洗涤得所述的荧光素FITC标记的CS-DTPA-Gd-FITC复合物。
所述的荧光素标记的CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒通过如下方法制得:
取适量的荧光素标记的CS-DTPA-Gd单独或与适量的FA-CS复合物混合溶液,边搅拌边缓慢滴加TPP溶液,经离心、冷冻干燥制得所述的荧光素标记的CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒。
本发明相对于现有技术具有如下的优点及效果:
(1)肿瘤组织具有高通透性及滞留效应(EPR),且肿瘤组织内部缺乏淋巴系统,纳米颗粒容易进入肿瘤并聚集。本发明以壳聚糖为材料制备具有较高肿瘤积累量的纳米颗粒磁共振造影剂,与传统的单一功能的造影剂相比,可实现体内长循环,增强对肿瘤靶向性,减少非特异性积累,降低对正常组织的损害,同时增强造影效果。
(2)本发明中所用叶酸是一种人体必需的维生素,叶酸受体(FR)是一种糖基磷脂酰肌醇(GPI)偶联蛋白。FR在人体许多部位的肿瘤细胞表面过度表达,尤其是在卵巢、子宫、大脑、结肠和乳腺中,而人体正常器官和组织的细胞表面基本没有FA的表达。本发明以叶酸受体为靶点,构建的叶酸受体靶向的大分子钆肿瘤磁共振造影剂可进一步选择靶向叶酸受体过度表达的肿瘤细胞,增强造影效果。
(3)用于本发明的叶酸及纳米颗粒材料壳聚糖对组织和细胞是无毒的,并且是可生物相容的,不会对正常组织产生损害。
附图说明
图1为实施例1的FA-CS复合物的FT-IR图。其中(a)FA-CS,(b)FA和(c)CS。
图2为实施例1的DTPA-Gd复合物和CS-DTPA-Gd复合物的FT-IR图。其中,(a)DTPA-Gd,(b)DTPA和(c)CS-DTPA-Gd。
图3为实施例1的FA-CS/CS-DTPA-Gd纳米粒的粒径分布(左)和Zeta电位(右)图。
图4为实施例1制得的FA-CS/CS-DTPA-Gd纳米粒的透射电子显微镜照片图。
图5为不同浓度的实施例1的DTPA-Gd复合物、CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒的MRI显影效果图。
图6为不同浓度的实施例1的DTPA-Gd复合物、CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒的弛豫速率关系图。
图7为不同浓度的实施例1的DTPA-Gd复合物、CS-DTPA-Gd复合物、CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒的细胞毒性结果分析图。其中(a)A549细胞,(b)HeLa细胞。
图8为CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒的A549细胞、HeLa细胞荧光成像结果分析图。其中,(a)和(c)未经游离叶酸阻断叶酸受体;(b)和(d)预先使用1mM游离叶酸阻断叶酸受体。
图9为CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒的细胞荧光强度值结果分析图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细地描述。
实施例1:叶酸受体靶向的大分子钆肿瘤磁共振造影剂的制备
(1)FA-CS复合物的制备
取适量的叶酸,用无水DMSO溶解,配制成浓度为20mg/mL的溶液,加入5倍量的碳化二亚胺盐酸盐和N-羟基琥珀酰亚胺,室温下避光搅拌约1h,得到活化后的叶酸溶液。取适量壳聚糖溶解于1%醋酸溶液中,制备5mg/mL壳聚糖溶液,用6M的氢氧化钠溶液调节pH=4.7。边搅拌边缓慢滴加活化后的叶酸溶液,室温避光反应24h后,用NaOH调节溶液pH=9.0。使用截留分子量为1000的透析袋,经pH7.4的PBS透析三天,再经二次蒸水透析三天(每天换三次溶液)后,经离心、冷冻干燥后即得淡黄色FA-CS复合物。
(2)DTPA-Gd复合物的制备
分别取2.5mmol的DTPA和六水氯化钆置于圆底烧瓶中,加入20mL纯化水,回流搅拌过夜,过滤,滤液加入三倍体积的丙酮,析出白色沉淀,抽滤,干燥,得到白色的DTPA-Gd复合物粉末。
(3)CS-DTPA-Gd复合物的制备
取适量DTPA加入pH4.7的TEMED/HCl缓冲溶液中,室温下避光搅拌使溶解,之后加入过量的碳化二亚胺盐酸盐和N-羟基琥珀酰亚胺,继续搅拌2h,将DTPA活化,反应过程中控制溶液pH值在3.5-4.5范围内。将活化后的DTPA缓慢滴加到pH4.7的壳聚糖溶液中,室温搅拌72h后,加入过量的六水氯化钆,继续搅拌30min。然后将溶液用截留分子量为1000的透析袋透析3天,每五个小时更换一次双蒸水,经冷冻干燥,得到CS-DTPA-Gd复合物。
(4)FITC荧光素的标记
将适量的步骤(3)制得的CS-DTPA-Gd复合物溶于0.5%的醋酸溶液中,然后加入10mL甲醇,再缓慢加入2mg/mL的FITC甲醇溶液,室温暗处反应3h后,用0.2M的NaOH沉淀产物,离心,用体积比为7:3的甲醇水溶液洗涤,直至上清液无荧光检出,干燥。
(5)FA-CS/CS-DTPA-Gd纳米粒的制备
取适量的步骤(1)制得的FA-CS复合物和适量的步骤(4)制得的标记有荧光素的CS-DTPA-Gd复合物混合,溶解于10mL的1%醋酸溶液中,并用1M的NaOH溶液调节pH值为5.0,边搅拌边缓慢滴加TPP溶液,继续搅拌10min,反应完成后,经低温离心、冷冻干燥,得到FA-CS/CS-DTPA-Gd纳米粒,即为所述的叶酸受体靶向的大分子钆肿瘤磁共振造影剂。
实施例2:叶酸受体靶向的大分子钆肿瘤磁共振造影剂的傅里叶红外光谱表征
取实施例1制得的FA-CS复合物、DTPA-Gd复合物和CS-DTPA-Gd复合物适量,以及CS、FA和DTPA,通过溴化钾压片法,在4000~500cm-1范围内用FT-IR谱仪测定。
CS、FA、FA-CS复合物的FT-IR结果如图1所示。
CS(c)1020cm-1处的峰是C-O-C的典型振动,FA(b)在1694、1606和1484cm-1处的强吸收峰,分别归因于FA的C=O、蝶啶环氨基和苯环特征吸收峰。FA-CS复合物(a)中原有的叶酸的1694cm-1消失,由于形成新的酰胺键在1649cm-1处吸收峰增强。此外,在1603cm-1处出现一个新峰,这是叶酸盐的典型振动,1504cm-1处为苯环的特征峰,证实FA-CS复合物成功制备。
DTPA、DTPA-Gd复合物、CS-DTPA-Gd复合物的FT-IR结果如图2所示。
DTPA(b),1733,1697,1633cm-1处分别为以单体、二聚体和羧酸盐形式下羧基的C=O伸缩振动吸收峰;DTPA-Gd复合物(a)在1733,1697,1633cm-1处峰消失,由于羧基形成配位键出现了1589cm-1新峰,表明DTPA螯合Gd形成新的配位化合物,证明DTPA-Gd复合物成功制备;CS-DTPA-Gd复合物(c)在1020cm-1附近由壳聚糖C-O-C的典型振动吸收峰的同时,1576cm-1DTPA-Gd络合物中羧基的吸收峰,证明CS-DTPA-Gd复合物成功制备。
实施例3:叶酸受体靶向的大分子钆肿瘤磁共振造影剂的粒径和Zeta电位表征
取实施例1制得的FA-CS/CS-DTPA-Gd纳米粒,配制成适宜浓度的溶液,用动态激光散射仪与电位分析仪测定粒径、粒径分布及Zeta电位。
结果如图3所示,FA-CS/CS-DTPA-Gd纳米粒粒径大小分布均匀,分散性良好,平均粒径为120.12±1.29nm,PDI为0.154±0.02;平均电位为6.61±0.24mV,体系较稳定。
实施例4:叶酸受体靶向的大分子钆肿瘤磁共振造影剂的透射电镜(TEM)表征
取实施例1制得的FA-CS/CS-DTPA-Gd纳米粒,配制成适宜浓度的溶液,用透射电镜观察纳米粒外观形态。
结果如图4所示,FA-CS/CS-DTPA-Gd纳米粒外观呈球形或类球形。
实施例5:叶酸受体靶向的大分子钆肿瘤磁共振造影剂的Gd3+浓度测定
取实施例1制得的CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒,配制成适宜浓度的溶液,通过电感耦合等离子体发射光谱仪测定纳米粒中Gd3+的浓度。
结果显示实施例1制得的CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒中Gd3+的浓度分别为178.23mg/L和102.93mg/L。
实施例6:叶酸受体靶向的大分子钆肿瘤磁共振造影剂的体外磁性能测试
使用磁共振成像仪在T1扫描序列下进行扫描,即固定回波时间(TE)为15.5ms,改变重复时间(TR)对不同浓度的实施例1制得的DTPA-Gd复合物、CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒进行扫描,记录弛豫时间(T1)。
结果显示实施例1制得的DTPA-Gd复合物、CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒的弛豫速率(R1)分别为为3.0mM-1·s-1、7.8mM-1·s-1和7.5mM-1·s-1,CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒的R1值均比DTPA-Gd复合物的高,证明实施例1制得的CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒具有更好的显影效果。显影效果图及弛豫速率关系图如图5,图6所示。
实施例7:叶酸受体靶向的大分子钆肿瘤磁共振造影剂的细胞毒性测试
对实施例1制得的DTPA-Gd复合物、CS-DTPA-Gd复合物、CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒进行细胞毒性进行测试,所用细胞为HeLa细胞和A549细胞,结果如图7所示,所制备的复合物及纳米粒对两种细胞均无明显的细胞毒性。
实施例8:叶酸受体靶向的大分子钆肿瘤磁共振造影剂的体外细胞靶向性测试
用荧光显微镜观察实施例1制得的CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒在经或不经叶酸受体饱和的HeLa细胞和A549细胞的荧光成像情况并通过0.10%的曲拉通X-100将细胞摄取的荧光素溶出,用荧光分光光度计测定荧光强度。
结果如图8所示,两种纳米粒对经或不经叶酸受体饱和的A549细胞均呈现较弱的荧光成像。没有叶酸靶向性的CS-DTPA-Gd纳米粒对HeLa细胞所呈现的荧光成像不受叶酸受体是否饱和的影响,呈现几乎相同荧光强度;而FA-CS/CS-DTPA-Gd纳米粒对经和未经叶酸受体饱和的HeLa细胞,分别表现出较不同的荧光强度,未经叶酸受体饱和的样品组荧光强度更强。荧光强度的大小如图9所示,所制备的FA-CS/CS-DTPA-Gd纳米粒具有较优异的肿瘤细胞靶向性,能特异性结合过度表达叶酸受体的肿瘤细胞。
Claims (10)
1.一种叶酸受体靶向的大分子钆肿瘤磁共振造影剂及其制备方法与应用。其特征在于:
所述磁共振造影剂由叶酸受体靶向分子叶酸(FA)、纳米材料壳聚糖(CS)、磁共振成像离子Gd3+、磁共振成像离子螯合分子二乙基三胺五乙酸(DTPA)和荧光素组成。
2.根据权利要求1所述的磁共振造影剂,其特征在于:
所述叶酸受体靶向分子叶酸与纳米材料壳聚糖通过羧基与氨基反应形成FA-CS复合物;所述磁共振成像离子Gd3+与磁共振成像离子螯合分子DTPA通过配位反应结合,形成DTPA-Gd复合物;所述DTPA-Gd复合物与纳米材料壳聚糖通过氨基与羧基偶联形成CS-DTPA-Gd复合物。
3.根据权利要求1所述的磁共振造影剂,其特征在于:
所述的CS-DTPA-Gd复合物单独或与所述的FA-CS复合物通过离子交联形成CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒。
4.根据权利要求1所述的磁共振造影剂,其特征在于:
所述的荧光标记的CS-DTPA-Gd复合物单独或与所述的FA-CS复合物通过离子交联形成荧光标记的CS-DTPA-Gd纳米粒和荧光标记的FA-CS/CS-DTPA-Gd纳米粒。
5.根据权利要求1~4任一项所述的磁共振造影剂的制备方法,其特征在于,包括如下步骤:
(1)叶酸受体靶向分子叶酸经羧基活化试剂活化后滴加到纳米材料壳聚糖的醋酸溶液中,调整反应体系pH为弱酸性,搅拌24h进行反应,纯化干燥后得到FA-CS复合物;
(2)将顺磁金属盐与金属离子螯合分子DTPA混合搅拌过夜进行配位化合物,过滤干燥得到DTPA-Gd复合物;
(3)将步骤(2)制得的DTPA-Gd复合物经羧基活化试剂活化后与纳米材料壳聚糖的醋酸溶液混合,调整反应体系pH为弱酸性,搅拌72h进行反应,纯化干燥后得到CS-DTPA-Gd复合物;将荧光素与制得的CS-DTPA-Gd复合物混合反应,得到荧光素标记的CS-DTPA-Gd复合物。
6.根据权利要求5所述的磁共振造影剂的制备方法,其特征在于:
步骤(1)和(3)中所述的羧基活化试剂为碳化二亚胺盐酸盐和N-羟基琥珀酰亚胺;所述弱酸性的pH值为3.5-4.5;所述纯化为透析纯化;步骤(2)中所述顺磁性金属离子由顺磁性金属盐提供,所述顺磁性金属离子为钆离子;步骤(3)中所述的荧光素为已活化的荧光物质,如异硫氰酸荧光素(FITC)。
7.根据权利要求1~4任一项所述的磁共振造影剂的制备方法,其特征在于,纳米粒的制备包括如下步骤:
向权利要求5中步骤(3)制得的荧光素标记的CS-DTPA-Gd复合物醋酸溶液或其与权利要求5中步骤(1)制得的FA-CS复合物混合的醋酸溶液中滴加三聚磷酸钠(TPP)交联反应10min,离心干燥,分别得到有荧光素标记的CS-DTPA-Gd纳米粒和FA-CS/CS-DTPA-Gd纳米粒。
8.根据权利要求5和权利要求6所述的磁共振造影剂的制备方法,其特征在于:所述干燥方法为冷冻干燥。
9.根据权利要求1所述的磁共振造影剂,作为肿瘤影像学诊断中的应用。
10.根据权利要求1所述的叶酸受体靶向的大分子,作为制备叶酸受体靶向药物中的应用。
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