CN113679836A - 一种靶向zif-8-聚多巴胺前药纳米粒子及其制备方法和应用 - Google Patents
一种靶向zif-8-聚多巴胺前药纳米粒子及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种靶向ZIF‑8‑聚多巴胺前药纳米粒子及其制备方法和应用，先将多巴胺‑阿霉素、多巴胺和氯化锌溶于乙醇/去离子水的混合溶剂中，再滴加氨水，调节溶液pH值至8.0～8.5；搅拌反应后，滴加2‑甲基咪唑的乙醇/去离子水混合溶液，继续搅拌反应，反应结束后，经透析得到ZIF‑8‑聚多巴胺前药纳米粒子；最后将ZIF‑8‑聚多巴胺前药纳米粒子与聚乙二醇‑叶酸混合加入去离子水中，搅拌反应后，经透析得到靶向ZIF‑8‑聚多巴胺前药纳米粒子。本发明用以解决现有技术中纳米药物结构单一、缺乏主动靶向性的问题，以及化疗与光热治疗的联合治疗等问题。
Description
技术领域
本发明属于生物医药技术领域，具体涉及一种靶向ZIF-8-聚多巴胺前药纳米粒子及其制备方法和应用。
背景技术
近年来，癌症已经超越了心脏病并成为全世界人类面临的主要死亡病因。因此，开发简便高效的抗癌策略是一项急需解决的重大技术难题。目前，临床化疗是最方便、应用最广泛的癌症有效治疗手段之一，其中应用最多的抗癌药物是阿霉素。但是，化疗往往存在着杀死正常细胞，破坏免疫***和增加二次癌症发病率的风险，而光热疗法作为治疗癌症的高效新型技术，虽然具有高选择性和微创性，也会受到间歇性照射、局部组织过热损伤、疤痕化、肿瘤消融不完全和复发等临床应用难题。因此，利用个体化治疗的优势进行联合治疗，开发具有光热疗-化疗一体化协同作用的纳米药物体系，为解决上述问题提供了一种提高疗效、减少副作用的综合治疗策略，具有实现肿瘤高效治疗的临床应用前景。
此外，传统的纳米药物大多是通过物理包埋的方式将化疗药物包封在纳米载体内部，利用EPR效应将药物输送到肿瘤部位。该方法虽然在一定程度上改善了抗肿瘤的效果，但存在载药率低、药物过早泄露、稳定性差等问题。为此，将小分子药物通过刺激响应性化学键制备成前药分子，不仅增强了药物的溶解性和稳定性，降低了药物的***毒性，而且链接的化学键在内部或外部刺激源的作用下，可以响应性地释放出药物，实现对药物的控制释放，提高治疗效果。因此，将刺激响应性、前药和纳米药物相结合，设计制备刺激响应性的纳米前药体系，对癌症治疗领域具有重要的研究意义以及实用价值。
文献检索发现，Chang Du等人在题目为《基于生物聚合物-药物偶联物的纳米治疗诊断学用于多模式成像引导的光热疗-化疗协同治疗》的论文中(《Biopolymer-DrugConjugate Nanotheranostics for Multimodal Imaging-Guided Synergistic CancerPhotothermal-Chemotherapy》，Chang Du,Jiwen Qian,Linzhu Zhou,Yue Su,Rong Zhang,Chang-Ming Dong*，ACS Appl.Mater.Interfaces 2017,9,31576-31588)报道了关于聚多巴胺-阿霉素前药纳米粒子的制备及其性能研究。但是，上述体系中聚多巴胺-阿霉素前药纳米粒子存在结构单一、缺乏主动靶向性等问题，不能实现对具有主动靶向性的光热疗法-化疗一体化治疗，难于在临床中转化和应用。
中国专利CN106831905B公开了一种pH响应性多巴胺-多巴胺缀合物及其前药纳米粒子的合成方法，即先由3,4-二羟基苯基丙酸合成叔丁基-2-(3-(3,4-二羟基苯基)丙酰基)联胺羧酸酯，经叔丁基-2-(3-(3,4-二羟基苯基)丙酰基)联胺羧酸酯脱去叔丁氧羰基合成3-(3,4-二羟基苯基)丙酰肼，再以3-(3,4-二羟基苯基)丙酰肼与阿霉素盐酸盐反应合成多巴胺-阿霉素缀合物分子，并以多巴胺-阿霉素缀合物分子与多巴胺盐酸盐合成阿霉素-聚多巴胺前药纳米粒子。但此阿霉素-聚多巴胺前药纳米粒子结构单一，且缺乏主动靶向肿瘤的作用。
发明内容
为了克服现有技术存在的缺陷，本发明提供一种靶向ZIF-8-聚多巴胺前药纳米粒子及其制备方法和应用，用以解决现有技术中纳米药物结构单一、缺乏主动靶向性的问题，以及化疗与光热治疗的联合治疗等问题，将增强细胞内摄的化疗与光热治疗相结合，通过二者联合疗法的协同治疗大大提高了抗肿瘤治疗的效果。
本发明是通过以下技术方案实现的：
一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，包括以下步骤：
步骤1)将多巴胺-阿霉素、多巴胺和氯化锌溶于乙醇/去离子水的混合溶剂中，再滴加氨水，调节溶液pH值至8.0～8.5；
步骤2)对步骤1)制得的混合溶液进行搅拌后，向其中滴加2-甲基咪唑的乙醇/去离子水混合溶液，继续搅拌，反应结束后，经透析得到ZIF-8-聚多巴胺前药纳米粒子；
步骤3)将ZIF-8-聚多巴胺前药纳米粒子与聚乙二醇-叶酸混合加入去离子水中，搅拌反应后，经透析得到所述靶向ZIF-8-聚多巴胺前药纳米粒子。
优选地，步骤1)所述多巴胺-阿霉素的浓度为0.016mg/mL；所述多巴胺的浓度为0.053mg/mL；所述氯化锌的浓度为0.036mg/mL。
优选地，步骤2)所述2-甲基咪唑的浓度为0.013mg/mL。
优选地，步骤3)所述ZIF-8-聚多巴胺前药纳米粒子的浓度为1.0mg/mL；所述聚乙二醇-叶酸的浓度为0.5mg/mL。
优选地，所述乙醇/去离子水的体积比为4:1。
优选地，步骤2)所述搅拌的时间依次为0.5h、48h；步骤3)所述搅拌的时间为24h。
优选地，所述透析的流程如下：用分子量3500的透析袋，去离子水500mL×1次/8h，透析2天。
一种靶向ZIF-8-聚多巴胺前药纳米粒子，是由上述的制备方法制得的。
上述靶向ZIF-8-聚多巴胺前药纳米粒子作为光热疗-化疗一体化的抗肿瘤药物载体使用。
优选地，所述靶向ZIF-8-聚多巴胺前药纳米粒子具有以下功能：抑制和杀死***细胞。
本发明的有益效果如下：
(1)本发明高效合成了一种靶向ZIF-8-聚多巴胺前药纳米粒子。
(2)该靶向ZIF-8-聚多巴胺前药纳米粒子能够通过叶酸的主动靶向功能，靶向肿瘤细胞，提高肿瘤细胞对药物的摄取。
(3)该靶向ZIF-8-聚多巴胺前药纳米粒子，在近红外光照条件下(光强2W/cm2、波长808nm、光照时间5min)，聚多巴胺组分能够吸收近红外光转换成热能，杀死肿瘤细胞，实现光热治疗。
(4)该靶向ZIF-8-聚多巴胺前药纳米粒子，在进入肿瘤细胞的酸性环境中，酰腙键断裂，响应性释放出抗癌药物阿霉素，杀死肿瘤细胞，实现化疗。
(5)该具有靶向功能的光热疗-化疗一体化治疗技术操作简单，仅需要一次静脉注射和一次光照，便可实现肿瘤的有效治疗，具有重要的临床应用前景。
(6)本发明为制备具有靶向功能的ZIF-8-聚多巴胺前药纳米粒子提供了一种简单而有效的途径，为获得具有靶向功能、光热疗-化疗一体化治疗的超分子聚肽前药纳米粒子提供了很好的实验平台。
附图说明
图1为靶向ZIF-8-聚多巴胺前药纳米粒子的制备流程示意图；
图2为靶向ZIF-8-聚多巴胺前药纳米粒子的示意图；
图3为实施例1制得的ZIF-8-聚多巴胺前药纳米粒子的动态光散射图谱；
图4为实施例1制得的靶向ZIF-8-聚多巴胺前药纳米粒子的动态光散射图谱；
图5为实施例1制得的靶向ZIF-8-聚多巴胺前药纳米粒子的透射电镜图；
图6为实施例2中各实验组的抗肿瘤效果图；
图7为实施例3中各实验组对小鼠体内肿瘤的影响；
图8为实施例3中各实验组对小鼠体重的影响。
具体实施方式
以下结合附图与具体实施例对本发明做进一步详细说明。
实施例1
一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，如图1所示，具体步骤如下：
(1)取2.5mg多巴胺-阿霉素(DA-DOX)、8.5mg多巴胺(DA)和5.72mg氯化锌溶解于160mL乙醇/去离子水(体积比4:1)的混合溶剂中，再滴加0.3mL氨水，调节溶液pH值至8.0～8.5。
(2)搅拌0.5h后，向其中滴加80mL 2-甲基咪唑(2.07mg)的乙醇/去离子水混合溶液，再搅拌反应48h。
(3)反应结束后，将溶液置于分子量3500的透析袋中，用500mL去离子水透析2天，中间每8小时换一次去离子水，透析结束后，经冷冻干燥得到ZIF-8-聚多巴胺前药纳米粒子(ZIF-8-聚多巴胺-阿霉素)，收率为68.4％～71.2％。
制得的ZIF-8-聚多巴胺前药纳米粒子的动态光散射图谱如图3所示，其数均粒径为159.7±3.6nm，PDI为0.21±0.05。
(4)取10mL 1.0mg/mL的ZIF-8-聚多巴胺前药纳米粒子水溶液，加入5mg聚乙二醇-叶酸，混合搅拌反应24h。
(5)反应结束后，将溶液置于分子量3500的透析袋中，用500mL去离子水透析2天，中间每8小时换一次去离子水，透析结束后，经冷冻干燥得到所述靶向ZIF-8-聚多巴胺前药纳米粒子(靶向ZIF-8-聚多巴胺-阿霉素)，如图2所示，其收率为87.7％～93.2％。
制得的靶向ZIF-8-聚多巴胺前药纳米粒子的动态光散射图谱如图4所示，其数均粒径为190.2±6.4nm，PDI为0.22±0.01；其透射电镜图如图5所示，成球形粒子结构。
实施例2靶向ZIF-8-聚多巴胺前药纳米粒子对***细胞的影响
将实施例1中制备得到的靶向ZIF-8-聚多巴胺前药纳米粒子(ZP-DOX-FA)、ZIF-8-聚多巴胺前药纳米粒子(ZP-DOX)和阿霉素(DOX)分别用细胞培养液配制成阿霉素浓度分别为0.1、0.2、0.5、1、2、4μg/mL，然后分别跟HeLa细胞(***腺癌)培养48h，此外，对于靶向ZIF-8-聚多巴胺前药纳米粒子和ZIF-8-聚多巴胺前药纳米粒子需要各另设一组，培养4h后，再用近红外激光对其进行光照5min(808nm，2W/cm2)，继续培养48h。
采用MTT方法进行细胞活性测试，结果如图6所示。图6中，纵坐标表示HeLa细胞活性，下横坐标DOX指代的是阿霉素的浓度，图中立柱从左到右依次为DOX、ZP-DOX、ZP-DOX+NIR、ZP-DOX-FA、ZP-DOX-FA+NIR，其中，ZP-DOX-FA、ZP-DOX和DOX是指靶向ZIF-8-聚多巴胺前药纳米粒子、ZIF-8-聚多巴胺前药纳米粒子和阿霉素分别单独使用的实验组，ZP-DOX-FA+NIR和ZP-DOX+NIR是指靶向ZIF-8-聚多巴胺前药纳米粒子和ZIF-8-聚多巴胺前药纳米粒子分别跟癌细胞培养4h后，再用近红外激光对其进行光照的实验组。
如图6所示，靶向ZIF-8-聚多巴胺前药纳米粒子在有近红外光照的条件下，表现出更强的杀死肿瘤细胞的能力；靶向ZIF-8-聚多巴胺前药纳米粒子比ZIF-8-聚多巴胺前药纳米粒子在相同条件下，表现出更强的抗癌能力。说明该靶向ZIF-8-聚多巴胺前药纳米粒子在增强肿瘤细胞内摄方面具有明显的效果，并且在近红外光照条件，实现了光热疗与化疗的联合治疗，对肿瘤细胞表现出更好的抗肿瘤效果。
实施例3靶向ZIF-8-聚多巴胺前药纳米粒子对HeLa肿瘤生长的影响实验
将接种了HeLa荷瘤的小鼠分别分为5组：生理盐水、阿霉素(5mg/kg)、ZIF-8-聚多巴胺前药纳米粒子(2mg/mL)+NIR、靶向ZIF-8-聚多巴胺前药纳米粒子(2mg/mL)、靶向ZIF-8-聚多巴胺前药纳米粒子(2mg/mL)+NIR。第0天注射一次，且注射12h后对ZIF-8-聚多巴胺前药纳米粒子+NIR和靶向ZIF-8-聚多巴胺前药纳米粒子+NIR进行光照5min(808nm，2W/cm2)，同时每隔1天对小鼠进行称重并对肿瘤体积进行测量，结果如图7和8所示。
图7中纵坐标表示小鼠肿瘤体积，图8中纵坐标表示小鼠的体重。图7、图8中，横坐标表示小鼠接受实验的天数，PBS是指注射生理盐水对照组，DOX是指注射阿霉素实验组，ZP-DOX+NIR是指注射ZIF-8-聚多巴胺前药纳米粒子12h后，再用近红外激光对其进行光照的实验组，ZP-DOX-FA是指注射靶向ZIF-8-聚多巴胺前药纳米粒子的实验组，ZP-DOX-FA+NIR是指注射靶向ZIF-8-聚多巴胺前药纳米粒子12h后，再用近红外激光对其进行光照的实验组。
如图7和8所示，对于HeLa肿瘤，游离的阿霉素对于该耐药肿瘤没有抑制的作用，而对于ZP-DOX-FA+NIR组，所有小鼠肿瘤明显得到抑制，且对小鼠体重几乎没有影响。
Claims (10)
1.一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，其特征在于，包括以下步骤：
步骤1)将多巴胺-阿霉素、多巴胺和氯化锌溶于乙醇/去离子水的混合溶剂中，再滴加氨水，调节溶液pH值至8.0～8.5；
步骤2)对步骤1)制得的混合溶液进行搅拌后，向其中滴加2-甲基咪唑的乙醇/去离子水混合溶液，继续搅拌，反应结束后，经透析得到ZIF-8-聚多巴胺前药纳米粒子；
步骤3)将ZIF-8-聚多巴胺前药纳米粒子与聚乙二醇-叶酸混合加入去离子水中，搅拌反应后，经透析得到所述靶向ZIF-8-聚多巴胺前药纳米粒子。
2.根据权利要求1所述的一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，其特征在于，步骤1)所述多巴胺-阿霉素的浓度为0.016mg/mL；所述多巴胺的浓度为0.053mg/mL；所述氯化锌的浓度为0.036mg/mL。
3.根据权利要求1所述的一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，其特征在于，步骤2)所述2-甲基咪唑的浓度为0.013mg/mL。
4.根据权利要求1所述的一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，其特征在于，步骤3)所述ZIF-8-聚多巴胺前药纳米粒子的浓度为1.0mg/mL；所述聚乙二醇-叶酸的浓度为0.5mg/mL。
5.根据权利要求1所述的一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，其特征在于，所述乙醇/去离子水的体积比为4:1。
6.根据权利要求1所述的一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，其特征在于，步骤2)所述搅拌的时间依次为0.5h、48h；步骤3)所述搅拌的时间为24h。
7.根据权利要求1所述的一种靶向ZIF-8-聚多巴胺前药纳米粒子的制备方法，其特征在于，所述透析的流程如下：用分子量3500的透析袋，去离子水500mL×1次/8h，透析2天。
8.一种靶向ZIF-8-聚多巴胺前药纳米粒子，其特征在于，是由权利要求1-7任一项所述的制备方法制得的。
9.权利要求8所述的一种靶向ZIF-8-聚多巴胺前药纳米粒子的应用，其特征在于，所述靶向ZIF-8-聚多巴胺前药纳米粒子作为光热疗-化疗一体化的抗肿瘤药物载体使用。
10.根据权利要求9所述的应用，其特征在于，所述靶向ZIF-8-聚多巴胺前药纳米粒子具有以下功能：抑制和杀死***细胞。
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