CN112791195A - 一种复合纳米载药体系的合成方法 - Google Patents

一种复合纳米载药体系的合成方法 Download PDF

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CN112791195A
CN112791195A CN202110209153.7A CN202110209153A CN112791195A CN 112791195 A CN112791195 A CN 112791195A CN 202110209153 A CN202110209153 A CN 202110209153A CN 112791195 A CN112791195 A CN 112791195A
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罗良平
王夺
史长征
肖泽宇
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Abstract

本发明提供了一种复合纳米载药体系PFe‑PFH@SiO2/PANI的合成方法，首先将粒径在10nm左右的Fe3O4颗粒、顺铂以及全氟己烯包裹于PLGA中，构建PFe‑PFH@PLGA。接着将二氧化硅包裹于PFe‑PFH@PLGA表面，形成PFe‑PFH@SiO2。最后，将苯胺在酸性条件下氧化形成聚苯胺，并将PEI掺杂在其中连接靶向分子，成功制备出纳米体系PFe‑PFH@SiO2/PANI。本发明的复合纳米载药体系具有良好的光热转换效率，可在短时间内破坏外层硅壳并有效释放药物。

Description

一种复合纳米载药体系的合成方法
技术领域
本发明涉及载药体系制备技术领域，尤其涉及一种复合纳米载药体系的合成方法。
背景技术
肺癌已经成为我国以及世界范围内发生率、死亡率最高的恶性肿瘤，其中NSCLC占据肺癌的大多数，近75％的患者发现时已进展为中晚期肺癌，5年生存率较差，是导致肺癌高死亡率的主要原因。含铂类的联合化疗目前仍然是临床治疗NSCLC的标准一线方案，其中顺铂作为第一代铂类药物，已经成为NSCLC化疗的基石。但是化疗本身带来的毒副作用以及继发的耐药性，是影响其临床疗效及应用的主要问题。纳米颗粒为载体的药物输送方案，由于纳米颗粒本身体积小、比表面积大，表面具有多个活性中心、反应活性高、吸附能力强等优点及其特殊的递送方式，成为克服传统药物毒副作用，避免继发性耐药产生的一个有效途径。同时，结合临床常用的影像学方法及显影剂构建的纳米诊疗一体化载药体系，在实现疾病早期精准诊断的同时对其疗效进行实时动态、定量客观的监测，集可视化的诊断、治疗于一体，对于提高临床肿瘤的诊疗效果具有很大的潜力。
然而，纳米药物传递过程中的生物安全性、组织渗透性、释药可控性以及活体评估的客观性等问题，成为阻碍其向临床应用转化的主要因素。而无机二氧化硅的应用、穿模肽的靶向性修饰、体外近红外光的响应性释放以及定量MR成像方法介导下的可视化监测，为解决以上问题提供了一种可能的解决方案。因此，本研究基于以上各点，在应用传统PLGA载药的基础上，在其外层裹以薄层硅壳以提高纳米体系的稳定性，减少不可控的药物泄露，将穿模肽R8与主动靶向受体RGD共修饰于纳米颗粒表面以提高其组织渗透性，同时涂抹光敏物质聚苯胺，利用其在近红外光下的热效应诱发纳米核心内部氟碳全氟己烷PFH的液气相变，达到药物的体外可控性释放，最后结合安全无辐射的MRI成像方法及包裹于纳米核心内部的MRI对比剂Fe3O4，在纳米药物肿瘤体内分布可视化的指导下，实现肿瘤治疗方式的个体化与疗效评估的定量化。
发明内容
基于此，本发明提供了一种复合纳米载药体系的合成方法，为获取一种新型高效可控的纳米诊疗一体化载药体系提供可靠的依据。
本发明提供的复合纳米载药体系的合成方法，包括以下步骤：
(1)将90-110mg的纳米复合物(PFe-PFH@SiO2)分散在20-50ml的N,N-二甲基甲酰胺(DMF)中，并加入0.2-0.5ml的苯胺，在冰浴的条件下搅拌5-15min；
(2)称取0.5-3g的过硫酸铵(APS)溶解到2-5ml盐酸中，将此溶液缓慢滴到含纳米复合物(PFe-PFH@SiO2)分散的溶液中，室温反应1-5h，离心，取沉淀；
(3)用截留量为6000-8000Da的透析袋透析，以除去没有反应的苯胺以及其他的杂质；
(4)将2-5mL浓度为10mg/mL的靶向分子用碳二亚胺盐酸盐和N-羟基琥珀酰亚胺活化2h。
(5)加入1mL浓度为0.8mg/mL的铁-全氟己烯-二氧化硅-聚苯胺的嵌段聚合物纳米粒子Fe-PFH@SiO2/PANI，反应过夜，将得到的纳米粒子分离，用超纯水重复洗三次以去除多余的碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，最后得到目标产物PFe-PFH@SiO2/PANI复合纳米载药体系。
优选的，步骤(1)所述的纳米复合物的合成方法包括以下步骤：
a.配制溶液A：取60～80mg聚乳酸-羟基乙酸共聚物(PLGA)溶于5～10mL丙酮中，然后加入0.5～2mL丙酮分散的Fe3O4纳米粒子和10mg的顺铂，接着逐滴加入70～100μL的全氟己烯并充分溶解，生成PFe-PFH@PLGA；
b.配制溶液B：以超纯水为溶剂，配制质量分数为0.5％的十六烷基三甲基溴化铵(CTAB)溶液；
c.将溶液A缓慢滴加于溶液B中轻微摇晃形成乳白色混合液，将混合液冰浴超声乳化10-15min，放置通风橱10-15h，使丙酮完全挥发，得到顺铂-铁-全氟己烯PFe-PFH纳米粒子；
d.将PFe-PFH纳米粒子以8000rpm的转速离心，用超纯水洗三次，以除去多余的十六烷基三甲基溴化铵。
e.将PFe-PFH纳米粒子用45mL水分散到100mL的圆底烧瓶中，混合均匀后慢慢滴加5mL的异丙醇，然后加入2mL浓度为25％的氨水；逐滴加入240～280μL正硅酸乙酯和10～25μL 3-氨丙基三乙氧基硅烷，反应持续8-12h。
f.离心分离提纯，用蒸馏水洗涤，重复三次，得到PFe-PFH@SiO2纳米复合物。
优选的，步骤(2)所述的盐酸浓度为0.1M。
优选的，步骤(3)所述的透析袋透析时间为2-5天。
优选的，步骤(4)所述的靶向分子为肾上腺皮质多肽及精氨酸-甘氨酸-天冬氨酸多肽ACPP-RGD。
本发明的另一目的是提供一种该方法合成的复合纳米载药体系及其应用，所述复合纳米载药体系在激光照射下通过热响应释放药物。
与现有技术相比，本发明具有以下优点：本发明应用二氧化硅包裹负载药物顺铂以及温敏物质PFH的PLGA形成核壳结构，并在外部修饰上光热转换试剂聚苯胺，成功合成并表征了一种近红外触发下光热效应诱发PFH液气相变以破坏硅壳结构，从而达到药物的体外可控性释放的纳米载药体系PFe-PFH@SiO2/PANI，该体系具有良好的光热转换效率，可在短时间内破坏外层硅壳并有效释放药物。
附图说明
图1表示在不同药物处理24h后细胞存活率图；
图2表示A549细胞在不同处理条件下的ROS图；
图3表示A549细胞对PFe-PFH@SiO2-PANI纳米体系的吸收量随时间的变化；
具体实施方式
下结合实施例对本发明提供的复合纳米载药体系的合成方法进行进一步说明。
实施例1
一种复合纳米载药体系的合成方法，具体步骤如下：
1、PFe-PFH@SiO2的合成：
a.配制溶液A：取70mgPLGA溶于9mL丙酮中，然后加入1mL丙酮分散的Fe3O4纳米粒子和10mg的顺铂，接着逐滴加入90μL的PFH并充分溶解。
b.配制溶液B：以超纯水为溶剂，配制质量分数为0.5％的CTAB溶液。
c.将溶液A缓慢滴加于溶液B中轻微摇晃形成乳白色混合液，将混合液冰浴超声乳化10min，放置通风橱12h以使丙酮完全挥发，得到PFe-PFH纳米粒子。
d.将PFe-PFH纳米粒子以8000rpm的转速离心，用超纯水洗涤三次，以除去多余的CTAB。
e.将步骤d洗涤后的PFe-PFH纳米粒子用45mL水分散到100mL的圆底烧瓶中，混合均匀后慢慢滴加5mL的异丙醇，然后加入2mL浓度为25％的氨水；逐滴加入256μLTEOS和20μLAPTES，反应持续10h。
f.离心分离提纯，用蒸馏水洗涤，重复三次，得到PFe-PFH@SiO2纳米复合物。
2、制备复合纳米载药体系PFe-PFH@SiO2/PANI：
(1)将100mg的PFe-PFH@SiO2纳米复合物分散在30ml的DMF中，并加入0.45ml的苯胺，在冰浴的条件下搅拌10min。
(2)称取1g的过硫酸铵(APS)溶解到3ml0.1M的盐酸中，将此溶液缓慢滴到含PFe-PFH@SiO2纳米复合物分散的溶液中，室温反应2h，离心，取沉淀。
(3)用截留量为6000-8000Da的透析袋透析3天，以除去没有反应的苯胺以及其他的杂质。
(4)将2mL浓度为10mg/mL的靶向ACPP-RGD用碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)活化2h。
(5)加入1mLFe-PFH@SiO2/PANI(0.8mg/mL)反应过夜，所得到的纳米粒子分离并用超纯水重复洗三次以去除多余的EDC和NHS，最后得到目标产物PFe-PFH@SiO2/PANI。
实施例2
PFe-PFH@SiO2/PANI的细胞存活率实验：
本实验检测原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶甲瓒并沉积在细胞中，而死细胞无此功能。
具体实验方法为：首先取对数生长期的A549细胞接种于密度为2×104cells/mL的96孔板中，100μL/孔，培养24h后将不同浓度的药物加入96孔板中。通过MTT法检测了单独顺铂，激光Laser和纳米药物PFe-PFH@SiO2/PANI以及纳米药物PFe-PFH@SiO2/PANI联合Laser对肺癌肿瘤细胞A549的抑制作用。将药物处理24h后每孔加入30μL的MTT溶液(5mg/mL，PBS溶液)并孵育3h。去除96孔板中的上层溶液，可见底部有紫色的结晶物，加入150μL/孔的DMSO，溶解10min，用多功能酶标仪在570nm波长处测量各个孔的吸光值(OD570)，并计算细胞存活率。结果如图1所示。
细胞存活率(％)＝(OD570实验组/OD570对照组)×100％。
实施例3
肿瘤细胞内活性氧(ROS)水平的检测：
取对数期生长的A549细胞(20×104cells/mL，100μL)接种于96孔板中。生长24h后，将上清换成无酚红的培养基，加入100μL的DHE-DA探针(终浓度为10μM)，并孵育30min。接着加入不同的药物，然后在荧光酶标仪下检测DHE探针的荧光变化。激发和发射波长分别为：300nm，600nm。结果如图2所示。
实施例4
PFe-PFH@SiO2-PANI纳米体系的细胞吸收：
测定非小细胞肺癌A549细胞对PFe-PFH@SiO2/PANI纳米体系的吸收量，结果如图3所示。
随着时间的延长，纳米药物进入细胞的量逐渐增多。
以上所述仅是本发明的优选实施方式，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的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (7)

1.一种复合纳米载药体系的合成方法，其特征在于，包括以下步骤：
(1)将90-110mg的纳米复合物分散在20-50ml的N,N-二甲基甲酰胺中，并加入0.2-0.5ml的苯胺，在冰浴的条件下搅拌5-15min；
(2)称取0.5-3g的过硫酸铵溶解到2-5ml盐酸中，将此溶液缓慢滴到含纳米复合物分散的溶液中，室温反应1-5h，离心，取沉淀；
(3)用截留量为6000-8000Da的透析袋透析，以除去没有反应的苯胺以及其他的杂质；
(4)将2-5mL浓度为10mg/mL的靶向分子用碳二亚胺盐酸盐和N-羟基琥珀酰亚胺活化两小时；
(5)加入1mL浓度为0.8mg/mL的铁-全氟己烯-二氧化硅-聚苯胺的嵌段聚合物纳米粒子Fe-PFH@SiO2/PANI，反应过夜，将得到的纳米粒子分离，用超纯水重复洗三次以去除多余的碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，最后得到目标产物复合纳米载药体系。
2.根据权利要求1所述的复合纳米载药体系的合成方法，其特征在于，步骤(1)所述的纳米复合物的合成方法包括以下步骤：
a.配制溶液A：取60～80mg聚乳酸-羟基乙酸共聚物溶于5～10mL丙酮中，然后加入0.5～2mL丙酮分散的Fe3O4纳米粒子和10mg的顺铂，接着逐滴加入70～100μL的全氟己烯并充分溶解；
b.配制溶液B：以超纯水为溶剂，配制质量分数为0.5％的十六烷基三甲基溴化铵溶液；
c.将溶液A缓慢滴加于溶液B中轻微摇晃形成乳白色混合液，将混合液冰浴超声乳化10-15min，放置通风橱10-15h，使丙酮完全挥发，得到顺铂-铁-全氟己烯PFe-PFH纳米粒子；
d.将PFe-PFH纳米粒子以8000rpm的转速离心，用超纯水洗三次，以除去多余的十六烷基三甲基溴化铵。
e.将磁性纳米粒子Fe3O4用45mL水分散到100mL的圆底烧瓶中，混合均匀后慢慢滴加5mL的异丙醇，然后加入2mL浓度为25％的氨水；逐滴加入240～280μL正硅酸乙酯和10～25μL3-氨丙基三乙氧基硅烷，反应持续8-12h。
f.离心分离提纯，用蒸馏水洗涤，重复三次，得到纳米复合物。
3.根据权利要求1所述的复合纳米载药体系的合成方法，其特征在于，步骤(2)所述的盐酸浓度为0.1M。
4.根据权利要求1所述的复合纳米载药体系的合成方法，其特征在于，步骤(3)所述的透析袋透析时间为2-5天。
5.根据权利要求1所述的复合纳米载药体系的合成方法，其特征在于，步骤(4)所述的靶向分子为肾上腺皮质多肽及精氨酸-甘氨酸-天冬氨酸多肽ACPP-RGD。
6.一种如权利要求1-5所述的复合纳米载药体系的合成方法合成的复合纳米载药体系。
7.根据权利要求6所述的复合纳米载药体系的应用，其特征在于，所述复合纳米载药体系在激光照射下通过热响应释放药物。
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