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CN109134869B - 过氧化氢响应型靶向荧光载药纳米材料及制备方法 - Google Patents

过氧化氢响应型靶向荧光载药纳米材料及制备方法 Download PDF

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CN109134869B
CN109134869B CN201810722761.6A CN201810722761A CN109134869B CN 109134869 B CN109134869 B CN 109134869B CN 201810722761 A CN201810722761 A CN 201810722761A CN 109134869 B CN109134869 B CN 109134869B
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李亚鹏
方超
王书唯
赵外欧
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Abstract

本发明的过氧化氢响应型靶向荧光载药纳米材料及制备方法属于纳米材料技术领域，结构式如下：
Figure DDA0001718917650000011
其制备方法包括PHEMA的合成、FPEG的合成、PHEMA‑Sim/Prv/Com/Lo的合成以及PHEMA‑Sim/Prv/Com/Lo‑FPEG‑ISO‑1的合成等步骤。本发明制备的纳米粒子具有药物利用度高、荧光标定功能以及靶向动脉粥样硬化斑块的功能。

Description

过氧化氢响应型靶向荧光载药纳米材料及制备方法
技术领域
本发明属于纳米材料技术领域，具体涉及一种具有过氧化氢响应及靶向荧光能力的纳米载药材料及其制备方法。
背景技术
聚甲基丙烯酸羟乙酯因独特的多羟基结构而易于修饰，在医学领域有一定的应用。但利用聚甲基丙烯酸羟乙酯同时运携药物，荧光聚合物及靶分子，作为诊疗两用的载体的研究并不常见。
动脉粥样硬化是一种常见的心脑血管疾病，作为一种慢性炎症疾病，动脉粥样硬化在初期潜伏隐蔽，症状不明显，而最终却能引发如心梗，中风的高危疾病。在治疗方面，动脉粥样硬化疾病在后期目前只能通过支架，手术等手段治愈。而早期则以口服他汀类药物较为常见，但这种治疗方式却存在着药物利用率低，见效慢，副作用严重等问题。此外，动脉粥样硬化缺乏传统疾病的pH敏感能力，在纳米医疗上必须寻找更具特异性的释药控制开关。其中，过氧化氢等活性氧簇在动脉粥样硬化早期较为活跃，可以作为特异性开关。
传统单一的功能型药物体系已经无法满足现阶段动脉粥样分子治疗的要求。只有将靶向定位，荧光检测，控制释药等综合多种功能综合应用才能发挥更好的诊疗作用。而在动脉粥样硬化疾病领域，诊疗一体的纳米载药体系的应用相对缺乏，亟待补充与完善。
发明内容
本发明要解决的技术问题是：克服背景技术上存在的缺陷和问题，提供一种对过氧化氢响应且具有靶向荧光特性的载药纳米材料及制备方法。
本发明的技术问题通过以下方案实现：
一种过氧化氢响应型靶向荧光载药纳米材料，其结构式如下：
Figure BDA0001718917630000021
其中m:n＝4:1；
Figure BDA0001718917630000022
选自如下结构：
Figure BDA0001718917630000023
一种过氧化氢响应型靶向荧光载药纳米材料的制备方法，包含以下步骤：
(1)取他汀类药物溶于无水二氯甲烷中，取5～10倍摩尔当量的草酰氯溶于无水二氯甲烷中，在冰盐浴条件下，将他汀类药物溶液滴入草酰氯溶液中，滴加完毕后继续反应2～3小时，随后旋蒸除去溶剂及过量的草酰氯，真空干燥后得黄色粉末；
(2)将步骤(1)制备的黄色粉末溶于二氯甲烷，将得到的溶液滴入到聚甲基丙烯酸羟乙酯的二氯甲烷溶液中，滴加完毕后，继续反应1～5h，后经旋蒸，干燥等获得黄色膏状固体，所述的黄色粉末与聚甲基丙烯酸羟乙酯的质量比为1:3。
(3)将荧光聚乙二醇、步骤(2)制备的黄色膏状固体、互变异构酶活性抑制剂(ISO-1)、4-二甲氨基吡啶(DMAP)按摩尔比为1:0.1～0.2:0.1～0.2:0.1～0.2溶于二氯甲烷中得到混合溶液，然后将二环己基碳二亚胺的二氯甲烷溶液滴入所述的混合溶液中，二环己基碳二亚胺的用量按摩尔计为荧光聚乙二醇的1.2～1.5倍，滴加结束后室温条件下继续反应24h，后经过滤、透析、干燥获得褐色固体，即为过氧化氢响应型靶向荧光载药纳米材料。
所述的他汀类药物可以是普伐他汀、辛伐他汀、美伐他汀或洛伐他汀。
所述的荧光聚乙二醇可以按照下述方法制备：
取无水柠檬酸、聚乙二醇单甲醚和半胱氨酸按摩尔比1:1～1.2:0.2～0.5加入至干燥的圆底烧瓶中，向瓶中反复冲抽氩气确保氧气被完全除净，之后加热使混合物在120～150℃的环境下融化并反应1～3h，将温度降至100～120℃继续反应1～2h，反应结束后将产物溶于去离子水中，经过滤、透析、旋蒸、干燥后得黄色蜡状固体，即为荧光聚乙二醇。
本发明分别将辛伐他汀前药、荧光聚乙二醇及靶向巨噬细胞抑制游走因子的靶分子ISO-1修饰到PHEMA上，合成具有能够靶向巨噬细胞的、过氧化氢敏感控制释药的、能发荧光的两亲聚合物PHEMA-Sim-FPEG-ISO-1，并形成纳米胶束。由于动脉硬化病灶的过氧化氢水平和巨噬细胞数量会明显升高，因此本发明制备的PHEMA-Sim-FPEG-ISO-1会主动向动脉硬化病灶聚集，且在到达病灶时进行释药，大幅度提高了药物的利用度。
综上，本发明具有以下有益效果：
1、本发明制备的纳米粒子通过新的释药方式，可有效提高药物利用度。
2、本发明对传统的聚乙二醇进行特殊修饰，在保留生物相容性的同时具有荧光功能。方便给药监测。
3、本发明通过引入巨噬细胞靶分子，使制备的纳米粒子具备靶向动脉粥样硬化斑块的功能。
附图说明：
图1是实施例2制备的荧光聚乙二醇的核磁图。
图2是实施例4制备的过氧化氢响应的靶向荧光载药纳米粒子的核磁图。
图3是实施例4制备的过氧化氢响应的靶向荧光载药纳米粒子的透射扫描电镜。
图4是实施例2制备的荧光聚乙二醇在紫外灯照射下的荧光实物照片。
图5是实施例4制备的过氧化氢响应的靶向荧光载药纳米粒子在紫外灯照射下的荧光实物照片。
具体实施方式
本发明的过氧化氢响应型靶向荧光载药纳米材料的合成路线如下：
Figure BDA0001718917630000041
实施例1：聚甲基丙烯酸羟乙酯(PHEMA)的合成
聚甲基丙烯酸羟乙酯(PHEMA)通过ATRP方法合成。在经多次烘烤，抽真空、充氩气的支口瓶中依次加入2-联吡啶(0.06g)、CuCl(0.28g)、4mL N,N'-二甲基甲酰胺、4mL甲基丙烯酸羟乙酯和0.15mL 2-溴-2甲基丙烯酸酯。再次进行抽真空充氩气操作确保反应体系处于无氧状态。将支口瓶置于70℃油浴锅中反应6h，反应终止后将混合物溶于甲醇，使用Al2O3中性柱除杂，滤液经旋蒸浓缩，并在乙醚中沉淀，后经离心，烘干等后处理，获得白色粉末PHEMA。
实施例2：荧光聚乙二醇(FPEG)的合成
取无水柠檬酸(0.96g)、聚乙二醇单甲醚2000(2g)和半胱氨酸(0.6g)加入预先干燥好的50mL圆底烧瓶中，向瓶中反复冲抽氩气3次确保氧气被完全除净。之后混合物在140℃的环境下融化并反应2h，将温度降至120℃继续反应1h。反应结束后将产物溶于去离子水中，并用截留分子量为2000的透析袋透析一周，旋蒸干燥后得黄色蜡状固体FPEG。从图1的核磁图中可看出目标产物各H位置和峰面积均有很好的归属。本实施例制备的荧光聚乙二醇在紫外灯照射下呈现黄色荧光，如图4所示(附图是黑白的，无颜色信息，但原始的彩色照片中样品呈黄色荧光)。
实施例3：过氧化氢响应型辛伐他汀聚合物(PHEMA-Sim)的合成
首先，取辛伐他汀(1.72g)溶于20mL无水二氯甲烷中，取草酰氯(5.02g)溶于5mL无水二氯甲烷中。在冰盐浴条件下，将辛伐他汀溶液按每秒1滴的速度滴入草酰氯溶液中，滴加完毕后继续反应2h，反应液由无色逐渐变为黄色，结束反应。随后旋蒸除去溶剂及过量的草酰氯，真空干燥后得酰氯化辛伐他汀黄色粉末1.84g，重新溶于20mL无水二氯甲烷。之后，取实施例1制备的PHEMA(0.9g)溶于50mL无水二氯甲烷中，在氩气保护下，将溶有酰氯化辛伐他汀的二氯甲烷溶液以每秒1滴的速度滴入到PHEMA溶液中，待滴加完毕后，继续反应2h，反应结束后，除去溶剂，获得粗产品。最后所得样品经截留分子量为5000的透析袋透析3天，以除去未反应的辛伐他汀和PHEMA，旋蒸烘干获得黄色膏状固体PHEMA-Sim。
实施例4：过氧化氢响应的靶向荧光载药纳米粒子(PHEMA-Sim-FPEG-ISO-1)的合成
将实施例3制备的PHEAM-Sim(0.92g)、实施例2制备的FPEG(0.56g)以及ISO-1(0.044g)和DMAP(0.012g)溶于30mL二氯甲烷中，另将DCC(0.08g)溶于4mL二氯甲烷中，以每秒1滴的速度滴入至前者混合溶液中。滴加结束后室温条件下继续反应24h。待反应结束后经过滤、透析、干燥获得目标产物PHEMA-Sim-FPEG-ISO-1。核磁图如图2所示，从图2中可看出目标产物各H位置和峰面积均有很好的归属。透射扫描电镜如图3所示，从图3中可以看出产物能形成粒径约为90nm左右的球形结构。所制备的样品在紫外灯照射下呈蓝色荧光，如图5所示(附图是黑白的，无颜色信息，但原始的彩色照片中样品蓝色荧光)。
实施例5：过氧化氢响应型他汀类聚合物(PHEMA-Prv/Com/Lo，)的合成
将实施例3中的辛伐他汀换成等摩尔的普伐他汀、美伐他汀或洛伐他汀均可得到与实施例3相似的结果。
实施例6:
将实施例4中的PHEAM-Sim换成PHEMA-Prv/Com/Lo，获得的纳米粒子与实施例4相似。

Claims (4)

1.一种过氧化氢响应型靶向荧光载药纳米材料，其结构式如下：
Figure FDA0002632874370000011
其中m:n＝4:1；
Figure FDA0002632874370000012
选自如下结构：
Figure FDA0002632874370000013
2.一种权利要求1所述的过氧化氢响应型靶向荧光载药纳米材料的制备方法，包含以下步骤：
(1)取他汀类药物溶于无水二氯甲烷中，取5～10倍摩尔当量的草酰氯溶于无水二氯甲烷中，在冰盐浴条件下，将他汀类药物溶液滴入草酰氯溶液中，滴加完毕后继续反应2～3小时，随后旋蒸除去溶剂及过量的草酰氯，真空干燥后得黄色粉末；
(2)将步骤(1)制备的黄色粉末溶于二氯甲烷，将得到的溶液滴入到聚甲基丙烯酸羟乙酯的二氯甲烷溶液中，滴加完毕后，继续反应1～5h，后经旋蒸，干燥等获得黄色膏状固体，所述的黄色粉末与聚甲基丙烯酸羟乙酯的质量比为1:3；
(3)将荧光聚乙二醇、步骤(2)制备的黄色膏状固体、互变异构酶活性抑制剂、4-二甲氨基吡啶按摩尔比为1:0.1～0.2:0.1～0.2:0.1～0.2溶于二氯甲烷中得到混合溶液，然后将二环己基碳二亚胺的二氯甲烷溶液滴入所述的混合溶液中，二环己基碳二亚胺的用量按摩尔计为荧光聚乙二醇的1.2～1.5倍，滴加结束后室温条件下继续反应24h，后经过滤、透析、干燥获得褐色固体，即为过氧化氢响应型靶向荧光载药纳米材料。
3.根据权利要求2所述的一种过氧化氢响应型靶向荧光载药纳米材料的制备方法，其特征在于，所述的他汀类药物是普伐他汀、辛伐他汀、美伐他汀或洛伐他汀。
4.根据权利要求2或3所述的一种过氧化氢响应型靶向荧光载药纳米材料的制备方法，其特征在于，所述的荧光聚乙二醇是按照下述方法制备的：
取无水柠檬酸、聚乙二醇单甲醚和半胱氨酸按摩尔比1:1～1.2:0.2～0.5加入至干燥的圆底烧瓶中，向瓶中反复冲抽氩气确保氧气被完全除净，之后加热使混合物在120℃～150℃的环境下融化并反应1～3h，将温度降至100～120℃继续反应1～2h，反应结束后将产物溶于去离子水中，经过滤、透析、旋蒸、干燥后得黄色蜡状固体，即为荧光聚乙二醇。
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