CN108434458A - 可用于肿瘤诊断和靶向治疗的纳米复合物及其制备方法 - Google Patents

可用于肿瘤诊断和靶向治疗的纳米复合物及其制备方法 Download PDF

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CN108434458A
CN108434458A CN201810371735.3A CN201810371735A CN108434458A CN 108434458 A CN108434458 A CN 108434458A CN 201810371735 A CN201810371735 A CN 201810371735A CN 108434458 A CN108434458 A CN 108434458A
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aldehyde radical
hyaluronic acid
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程翠
孟亚彬
章志鸿
李亚
张其清
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Abstract

本发明公开了一种可用于肿瘤诊断和靶向治疗的纳米复合物及其制备方法。制备方法为：先将Cy5.5标记聚乙二醇胺通过酰胺化反应接枝到醛基化透明质酸上，制备Cy5.5标记聚乙二醇接枝醛基化透明质酸，再将其通过离子配位和席夫碱反应与顺铂进行复合，得到顺铂‑Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物。本发明所需原料简单，制备工艺纯熟，易于操作，制备的纳米复合物尺寸适中、生物相容性好、载药适中，不仅具有良好的肿瘤主/被动靶向和药物控释作用，提高了肿瘤部位的药物聚积，延长了药物在血液中的循环时间，降低了药物毒性，还具有荧光成像特性，利于对肿瘤部位进行诊断。

Description

可用于肿瘤诊断和靶向治疗的纳米复合物及其制备方法
技术领域
本发明属于高分子药物载体领域，具体涉及一种可用于肿瘤诊断和靶向治疗的纳米复合物及其制备方法。
背景技术
顺铂是临床上最常用的抗肿瘤药之一，具有抗癌作用强、抗癌活性高、可与多种抗肿瘤药物配伍产生协同作用且无交叉耐药等特点，是化疗中不可缺少的药物。顺铂在临床上多以注射剂使用，但其在体内很快与蛋白质结合而失效，且容易被体内所有快代谢细胞同等摄取、经肾排泄，产生了剂量限制性毒性。因此，寻求一种方法来增加顺铂的体内循环时间、降低药物对正常细胞的毒性成为关键。为此，纳米载体应运而生。纳米载体不仅具有能穿过组织间隙、进入细胞、通过人体最小的毛细血管，甚至具有能通过血脑屏障的特性，还具有靶向、缓释、高效、低毒，可以实现口服、静脉注射及敷贴等多种给药途径等诸多优点。其中，靶向性纳米载体是一类由天然高分子物质或合成高分子材料制成的粒径为纳米级的载体，其表面经过生物修饰或理化修饰后具有靶向作用。靶向性纳米载体又分为被动靶向和主动靶向。被动靶向性纳米载体主要指通过利用载体的亲/疏水性、静电作用、载体的大小、质量、pH值等理化因素增加载药载体与靶器官接触，减少与非靶器官接触，从而增加靶部位与非靶部位药物的比率。常用的被动靶向载体有聚乙二醇、多糖等修饰的纳米颗粒。主动靶向性纳米载体是指由单克隆抗体、磁趋向、受体介导的靶向制剂，由于它对靶器官具有高度的选择性和特异性而具有很好的发展前景。如磁性纳米载体、叶酸介导纳米载体、透明质酸纳米颗粒等。
其中，透明质酸（HA）是存在于细胞外基质和滑液中的天然多糖。由于其良好的生物相容性和生物降解性，HA已被广泛用于生物医学，如组织工程，药物递送和分子成像。研究发现，HA可以特异性地与表面过表达CD44的各种癌细胞结合，因此，HA被作抗肿瘤药物的靶向载体而广泛研究。但是，HA纳米颗粒在全身给药后存在一个缺点，那就是，纳米颗粒进入血液循环后，浓度被大大稀释，极易被运输至肝脏、肾脏处代谢，只有极少量的纳米颗粒保留在血液中。为解决此问题，可在纳米颗粒表面修饰聚乙二醇及其衍生物，因为聚乙二醇能防止与血液接触时血小板在材料表面的沉积，有效延长纳米颗粒在体内的半衰期，从而达到血液长循环的效果。因此，将聚乙二醇衍生物接枝到透明质酸衍生物上，用作顺铂的药物载体，不仅可大大延长顺铂在体内的血液循环时间，还可主动靶向CD44等受体富集的肿瘤部位，增强顺铂的治疗效果，降低药物对正常组织的毒副作用。此外，在纳米粒外接有少量近红外荧光染料Cy5.5有利于实时监控纳米粒在体内轨迹从而更好的研究纳米粒在治疗过程中的分布以及在血液中的循环情况。
发明内容
本发明的目的旨在提供一种可用于肿瘤诊断和治疗的醛基化透明质酸纳米复合物及其制备方法。本发明所需原料简单，制备工艺纯熟，易于操作，不需要昂贵的仪器，且制备的纳米复合物尺寸适中、生物相容性好、载药适中，不仅具有良好的靶向作用和药物控释作用，还可以大大提高纳米粒在血液中的循环时间，血液长循环有利于顺铂纳米微粒通过渗透增强和滞留效应提高肿瘤部位的药物聚积，从而实现对肿瘤部位的主动和被动靶向性输送，提高治疗效果。此外，在纳米粒外接有少量近红外荧光染料Cy5.5有利于实时监控纳米粒在体内轨迹从而更好的研究纳米粒在治疗过程中的分布以及在血液中的循环情况。
为实现上述目的，本发明采用如下技术方案：
Cy5.5标记聚乙二醇接枝醛基化透明质酸的制备：室温下将醛基化透明质酸（A-HA）溶于双蒸水，向该溶液中加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDC）和N-羟基琥珀酰亚胺（NHS），避光反应4 h后，加入Cy5.5标记聚乙二醇（Cy5.5-PEG-NH2）继续反应8 h，然后将溶液转移至透析袋（MWCO 3500）在室温条件下透析3 d，每隔8 h换一次水，随后冷冻干燥3 d，得到Cy5.5标记聚乙二醇接枝醛基化透明质酸（Cy5.5-PEG-g-A-HA）。其中醛基化透明质酸与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的摩尔比为1:1:1，醛基化透明质酸与Cy5.5标记聚乙二醇质量比为1:0.25，醛基化透明质酸与双蒸水的质量比为：1:100。
顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物的制备：将顺铂（CDDP）和Cy5.5标记聚乙二醇接枝醛基化透明质酸（Cy5.5-PEG-g-A-HA）在37℃分别溶于双蒸水中，配成2 mg/mL的顺铂溶液和10 mg/mL的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液。在37℃超声作用下，将上述顺铂溶液逐滴滴加到Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液中，然后室温搅拌2 d，即可形成顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物（Cy5.5-PEG-g-A-HA-CDDP）。将所得纳米复合物溶液置于透析袋（MWCO 2000）中透析6h除去未反应的顺铂，之后进行预冻，再转入真空冷冻干燥箱中冷冻干燥3 d，即得干燥的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物（Cy5.5-PEG-g-A-HA-CDDP），其粒径为213.7-268.2 nm。所述Cy5.5标记聚乙二醇接枝醛基化透明质酸与顺铂质量比为：1:0.10-0.30。
本发明的显著优点在于：本发明所制备的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物，顺铂是通过与Cy5.5标记聚乙二醇接枝醛基化透明质酸上的醛基和羧基发生席夫碱反应或离子配位反应，形成以亚胺键或配位键连接的顺铂透明质酸复合物，复合物再通过自组装形成顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物。此外，醛基化透明质酸分子中的C-O-C 和-OH 结构非常容易给出电子，可与顺铂中的N-H 部位发生氢键相互作用，此时顺铂在醛基化透明质酸内部吸附时，体系更加稳定。由于顺铂与醛基化透明质酸有氢键作用，因此很容易在环境pH 值改变时，导致氢键裂解，从而释放顺铂分子。通过此种方式的纳米复合物，用于静脉注射给药时，顺铂以稳定方式负载，具有一定的缓释效果，表面修饰Cy5.5标记聚乙二醇可以大大提高纳米粒在血液中的循环时间，血液长循环有利于顺铂纳米微粒通过渗透增强和滞留效应提高肿瘤部位的药物聚积，从而实现对肿瘤部位的主动和被动靶向性输送，提高治疗效果，且纳米复合物中透明质酸对肿瘤细胞具有靶向作用，减少了顺铂在正常组织的聚集，更多的作用于肿瘤部位，达到在肿瘤治疗中高效减毒的目的。此外，在纳米粒外接有少量近红外荧光染料Cy5.5有利于实时监控纳米粒在体内轨迹从而更好的研究纳米粒在治疗过程中的分布以及在血液中的循环情况。
附图说明
图1是顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物扫描电镜图（Cy5.5标记聚乙二醇接枝醛基化透明质酸与顺铂的质量比为1:0.15）。
具体实施方式
以下结合具体实施例对本发明做进一步说明，但本发明不仅仅限于这些实施例。
实施例1
1）称取1.000 g醛基化透明质酸，溶于100 mL双蒸水中，磁力搅拌至完全溶解；
2）称取1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺各0.504 g和0.303 g加入步骤1）所得溶液中避光反应4 h；
3）称取0.25 g Cy5.5标记聚乙二醇加入步骤2）所得溶液中反应8 h；
4）将步骤3）得到的溶液置于MWCO 3500的透析袋中于室温下透析3 d，期间每隔8 h换一次水，冷冻干燥3 d得到Cy5.5标记聚乙二醇接枝醛基化透明质酸；
5）称取1.000 g Cy5.5标记聚乙二醇接枝醛基化透明质酸，在37℃下溶于双蒸水中，配成10 mg/mL的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液；
6）称取100 mg顺铂，在37℃下溶于双蒸水中配成2 mg/mL的顺铂溶液；
7）超声作用下将步骤6）得到的顺铂溶液逐滴滴加至步骤5）得到的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液之后转移至磁力搅拌器上室温搅拌2 d；
8）将步骤7）制得的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米粒转移至MWCO2000透析袋中避光透析6 h；
9）将步骤8）中透析后的纳米粒冷冻干燥3 d，得到干燥的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸复合物。
实施例2
1）称取1.000 g醛基化透明质酸，溶于100 mL双蒸水中，磁力搅拌至完全溶解；
2）称取1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺各0.504 g和0.303 g加入步骤1）所得溶液中避光反应4 h；
3）称取0.25 g Cy5.5标记聚乙二醇加入步骤2）所得溶液中反应8 h；
4）将步骤3）得到的溶液置于MWCO 3500的透析袋中于室温下透析3 d，期间每隔8 h换一次水，冷冻干燥3 d得到Cy5.5标记聚乙二醇接枝醛基化透明质酸；
5）称取1.000 g Cy5.5标记聚乙二醇接枝醛基化透明质酸，在37℃下溶于双蒸水中，配成10 mg/mL的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液；
6）称取150 mg顺铂，在37℃下溶于双蒸水中配成2 mg/mL的顺铂溶液；
7）超声作用下将步骤6）得到的顺铂溶液逐滴滴加至步骤5）得到的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液之后转移至磁力搅拌器上室温搅拌2 d；
8）将步骤7）制得的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米粒转移至MWCO2000透析袋中避光透析6 h；
9）将步骤8）中透析后的纳米粒冷冻干燥3 d，得到干燥的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸复合物。
实施例3
1）称取1.000 g醛基化透明质酸，溶于100 mL双蒸水中，磁力搅拌至完全溶解；
2）称取1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺各0.504 g和0.303 g加入步骤1）所得溶液中避光反应4 h；
3）称取0.25 g Cy5.5标记聚乙二醇加入步骤2）所得溶液中反应8 h；
4）将步骤3）得到的溶液置于MWCO 3500的透析袋中于室温下透析3 d，期间每隔8 h换一次水，冷冻干燥3 d得到Cy5.5标记聚乙二醇接枝醛基化透明质酸；
5）称取1.000 g Cy5.5标记聚乙二醇接枝醛基化透明质酸，在37℃下溶于双蒸水中，配成10 mg/mL的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液；
6）称取200 mg顺铂，在37℃下溶于双蒸水中配成2 mg/mL的顺铂溶液；
7）超声作用下将步骤6）得到的顺铂溶液逐滴滴加至步骤5）得到的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液之后转移至磁力搅拌器上室温搅拌2 d；
8）将步骤7）制得的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米粒转移至MWCO2000透析袋中避光透析6 h；
9）将步骤8）中透析后的纳米粒冷冻干燥3 d，得到干燥的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸复合物。
实施例4
1）称取1.000 g醛基化透明质酸，溶于100 mL双蒸水中，磁力搅拌至完全溶解；
2）称取1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺各0.504 g和0.303 g加入步骤1）所得溶液中避光反应4 h；
3）称取0.25 g Cy5.5标记聚乙二醇加入步骤2）所得溶液中反应8 h；
4）将步骤3）得到的溶液置于MWCO 3500的透析袋中于室温下透析3 d，期间每隔8 h换一次水，冷冻干燥3 d得到Cy5.5标记聚乙二醇接枝醛基化透明质酸；
5）称取1.000 g Cy5.5标记聚乙二醇接枝醛基化透明质酸，在37℃下溶于双蒸水中，配成10 mg/mL的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液；
6）称取300 mg顺铂，在37℃下溶于双蒸水中配成2 mg/mL的顺铂溶液；
7）超声作用下将步骤6）得到的顺铂溶液逐滴滴加至步骤5）得到的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液之后转移至磁力搅拌器上室温搅拌2 d；
8）将步骤7）制得的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米粒转移至MWCO2000透析袋中避光透析6 h；
9）将步骤8）中透析后的纳米粒冷冻干燥3 d，得到干燥的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸复合物。
以上所述仅为本发明的制备方法，凡依本发明申请专利范围所做的均等变化与修饰，皆应属本发明的涵盖范围。

Claims (6)

1.一种可用于肿瘤诊断和靶向治疗的纳米复合物，其特征在于：该纳米复合物由醛基化透明质酸、Cy5.5标记聚乙二醇胺和顺铂组成，其粒径为213.7-268.2 nm。
2.一种如权利要求1所述的可用于肿瘤诊断和靶向治疗的纳米复合物的制备方法，其特征在于：将醛基化透明质酸与Cy5.5标记聚乙二醇胺在1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺作用下发生酰胺化反应，形成Cy5.5标记聚乙二醇接枝醛基化透明质酸，之后将Cy5.5标记聚乙二醇接枝醛基化透明质酸与顺铂在水溶液中复合，所得溶液再经透析、干燥后即制得顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物。
3.根据权利要求2所述的制备方法，其特征在于：包括以下步骤：
1）室温下将醛基化透明质酸溶于双蒸水，向该溶液中加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，避光反应4 h，然后加入Cy5.5标记聚乙二醇胺继续反应8 h；
2）将步骤1）反应所得溶液置于透析袋中，在室温条件下透析3 d，每隔8 h换一次水，冷冻干燥3 d，得到Cy5.5标记聚乙二醇接枝醛基化透明质酸；
3）将顺铂和Cy5.5标记聚乙二醇接枝醛基化透明质酸在37 ℃下分别溶于双蒸水中，分别配成2 mg/mL的顺铂溶液和10 mg/mL的Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液，超声作用下将顺铂溶液逐滴滴加至Cy5.5标记聚乙二醇接枝醛基化透明质酸溶液中，然后室温搅拌2 d；
4）将步骤3）所得溶液置于透析袋中透析6 h除去未反应的顺铂，冷冻干燥3 d，即得干燥的顺铂-Cy5.5标记聚乙二醇接枝醛基化透明质酸纳米复合物。
4.根据权利要求3所述的制备方法，其特征在于：步骤1）中，所述醛基化透明质酸与双蒸水的质量比为：1:100，醛基化透明质酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的摩尔比为1:1:1。
5.根据权利要求3所述的制备方法，其特征在于：步骤1）中，所述醛基化透明质酸与Cy5.5标记聚乙二醇胺的质量比为1:0.25。
6.根据权利要求3所述的制备方法，其特征在于：步骤3）中所述的Cy5.5标记聚乙二醇接枝醛基化透明质酸和顺铂的质量比为：1:0.10-0.30。
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