CN113713115A - 一种采用碳多孔材料构建抗癌载药系统的方法 - Google Patents
一种采用碳多孔材料构建抗癌载药系统的方法 Download PDFInfo
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Abstract
本申请提供一种采用碳多孔材料构建抗癌载药系统的方法，该方法包括碳多孔材料的合成、碳多孔材料表面改性、包载阿霉素与连接小干扰RNA和载药系统表面修饰叶酸FA。本申请以碳多孔材料为载药材料，具有更好的生物相容性，通过包载阿霉素，并在表面连接siRNA，达到肿瘤细胞内双重治疗的效果，并在表面修饰叶酸来靶向肿瘤细胞，构建了一种新型的载药系统，与传统的金属粒子载药系统相比，此方法不仅有更好的治疗效果，而且生物毒性低，靶向性好。
Description
技术领域
本发明涉及抗癌药物制备方法，尤其涉及一种采用碳多孔材料构建抗癌载药系统的方法。
背景技术
在药物研究学中，以纳米材料为载体运送药物是常见的方式，应用较多的有包裹放射性同位素的脂质体、表面标记荧光基团的脂质体、表面标记放射性同位素的共轭聚合物、负载药物的聚合物胶束，表面标记放射性同位素的纳米颗粒、表面标记荧光基团的氧化铁纳米颗粒、表面包裹光声或光热材料的氧化铁纳米颗粒、金纳米棒等材料。这些材料有载药量不稳定、易分解、生物毒性大等问题。而碳纳米载药材料因为其纳米粒径可控、良好的生物相容性、可编码修饰性和多重响应性，在新型纳米生物材料中有较好的发展前景。
设计基于碳多孔材料的载药系统旨在于解决药物的传递问题。目前，抗癌药物的疏水性使其药效大大降低无法达到治愈肿瘤的作用。在复杂的生物内环境条件下，药物的稳定性差，利用率低，生物毒性高已经成为亟待解决的问题。
发明内容
本申请为解决上述技术问题而提供。
本申请所采取的技术方案是：一种采用碳多孔材料构建抗癌载药系统的方法，其特征在于，包括以下步骤：
(一)碳多孔材料的合成
S1、称取0.005-20mg3-氨基苯酚，水浴搅拌溶解在有机溶剂中，加入0.5-100mL乙醇和0.5-100mL去离子水，水浴搅拌溶解并升温至37℃恒定，然后加入0.005-15mL甲醛，以及催化剂，37℃条件下反应10-60min，最后10000r离心1-20min，用去离子水洗涤两次后真空干燥，得前体；
S2、将前体置于通有保护气的管式炉中，200-1200℃碳化3-8h，研磨得碳多孔材料；
(二)碳多孔材料表面改性
S3、碳多孔材料表面的氧化
称取步骤S2获得的碳多孔材料0.1-40mg，加入0.1-20mL过氧化氢，超声处理4h后用去离子水洗涤两次，然后将碳多孔材料真空干燥，获得氧化的碳多孔材料；
S4、碳多孔材料表面的氨基化
将0.1-40mg步骤S3氧化的碳多孔材料分散于0.2-25mL异丙醇中，搅拌加热至50-100℃，再加入0.1-15mL3-氨丙基三乙氧基硅烷，回流冷凝反应6-48h，然后离心并用异丙醇洗涤两次，真空干燥，得氨基化的碳多孔材料；
(三)包载阿霉素与连接小干扰RNA
S5、取步骤S4获得的0.05-15mg氨基化的碳多孔材料分散于0.1-25mL去离子水中，并加入1.0-20μL3-(2-吡啶二巯基)丙酸N-羟基琥珀酰亚胺酯(SPDP)，并在25℃下孵育。0.5-5h后加入0.1-20μL浓度为0.001mol/L的二硫苏糖醇(DTT)，反应1-10h后离心洗涤即得连接有SPDP的碳多孔材料；
S6、将连接有SPDP的碳多孔材料重分散于0.1-25mLDEPC水，然后加入0.1-50μL10- 5M的小干扰RNA和0.5-15mg阿霉素，反应0.5-18h，然后离心将沉淀分散在0.1-20mLDEPC水中，得到小干扰RNA包载阿霉素的载药系统。
(四)载药系统表面修饰叶酸FA
S7、取0.05-15mL浓度为10-2mg/L的叶酸，加入0.1mol/L1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)100μL和0.1mol/LN-羟基琥珀酰亚胺(NHS)50μL活化叶酸；
S8、取步骤S6获得的小干扰RNA包载阿霉素的探针0.2-15mL，加入100μL步骤S7活化后的叶酸，反应1-18h，然后离心分散，即得碳多孔材料包载阿霉素并连接siRNA和叶酸FA的载药系统。
进一步的，所述步骤S1中，加入的催化剂为氨水，所述氨水加入的体积和甲醛的体积比为1:1。
进一步的，所述保护气为氮气。
进一步的，所述步骤S6中，小干扰RNA包括一条5’端修饰有巯基的RNA链和一条5’端修饰有FAM荧光团的RNA。
进一步的，所述5’端修饰有巯基的RNA链为SH-GAG UAC CAA GAG AUU CAU ATT。
进一步的，所述5’端修饰有FAM荧光团的RNA为FAM-UAU GAA UCU CUU GGU ACUCTT。
本申请具有的优点和积极效果是：
1、本申请使用多孔碳材料作为基本骨架之一，构建了一种新颖的药物释放体系，由于多孔碳材料良好的生物相容性和刺激响应性，使其可以更好的在生物体内传递，直达病灶，提高药效，多孔碳材料结构表面通过氨基和羧基脱水缩合作用，成功修饰叶酸FA，使其能够通过癌细胞表面的受体进入胞内，实现药物的精准释放。
2、本申请通过使用3-(2-吡啶二巯基)丙酸N-羟基琥珀酰亚胺酯成功引入二硫键，癌细胞内的谷胱甘肽分子结构中具有活泼的巯基，能够切断双硫键，成功释放抗癌药物阿霉素。
3、本申请通过在多孔碳材料中包载阿霉素DOX，并在表面修饰小干扰RNA(siRNA)，实现杀死癌细胞并沉默相关基因的表达，达到协同治疗的效果。
4、本申请通过阿霉素DOX的荧光与小干扰RNA(siRNA)修饰的FAM荧光团，能够实现在癌细胞中成像，并实现通过荧光强度表征体外谷胱甘肽的浓度，可以在细胞成像分析，靶标浓度检测，抗癌药物的递送等方面具有广泛的应用。
5、本申请操作流程简单，合成条件温和，能够在短时间大量合成，实现载药系统快速大量生产。
除了上面所描述的本申请解决的技术问题、构成技术方案的技术特征以及由这些技术方案的技术特征所带来的优点之外，本申请所能解决的其他技术问题、技术方案中包含的其他技术特征以及这些技术特征所带来的优点，将在下文中结合附图作进一步详细的说明。
附图说明
图1是本申请提供的碳多孔材料抗癌载药系统的构建示意图；
图2是本申请提供的碳多孔材料抗癌载药系统在癌细胞内释放示意图；
图3是本申请提供的碳多孔纳米材料、氧化的碳多孔纳米材料O-PCNs、氨基化的碳多孔纳米材料N-PCNs和合成的载药系统的透射电镜表征图；
图4是本申请提供的抗癌载药系统合成过程的电位验证图；
图5是本申请提供的采用碳多孔材料合成的载药系统对海拉细胞作用不同时间的显微镜观察示意图；
图6是本申请提供的PCN-DOX-FA，PCN-siRNA-FA，PCN-siRNA-DOX，PCN-siRNA-DOX-FA作用于海拉细胞的效果的验证图；
图7是本申请提供的采用碳多孔材料合成的载药系统的专一性验证图。
具体实施方式
下面结合附图和实施例对本申请作进一步的详细说明。可以理解的是，此处所描述的具体实施例仅仅用于解释相关发明，而非对该发明的限定。另外还需要说明的是，为了便于描述，附图中仅示出了与发明相关的部分。
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本申请。
实施例1
(一)碳多孔材料的合成
S1、称取0.1mg3-氨基苯酚，加入10mL乙醇和20mL去离子水，水浴搅拌溶解并升温至37℃恒定，然后加入0.1mL甲醛，以及催化剂0.1ml氨水，反应20min，最后10000r离心10min，用去离子水洗涤两次后真空干燥，得前体；
S2、将前体置于通有保护气的管式炉中，800℃碳化5h，研磨得碳多孔材料；
(二)碳多孔材料表面改性
S3、碳多孔材料表面的氧化
称取步骤S2获得的碳多孔材料10mg，加入5mL过氧化氢，超声处理4h后用去离子水洗涤两次，然后将碳多孔材料真空干燥，获得氧化的碳多孔材料；
S4、碳多孔材料表面的氨基化
将10mg步骤S3氧化的碳多孔材料分散于8mL异丙醇中，搅拌加热至85℃，再加入2mL3-氨丙基三乙氧基硅烷，回流冷凝反应24h，然后离心并用异丙醇洗涤两次，真空干燥，得氨基化的碳多孔材料；
(三)包载阿霉素与连接小干扰RNA
S5、取步骤S4获得的1.0mg氨基化的碳多孔材料分散于1.0mL去离子水中，并加入10μL3-(2-吡啶二巯基)丙酸N-羟基琥珀酰亚胺酯(SPDP)，并在25℃下孵育。0.5-5h后加入10μL浓度为0.001mol/L的二硫苏糖醇(DTT)，反应2h后离心洗涤即得连接有SPDP的碳多孔材料；
S6、将连接有SPDP的碳多孔材料分散DEPC水中(DEPC水为一种溶剂)，加入15μL10- 5M的小干扰RNA和1.0mg阿霉素，反应6h，然后离心将沉淀分散在1.0mLDEPC水中，得到小干扰RNA包载阿霉素的载药系统。
(四)抗癌药物制备方法表面修饰叶酸FA
S7、取1.0mL浓度为10-2mg/L的叶酸，加入0.1mol/L1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)100μL和0.1mol/LN-羟基琥珀酰亚胺(NHS)50μL活化叶酸；
S8、取步骤S6获得的小干扰RNA包载阿霉素的探针1.0mL，加入100μL步骤S7活化后的叶酸，反应6h，然后离心分散，即得碳多孔材料包载阿霉素并连接siRNA和叶酸FA的载药系统。
本实施例中，小干扰RNA链结构序列如下：
实施例2：碳多孔材料载药系统透射电镜表征
分别对实施例1中制得的碳多孔纳米材料、氧化的碳多孔纳米材料O-PCNs、氨基化的碳多孔纳米材料N-PCNs和合成的载药系统进行电镜检测，考察粒径大小及粒径均匀性，其结果分别如图3所示：
图3为电镜表征图，其中，图a为碳多孔材料PCNs结构图，图b为氧化的碳多孔材料O-PCNs结构图，图c为氨基化的碳多孔材料N-PCNs结构图，图d为合成的载药系统结构图。由图a可知，在碳多孔材料的碳球表面具有孔径均匀的孔道；由图b和图c可知，在碳多孔材料氧化与氨基化过程中并未对孔道造成影响，即碳多孔材料氧化与氨基化并未影响碳多孔材料包载药物的能力；由图d可知，所制备的载药系统粒径为280nm左右，粒径均一。
实施例3：载药系统合成过程的电位验证
a、将碳多孔材料连接小干扰RNA(siRNA)后分散到1mL的去离子水中，使用Mavern公司动态光散射仪器测定其zeta电位；
b、将碳多孔材料包载阿霉素DOX并连接叶酸FA后分散到1mL的去离子水中，使用Mavern公司动态光散射仪器测定其zeta电位；
c、将实施例1中步骤S6获得的碳多孔材料包载阿霉素DOX并连接小干扰RNA(siRNA)分散到1mL的去离子水中，使用Mavern公司动态光散射仪器测定其zeta电位；
d、将实施例1合成的载药系统，即碳多孔材料包载DOX并连接小干扰RNA(siRNA)和叶酸FA，分散到1mL的去离子水中，使用Mavern公司动态光散射仪器测定其zeta电位。
测定结果如图4所示，其中,a为碳多孔材料连接小干扰RNA(siRNA)的电位图，b为碳多孔材料包载阿霉素DOX和连接叶酸FA的电位图，c为碳多孔材料包载阿霉素DOX并连接小干扰RNA(siRNA)的电位图，d为碳多孔材料包载DOX并连接小干扰RNA(siRNA)和叶酸FA的电位图。
本实施例中，由于阿霉素电位为正值，小干扰RNA(siRNA)和叶酸FA电位为负值，所以合成的载药系统电位最负，由图4可知，实施例1成功合成了载药系统。
实施例4：采用碳多孔材料合成的载药系统的效果验证
1、取实施例1合成的载药系统转染组织细胞
将实施例1制备好的基于修饰小干扰RNA的碳多孔材料构建的载药系统置于离心管中，加入血清浓度为20％的DMEM细胞培养液1mL，充分混匀后，加入到培养海拉细胞的细胞培养皿中，并将培养皿置于37℃，5％的二氧化碳培养箱中，培养2h。
2、抗癌药物阿霉素的释放与检测
取出培养2h后的细胞培养皿，去除其中的混合培养液，向培养皿中加入DMEM培养液，重复冲洗，最后，加入1mL含有20％血清的培养液。
在激光共聚焦显微镜下观察海拉细胞内FAM和阿霉素的荧光，以488nm为激发光源，采集510-535nm与570-590nm的发射光。观测随着时间变化，海拉细胞的生存情况。
由图5可知：海拉细胞质中有较强的FAM绿色荧光和阿霉素的红色荧光，随着时间的推移，细胞皱缩，至凋亡只需要5h，表明此载药系统具有较好的治疗效果。
实施例5：采用碳多孔材料合成的载药系统作用于海拉细胞的效果的验证
将HeLa细胞接种在培养皿中，加入DMEM培养基，并在CO2浓度为5％的CO2培养箱中，37℃下孵育24小时，然后分别加入PCN-DOX-FA，PCN-siRNA-FA，PCN-siRNA-DOX，PCN-siRNA-DOX-FA，温育6小时后将混合物洗涤三次，然后通过荧光显微镜在488nm激发下记录DOX和FAM信号，结果如图6所示。
在图6中，bright为共聚焦显微镜明场中所示的细胞状态图，DOX+FA为碳多孔材料包载阿霉素并连接叶酸FA在明场通道中的细胞成像图，siRNA+FA为碳多孔材料连接小干扰RNA(siRNA)和叶酸FA在明场中的细胞成像图像，DOX+siRNA为碳多孔材料包载阿霉素并连接siRNA在明场中的细胞成像图像，DOX+siRNA+FA为碳多孔材料包载阿霉素并连接siRNA和叶酸FA在明场中的细胞成像图像，FAM通道为荧光基团FAM发光通道，DOX通道为阿霉素DOX的发光通道，Merge为上述通道的叠加图像。
由图6可知，海拉细胞基本不吞噬未修饰叶酸的探针，而基于碳多孔材料的载药系统有明显的绿色和红色荧光，说明细胞结构被破坏，释放药物，表明本申请的碳多孔材料包载DOX并连接小干扰RNA(siRNA)和叶酸FA的载药系统对海拉细胞具有较强的杀伤作用。
实施例6：基于碳多孔材料合成的载药系统的专一性验证
将人乳腺癌细胞MCF-7，以及人脐静脉内皮细胞(人正常细胞)HUVEC细胞分别接种在相应的培养皿中并加入对应培养基，在CO2浓度为5％的CO2培养箱中，37℃下孵育24小时，然后分别加入实施例1合成的载药系统，即碳多孔材料包载DOX并连接小干扰RNA(siRNA)和叶酸FA(PCN-siRNA-DOX-FA)，温育6小时后将混合物洗涤三次，最后通过荧光显微镜在488nm激发下记录DOX和FAM信号，结果如图7所示。
本实施例中，FAM通道为荧光基团FAM发光通道，DOX通道为阿霉素DOX的发光通道，由图7可知，FAM通道和DOX通道均未观察到相应的荧光基团FAM的绿色荧光和阿霉素DOX的红色荧光，表明本申请实施例1获得的碳多孔材料包载DOX并连接小干扰RNA(siRNA)和叶酸FA的载药系统对其他癌细胞以及正常细胞没有杀伤力。
以上对本申请的实施例进行了详细说明，但所述内容仅为本申请的较佳实施例，不能被认为用于限定本申请的实施范围。凡依本申请的申请范围所作的均等变化与改进等，均应仍归属于本申请的专利涵盖范围之内。
序列表
<110> 青岛科技大学
<120> 一种采用碳多孔材料构建抗癌载药系统的方法
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Claims (6)
1.一种采用碳多孔材料构建抗癌载药系统的构建方法，其特征在于，包括以下步骤：
(一)碳多孔材料的合成
S1、称取0.005-20mg3-氨基苯酚，水浴搅拌溶解在有机溶剂中，加入0.5-100mL乙醇和0.5-100mL去离子水，水浴搅拌溶解并升温至37℃恒定，然后加入0.005-15mL甲醛，以及催化剂，37℃条件下反应10-60min，最后10000r离心1-20min，用去离子水洗涤两次后真空干燥，得前体；
S2、将前体置于通有保护气的管式炉中，200-1200℃碳化3-8h，研磨得碳多孔材料；
(二)碳多孔材料表面改性
S3、碳多孔材料表面的氧化
称取步骤S2获得的碳多孔材料0.1-40mg，加入0.1-20mL过氧化氢，超声处理4h后用去离子水洗涤两次，然后将碳多孔材料真空干燥，获得氧化的碳多孔材料；
S4、碳多孔材料表面的氨基化
将0.1-40mg步骤S3氧化的碳多孔材料分散于0.2-25mL异丙醇中，搅拌加热至50-100℃，再加入0.1-15mL3-氨丙基三乙氧基硅烷，回流冷凝反应6-48h，然后离心并用异丙醇洗涤两次，真空干燥，得氨基化的碳多孔材料；
(三)包载阿霉素与连接小干扰RNA
S5、取步骤S4获得的0.05-15mg氨基化的碳多孔材料分散于0.1-25mL去离子水中，并加入1.0-20μL 3-(2-吡啶二巯基)丙酸N-羟基琥珀酰亚胺酯(SPDP)，并在25℃下孵育,0.5-5h后加入0.1-20μL浓度为0.001mol/L的二硫苏糖醇(DTT)，反应1-10h后离心洗涤即得连接有SPDP的碳多孔材料；
S6、将连接有SPDP的碳多孔材料重分散于0.1-25mLDEPC水，然后加入0.1-50μL 10-5M的小干扰RNA和0.5-15mg阿霉素，反应0.5-18h，然后离心将沉淀分散在0.1-20mL DEPC水中，得到小干扰RNA包载阿霉素的载药系统。
(四)载药系统表面修饰叶酸FA
S7、取0.05-15mL浓度为10-2mg/L的叶酸，加入0.1mol/L 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)100μL和0.1mol/LN-羟基琥珀酰亚胺(NHS)50μL活化叶酸；
S8、取步骤S6获得的小干扰RNA包载阿霉素的探针0.2-15mL，加入100μL步骤S7活化后的叶酸，反应1-18h，然后离心分散，即得碳多孔材料包载阿霉素并连接siRNA和叶酸FA的载药系统。
2.如权利要求1所述的一种采用碳多孔材料构建抗癌载药系统的构建方法，其特征在于，所述步骤S1中，加入的催化剂为氨水，所述氨水加入的体积和甲醛的体积比为1:1。
3.如权利要求2所述的一种采用碳多孔材料构建抗癌载药系统的方法，其特征在于，所述保护气为氮气。
4.如权利要求3所述的一种采用碳多孔材料构建抗癌载药系统的方法，其特征在于，所述步骤S6中，小干扰RNA包括一条5’端修饰有巯基的RNA链和一条5’端修饰有FAM荧光团的RNA。
5.如权利要求4所述的一种采用碳多孔材料构建抗癌载药系统的方法，其特征在于，所述5’端修饰有巯基的RNA链为SH-GAG UAC CAA GAG AUU CAU ATT。
6.如权利要求5所述的一种采用碳多孔材料构建抗癌载药系统的方法，其特征在于，所述5’端修饰有FAM荧光团的RNA为FAM-UAU GAA UCU CUU GGU ACU CTT。
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