CN108853055B - 一种多功能核壳结构Fe3O4@TiO2@ZIF-8纳米粒子载药体系及其制备方法 - Google Patents
一种多功能核壳结构Fe3O4@TiO2@ZIF-8纳米粒子载药体系及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种多功能核壳结构Fe3O4@TiO2@ZIF‑8纳米粒子载药体系及其制备方法,包括Fe3O4@TiO2@ZIF‑8纳米粒子和负载在其上面的药物,Fe3O4@TiO2@ZIF‑8纳米粒子以Fe3O4纳米颗粒作为磁核,以TiO2为内层包被材料,以ZIF‑8纳米粒子为外层包被材料,其对肿瘤部位靶向性更强,提高药物的利用度和减少药物的毒副作用,并且可借助MRI显影技术,随时监测药物与肿瘤靶点的作用情况。
Description
技术领域
本发明涉及纳米载药颗粒领域,更具体的说是涉及一种多功能核壳结构 Fe3O4@TiO2@ZIF-8纳米粒子载药体系及其制备方法。
背景技术
近年来,纳米技术的研究越来越受到研究工作者的关注,特别是工程纳米材料受到了非常高的关注。工程纳米材料如碳纳米管,量子点等磁性纳米粒子是最有前途的材料之一,它们被用作靶向药物递送、成像和监测疗效一体化的治疗癌症的平台。工程纳米材料可以通过某些化学或物理方法进行修饰,使其具有非常特定的性质从而使它们能够快速进入到快速发展的纳米科学技术的前言。磁性纳米颗粒(MNPs)是一种重要的一类工程纳米材料,因其具有生物相容性好、易被修饰、靶向性好、超顺磁性等特点,在生物医学领域有着极高的应用价值。目前,许多研究表明,经过在外施加磁场,能够使经修饰的磁性材料表面负载药物送至病变部位达到靶向给药的目的,从而可以减少药物对正常组织的毒副作用。
近些年来,TiO2纳米粒子被作为癌症治疗的潜在治疗剂,主要是其具有良好的生物相容性和独特的光催化性能。另外,由于其在生物系统中无毒,易于制备和高度稳定,因此在化学治疗剂的药物递送领域也受到了很多关注。 Fe3O4@TiO2纳米复合材料可以用于磁共振成像(Fe3O4成分)和无机光动力疗法 (TiO2成分)进行结合诊断治疗。然而,由于在紫外光的照射下具有很多局限性,而且Fe3O4@TiO2Nps的pH响应不是非常敏感,导致其在临床应用方面价值不是很大。
发明内容
针对现有技术存在的不足,本发明的目的在于提供一种多功能核壳结构 Fe3O4@TiO2@ZIF-8纳米粒子载药体系,其对肿瘤部位靶向性更强,提高药物的利用度和减少药物的毒副作用,并且可借助MRI显影技术,随时监测药物与肿瘤靶点的作用情况。
为实现上述目的,本发明提供了如下技术方案:一种多功能核壳结构 Fe3O4@TiO2@ZIF-8纳米粒子载药体系,包括Fe3O4@TiO2@ZIF-8纳米粒子和负载在其上面的药物,所述Fe3O4@TiO2@ZIF-8纳米粒子以Fe3O4纳米颗粒作为磁核,以TiO2为内层包被材料,以ZIF-8纳米粒子为外层包被材料。
优选的,所述药物为选自抗肿瘤剂或者抗肿瘤剂与抗生素、防腐剂、镇痛剂、双膦酸盐和/或酯类、生长因子、肽、他汀类中一种或者多种的组合。
一种多功能核壳结构Fe3O4@TiO2@ZIF-8纳米粒子载药体系用于制备抗肿瘤药物的用途。
一种多功能核壳结构Fe3O4@TiO2@ZIF-8纳米粒子制备方法,包括以下步骤:
1)通过共沉淀方法合成将Fe3O4纳米颗粒;
2)将TiO2修饰到Fe3O4纳米粒子的表面,得到Fe3O4@TiO2纳米粒子;
3)通过共沉淀的方法在Fe3O4@TiO2纳米粒子表面修饰ZIF-8纳米粒子,得到 Fe3O4@TiO2@ZIF8纳米颗粒。
作为本发明进一步的改进,步骤1)中Fe3O4纳米颗粒具体制备步骤如下:
(1)加入二价铁盐和三价铁盐,在氮气保护下配制含有Fe3+和Fe2+的混合溶液;
(2)加入油酸,在40-60℃,搅拌转速500-1500rpm的条件下反应3h;
(3)加入氨水,将pH值调制12-14,继续加热至75-85℃,反应1h;
(4)冷却至室温,将上一步骤合成的产物进行磁分离后,用蒸馏水洗至上清液呈中性,去除上清液,得到Fe3O4纳米颗粒。
作为本发明进一步的改进,所述二价铁盐、三价铁盐和氨水的摩尔比为 (0.2~1):1:(4-8)。
作为本发明进一步的改进,步骤2)中Fe3O4@TiO2纳米颗粒具体制备步骤如下:
(1)将Fe3O4纳米颗粒分用无水乙醇洗涤1-3次,加入无水乙醇和乙腈,超声 5-10min,制备成分散的Fe3O4纳米颗粒磁流体;
(2)加入氨水,超声5-10min,在搅拌条件下,滴加酞酸丁酯,反应1-2h。
(3)将上一步骤合成的产物进行磁分离后,用蒸馏水洗至上清液呈中性,去除上清液,得到Fe3O4@TiO2纳米颗粒。
作为本发明进一步的改进,步骤3)中Fe3O4@TiO2@ZIF-8具体制备步骤如下:
(1)将Fe3O4@TiO2纳米颗粒用甲醇洗涤1-3次,再加入甲醇,超声均匀;
(2)加入六水合硝酸锌和2-甲基咪唑搅拌加热至55-65℃后,反应0.5-1.5h;
(3)冷却至室温,将上一步骤合成的产物进行磁分离后,用蒸馏水洗至上清液呈中性,去除上清液,得到Fe3O4@TiO2@ZIF-8纳米颗粒。
本发明的有益效果为:本发明以核壳杂化纳米粒子(Fe3O4@TiO2@ZIF-8) 为载体,负载抗肿瘤活性药物,Fe3O4@TiO2@ZIF-8具有很好的生物相容性和稳定性,其中Fe3O4@TiO2纳米粒子内核起到靶向性和磁共振成像双功能的作用,而ZIF-8的壳层则作为药物递送的pH响应平台,本发明提供载药体系药物在中性以及碱性环境下释放缓慢,而在类似肿瘤部位的弱酸环境中快速释放,从而该载药系统不仅可借助MRI显影技术,随时监测药物与肿瘤靶点的作用情况,而且该载药系统制备简单成本较低,本发明提供的一种多功能核壳结构Fe3O4@TiO2@ZIF-8纳米粒子载药体系可以作为pH响应性、靶向性、磁共振成像和监测疗效一体化的多功能治疗癌症的平台,还可以通过靶向的作用提高药物的利用度和减少药物的毒副作用。
附图说明
图1为Fe3O4@TiO2和Fe3O4@TiO2@ZIF8Nps红外图谱;
图2为Fe3O4@TiO2@ZIF8Nps的TEM图;
图3为Fe3O4Nps、Fe3O4@TiO2Nps、Fe3O4@TiO2@ZIF8Nps的电位图;
图4为Fe3O4@TiO2@ZIF-8-DNM Nps在pH5.6和pH7.4条件下的缓释率;
图5为Fe3O4@TiO2@ZIF-8-DNM NPs在Hela细胞中的药物释放后 Fe3O4@TiO2@ZIF-8-DNM Nps和游离DNM的流式图;
图6为Fe3O4@TiO2@ZIF-8-DNM NPs在Hela细胞中的药物释放后DNM荧光强度分析直方图;
图7为划痕实验测定对照组和Fe3O4@TiO2@ZIF-8-DNM Nps对HeLa细胞的迁移抑制结果图。
具体实施方式
本发明所用的试剂除非特别指明,以下实施例所用的试验方法均为本领域中所用的常规方法。
除非特别指明,以下实施例中所用的试剂均为分析纯级试剂,且可从正规渠道商购获得。
一种多功能核壳结构Fe3O4@TiO2@ZIF-8纳米粒子载药体系,包括 Fe3O4@TiO2@ZIF-8纳米粒子和负载在其上面的药物,所述Fe3O4@TiO2@ZIF-8 纳米粒子以Fe3O4纳米颗粒作为磁核,以TiO2为内层包被材料,以ZIF-8纳米粒子为外层包被材料,所述药物为选自抗肿瘤剂或者抗肿瘤剂与抗生素、防腐剂、镇痛剂、双膦酸盐和/或酯类、生长因子、肽、他汀类中一种或者多种的组合。
提供一种具体的实施方式:一种多功能核壳结构Fe3O4@TiO2@ZIF-8纳米粒子制备方法,包括以下步骤:
一、合成Fe3O4纳米粒子
称取2.300g氯化铁和1.200g氯化亚铁于容器中,在机械搅拌、氮气保护下加入100mL蒸馏水溶解,再取2mL油酸,待温度上升至50℃,在高速转速下反应3h;再滴加3mol/L稀氨水,调节体系的pH值等于13,继续加热至80℃,保温1h;反应结束后,冷却至室温,合成的产物磁分离后用水洗至上清液呈中性,分散在蒸馏水中保存。
二、合成Fe3O4@TiO2纳米粒子
取出30mg上述合成的Fe3O4于容器中,磁分离,除去上清液,用无水乙醇洗涤3次,再向烧瓶中加入90mL无水乙醇和30mL乙腈,超声5-10min,使磁流体分散均匀,再加0.5mL28%氨水,超声5min,然后机械搅拌均匀后,滴加500μL酞酸丁酯,反应1.5h;反应结束后,将合成的产物磁分离,用蒸馏水洗至上清液呈中性,分散在蒸馏水中保存。
三、合成Fe3O4@TiO2-ZIF8
取出30mg上述合成的Fe3O4@TiO2于容器中,磁分离,除去上清液,用甲醇洗涤3次,再加入15mL甲醇,超声均匀,然后加入36.8mg六水合硝酸锌和 138mg 2-甲基咪唑,搅拌加热至60℃后,反应1h;反应结束后,冷却至室温,合成的产物磁分离后用蒸馏水洗涤三次,分散在蒸馏水中保存。
合成Fe3O4@TiO2@ZIF-8Nps后,我们对其进行了红外表征和TEM表征,如图1所示,591cm-1和599cm-1处是Ti-O-Ti的特征峰,在1100cm-1-1400cm-1 处是C-N的特征吸收峰,而在3410cm-1和1410cm-1处是-OH基团的特征吸收峰,可以证明TiO2和ZIF-8已经被修饰到Fe3O4上去了。图2Fe3O4@TiO2@ZIF-8Nps 的电镜图可以看出,Fe3O4@TiO2@ZIF-8Nps呈近似的圆球形状,有比较明显的壳核结构,粒径大概在400nm左右。图3的电位图可以看出,Fe3O4Nps的电荷为-31.8±1.5,Fe3O4@TiO2Nps的电荷为-33.35±3.65,Fe3O4@TiO2@ZIF-8Nps 的电荷为7.04±1.08,这从负电荷到正电荷的转变,可以说明ZFI8已经修饰到 Fe3O4@TiO2Nps上去了。
实施例1公开一种以道诺霉素为抗肿瘤活性药物为模型的 Fe3O4@TiO2@ZIF-8载药体系;优选的道诺霉素的固载浓度为0.3mg/mL。
一、测试Fe3O4@TiO2@ZIF-8-DNM Nps pH响应性,将Fe3O4@TiO2@ZIF-8-DNM Nps颗粒溶解在不同PH值的缓冲溶液中,如图4所示,负载有道诺霉素的 Fe3O4@TiO2@ZIF-8载药颗粒在pH 7.4的中性环境下,从纳米粒子中释放道诺霉素非常的缓慢,96h内释放的药物总量只有14.3%,但是在pH 5.6条件下,有 79.01%的药物从载药纳米粒子中释放出来,与pH 7.4条件下相比,特别是在1h 至24h之间,道诺霉素在pH 5.6条件下显著加快,这些结果表明,Fe3O4@TiO2@ZIF-8-DNM Nps具有很好的pH值响应性,会增加道诺霉素在肿瘤中的释放。
二、测试Fe3O4@TiO2@ZIF-8-DNM Nps的生物相容性,进行体外MTT试验。对Fe3O4@TiO2@ZIF-8-DNM Nps在一定的剂量范围内的细胞毒作用进行评价。设置该Fe3O4@TiO2@ZIF-8-DNM Np的最大浓度为200μg·L-1,最小浓度为6.25 μg·L-1,设置六个浓度,以PBS为对照组。当加入Fe3O4@TiO2@ZIF-8-DNM Nps 浓度范围为6.25μg·L-1至200μg·L-1时,让其在培养箱中培养48h,细胞的存活率都达到了90%以上,没有表现出明显的增殖抑制,因此体外MTT试验可以说明Fe3O4@TiO2@ZIF-8-DNM Nps载体对HeLa细胞无明显的细胞毒作用。
三、测试细胞对Fe3O4@TiO2@ZIF-8-DNM Nps的摄取,通过普鲁士蓝染色实验来进行验证。在细胞培养过程中,没有加Fe3O4@TiO2@ZIF-8-DNM Nps纳米粒子,可见细胞里面只是红色没有任何细胞被染成蓝色,在细胞培养过程中加了 Fe3O4@TiO2@ZIF-8-DNM Nps纳米粒子的,通过南京森贝伽公司生产的普鲁士蓝染色试剂盒对其进行染色,细胞里面可以看见有很多小的蓝色颗粒点贯穿细胞中,这说明Fe3O4@TiO2@ZIF-8-DNM Nps已经进入细胞里面了。
为了进一步证明Fe3O4@TiO2@ZIF-8-DNM Nps进入到癌细胞并在癌细胞中释放药物道诺霉素,因为道诺霉素本身带有荧光,我们通过流式细胞仪来定量测定其荧光值,如图5-6所示,而且荧光强度与细胞内化的道诺霉素量成正比。没有药物处理的细胞作为阴性对照组,仅显示出其细胞的自身荧光。当用道诺霉素或Fe3O4@TiO2@ZIF-8-DNM NPs处理细胞时,细胞中的荧光信号明显增加。游离道诺霉素和Fe3O4@TiO2@ZIF-8-DNM Nps均由细胞摄取,然而,摄取效率不同。加完药物在细胞培养箱孵育24h后,Fe3O4@TiO2@ZIF-8-DNM Nps(MFI =148)的细胞摄取量约为游离道诺霉素的两倍(MFI=79)。这是由于 Fe3O4@TiO2@ZIF-8本身带有正电荷,可以选择性内化到癌细胞中。
四、进行体外靶向实验来测定Fe3O4@TiO2@ZIF-8-DNM NPs的磁靶向性质。在培养皿内培养HeLa细胞,在培养皿一侧设置有磁铁为靶向区域,在培养皿另一侧则是无磁铁区域,经过培养后48h后,在显微镜下观察两个区域内的细胞形状,靶向区域的细胞形状变圆,没有固定的形态,而无靶向区域细胞形态良好,细胞呈现棱形状态。从这个实验结果可以推出,磁性纳米粒子在外界的磁场作用写可以移动到特定的部位,增加局部药物的浓度,从而达到靶向治疗的效果。
五、测试Fe3O4@TiO2@ZIF-8-DNM Nps抑制癌细胞迁移能力,为了进一步评估 Fe3O4@TiO2@ZIF-8-DNM Nps对癌细胞的迁移抑制,采用细胞划痕实验来对其进行探究。如图7所示,相比于对照组,Fe3O4@TiO2@ZIF-8-DNM Nps显著抑制了细胞的迁移,导致伤痕修复率很低。特别是在48h,对照组相对0h已经迁移了Δm=264.64μm,而Fe3O4@TiO2@ZIF-8-DNM Nps组癌细胞只迁移了Δm=75.87μm,由此可知Fe3O4@TiO2@ZIF-8-DNM Nps对癌细胞迁移具有很好的迁移抑制作用。
以上仅是本发明的优选实施方式,本发明的保护范围并不仅局限于上述实施例,凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理前提下的若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.一种多功能核壳结构 Fe 3 O 4 @TiO 2 @ZIF-8 纳米粒子载药体系,其特征在于:包括 Fe 3 O 4 @TiO 2 @ZIF-8 纳米粒子和负载在其上面的药物,所述Fe 3 O 4 @TiO 2 @ZIF-8 纳米粒子以 Fe 3 O 4纳米颗粒作为磁核,以 TiO 2为内层包被材料,以 ZIF-8 纳米粒子为外层包被材料。
2.根据权利要求 1 所述的一种多功能核壳结构 Fe 3 O 4 @TiO 2 @ZIF-8 纳米粒子载药体系,其特征在于:所述药物为选自抗肿瘤剂或者抗肿瘤剂与抗生素、镇痛剂、双膦酸盐和/或酯类、生长因子、肽、他汀类中一种或者多种的组合。
3.根据权利要求 1 所述的一种多功能核壳结构Fe 3 O 4 @TiO 2 @ZIF-8 纳米粒子载药体系用于制备抗肿瘤药物的用途。
4.一种多功能核壳结构 Fe 3 O 4 @TiO 2 @ZIF-8 纳米粒子制备方法,其特征在于:包括以下步骤:
1)通过共沉淀方法合成Fe 3 O 4纳米颗粒;
2)将 TiO 2修饰到 Fe 3 O 4 纳米粒子的表面,得到 Fe 3 O 4 @TiO 2纳米粒子;
3)通过共沉淀的方法在 Fe 3 O 4 @TiO 2纳米粒子表面修饰 ZIF-8 纳米粒子,得到Fe3 O 4 @TiO 2 @ZIF8纳米颗粒;
步骤 1)中Fe 3 O 4纳米颗粒具体制备步骤如下:
(1)加入二价铁盐和三价铁盐,在氮气保护下配制含有 Fe3+和 Fe2+的混合溶液;
(2)加入油酸,在 40-60℃,搅拌转速 600 rpm/min 的条件下反应 3 h;
(3)加入氨水,将 pH 值调至 12-14,继续加热至 75-85℃,反应 1 h;
(4)冷却至室温,将上一步骤合成的产物进行磁分离后,用蒸馏水洗至上清液呈中性,去除上清液,得到 Fe 3 O 4纳米颗粒;
所述二价铁盐、三价铁盐和氨水的摩尔比为(0.2~1):1:(4-8)。
5.根据权利要求 4 所述的一种多功能核壳结构Fe 3 O 4 @TiO 2 @ZIF-8 纳米粒子制备方法,其特征在于:步骤 2)中 Fe 3 O 4 @TiO 2纳米颗粒具体制备步骤如下:
(1)将 Fe 3 O 4纳米颗粒分用无水乙醇洗涤 1-3 次,加入无水乙醇和乙腈,超声5-10min,制备成分散的Fe 3 O 4纳米颗粒磁流体;
(2)加入氨水,超声 5-10 min,在搅拌条件下,滴加酞酸丁酯,反应 1-2 h;
(3)将上一步骤合成的产物进行磁分离后,用蒸馏水洗至上清液呈中性,去除上清液,得到 Fe 3 O 4 @TiO 2纳米颗粒。
6.根据权利要求 4 所述的一种多功能核壳结构 Fe 3 O 4 @TiO 2 @ZIF-8 纳米粒子制备方法,其特征在于:步骤 3)中Fe 3 O 4 @TiO 2 @ZIF-8 具体制备步骤如下:
(1)将 Fe 3 O 4 @TiO 2纳米颗粒用甲醇洗涤 1-3 次,再加入甲醇,超声均匀;
(2)加入六水合硝酸锌和 2-甲基咪唑搅拌加热至 55-65℃后,反应 0.5-1.5 h;
(3)冷却至室温,将上一步骤合成的产物进行磁分离后,用蒸馏水洗至上清液呈中性,去除上清液,得到 Fe 3 O 4 @TiO 2 @ZIF-8 纳米颗粒。
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