CN112807433B - 一种绿光响应高分子纳米药物载体 - Google Patents
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Abstract
本发明公开了一种绿光响应高分子纳米药物载体。其特征在于首先合成了一种含给体‑受体斯坦豪斯加合物的绿光响应两亲(亲水亲油)高分子,然后该高分子和药物在溶液中自组装形成囊泡,最后获得包载有亲/疏水性药物的绿光响应纳米药物载体。本专利制备的纳米药物载体利用低能量绿光作为响应开关,避免了激发光源对生物组织造成光损伤的问题;与传统高分子胶束药物载体相比,该方法制备的高分子囊泡药物载体具有更大的载药量、更多的载药及释药模式。
Description
技术领域
本发明具体涉及一种绿光响应高分子纳米药物载体,属于生物医用材料领域。
背景技术
近年来,由于刺激响应纳米药物载体可以实现抗癌药物在病灶部位的富集,降低了相应药物的毒副作用而被批准进入临床,已成为纳米医学领域的重要发展方向。截止目前,已发展了pH响应、氧化还原响应、光响应、热响应和酶响应等刺激响应纳米药物载体。其中,光响应高分子纳米药物载体由于其独特的优势受到广泛的研究。首先,光响应高分子纳米药物载体具有极强设计性、体内无毒性和长循环性等优点,并且能够提高病灶部位的药物浓度,降低注射量,减少副作用。其次,在光照下,光响应高分子纳米药物载体能够实现药物快速释放,无需添加额外的助剂。再次,可以通过调节光强、波长和辐照时间来控制它们的药物释放行为。总之,由于以上各种优点,使得光响应高分子纳米药物载体在肿瘤学和临床医学中受到广泛关注。
目前,光响应高分子纳米药物载体主要使用紫外光作为响应开关。这是因为紫外光的设备价格便宜,容易搭建。为构建该类纳米药物载体,往往在高分子的结构中引入紫外光响应基元,如偶氮苯、邻硝基苄酯、香豆素和螺吡喃等化合物的衍生物。
公开号为CN109821025A的专利公布了一种光和氧化还原双重刺激响应环糊精高分子载体,包括与亲水高分子链段相连的环糊精、和末端修饰有偶氮苯基团的疏水高分子链段。首先通过偶氮苯与环糊精的主客体识别作用来形成两亲高分子,其中端部修饰有偶氮苯基团嵌入环糊精的空腔中;随后将形成的两亲高分子在水溶液中和药物自组装形成囊泡。在光照条件下偶氮苯和环糊精分离,导致高分子亲水段和疏水段分开,致使囊泡破裂,进而释放药物。然而,紫外光本身具有一定的光毒性,这限制了紫外光响应高分子纳米药物载体的临床应用。
发明内容
本发明的目的是针对上述现有技术的不足而提供一种绿光响应高分子纳米药物载体。我们首先利用给体-受体斯坦豪斯加合物作为光响应单元设计了一种新的绿光响应两亲高分子,随后将该高分子和药物在溶液中自组装形成囊泡,最后获得包载有亲/疏水性药物的绿光响应纳米药物载体。在530nm左右的绿光照射下,绿光响应纳米药物载体中给体-受体斯坦豪斯加合物会从疏水状态迅速转变成为亲水状态,导致疏水性药物与纳米载体相互作用减弱而释放,同时亲水性药物由于囊泡双层膜渗透性的增加而释放。与传统的紫外光响应高分子纳米药物载体相比,所制备的绿光响应高分子纳米药物载体采用能量更低的绿光作为响应开关,避免了高能紫外光的使用对生物组织造成的光损伤问题,进一步推动光响应高分子纳米药物载体的临床应用。
一种绿光响应高分子纳米药物载体包括:
(1)呋喃衍生物的制备:将1.51g米氏酸或1,3-二甲基巴比妥酸和0.961g糠醛溶解在30mL水中,室温反应16h;反应完成后,经过滤、水洗处理,获得黄色固体;将黄色固体重新溶解在二氯甲烷中,依次使用饱和亚硫酸氢钠溶液、超纯水、饱和碳酸钠溶液和饱和氯化钠溶液进行洗涤;最后经无水硫酸镁干燥、过滤和旋蒸处理,获得呋喃衍生物;
(2)聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯)的制备:将1~10份2-(十二烷基三硫代碳酸酯基)-2-甲基丙酸聚乙二醇单甲醚酯、0.05~0.2份偶氮二异丁腈、4~8份甲基丙烯酸五氟苯酯、40~80份丙烯酸己酯溶解在1~10mL二恶烷中,60~90℃反应2~30h;反应完成后,经透析处理,获得聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯);
(3)烷基胺修饰的两亲高分子的制备:将1~10份步骤(2)产物、5~30份N-甲基-1,3-丙二胺和1~10mL三乙胺溶解在1~20mL四氢呋喃和1~20mL N,N-二甲基甲酰胺的混合溶液中,30~80℃下反应1~10天;经过滤、透析和旋蒸处理,获得烷基胺修饰的两亲高分子;
(4)绿光响应两亲高分子的制备:将1~5份步骤(3)产物和1~20份呋喃衍生物溶解在1~10mL四氢呋喃中,室温下反应1~7天;随后经透析处理,获得绿光响应两亲高分子;
(5)绿光响应高分子纳米药物载体的制备:将1~10份步骤(4)产物和0.05~1份疏水性药物溶解在1~10mL四氢呋喃溶液中,并以0.1~1mL/min的速率向该溶液中滴加10~60mL含有亲水性药物的水溶液,搅拌2h;经旋蒸、过滤和离心处理,获得负载抗癌药物的绿光响应高分子纳米药物载体。
所述的一种绿光响应高分子纳米药物载体,其特征在于所述的呋喃衍生物的结构式为:
所述的一种绿光响应高分子纳米药物载体,其特征在于所述的绿光响应两亲高分子的结构式为:
其中x:y:z=50:100:1~10:10:1,x、y、z均为1~100的整数。
所述的一种绿光响应高分子纳米药物载体,其特征在于所用疏水性药物包括但不限于阿霉素、紫杉醇或者喜树碱中的一种或多种。
所述的一种绿光响应高分子纳米药物载体,其特征在于所用亲水性药物包括但不限于5-氟尿嘧啶、硫鸟嘌呤或者阿糖胞苷中的一种或多种。
本发明与现有技术相比,具有以下积极效果:
(1)激发光能量低。相较于传统的紫外光响应高分子纳米药物载体,本专利制备的纳米药物载体采用低能量绿光作为响应开光,避免了激发光源对生物组织造成的光损伤;
(2)载药量大。由于高分子囊泡纳米药物载体拥有巨大的内部空腔,相较于高分子胶束纳米药物载体,本专利制备的纳米药物载体具有极大的载药量;
(3)可同时负载亲/疏水性药物。可利用囊泡的疏水双层膜及内部空腔分别实现对疏水性药物和亲水性药物的装载;
(4)具有多重载药模式。通过调控制备工艺,不仅可以实现对亲水性或疏水性药物的单独负载,还可同时实现亲/疏水性药物的共同负载;
(5)具有多重释药模式。根据不同的载药模式,不仅可以实现单一亲水性或疏水性药物的释放,还可同时实现多种亲/疏水性药物的释放。
附图说明
图1是本发明所述的绿光响应高分子纳米药物载体的形貌图。
图2是本发明所述的绿光响应高分子纳米药物载体在绿光照射下的药物释放散点图。
具体实施方式
下面通过实施例对本发明进行具体的描述,有必要指出的是以下实施例只是用于对本发明进行进一步的说明,不能理解为对本发明保护范围的限制,该领域的技术熟练人员可根据上述发明的内容做出一些非本质的改进和调整,仍属于本发明的保护范围。
实施例1:
(1)呋喃衍生物的制备:将1.51g米氏酸或1,3-二甲基巴比妥酸和0.961g糠醛溶解在30mL水中,室温反应16h;反应完成后,经过滤、水洗处理,获得黄色固体;将黄色固体重新溶解在二氯甲烷中,依次使用饱和亚硫酸氢钠溶液、超纯水、饱和碳酸钠溶液和饱和氯化钠溶液进行洗涤;最后经无水硫酸镁干燥、过滤和旋蒸处理,获得呋喃衍生物;
(2)聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯)的制备:将1份2-(十二烷基三硫代碳酸酯基)-2-甲基丙酸聚乙二醇单甲醚酯、0.05份偶氮二异丁腈、4份甲基丙烯酸五氟苯酯、40份丙烯酸己酯溶解在1mL二恶烷中,60℃反应2h;反应完成后,经透析处理,获得聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯);
(3)烷基胺修饰的两亲高分子的制备:将1份步骤(2)产物、5份N-甲基-1,3-丙二胺和1mL三乙胺溶解在1mL四氢呋喃和1mL N,N-二甲基甲酰胺的混合溶液中,30℃下反应1天;经过滤、透析和旋蒸处理,获得烷基胺修饰的两亲高分子;
(4)绿光响应两亲高分子的制备:将1份步骤(3)产物和1份呋喃衍生物溶解在1mL四氢呋喃中,室温下反应1天;随后经透析处理,获得绿光响应两亲高分子;
(5)绿光响应高分子纳米药物载体的制备:将1份步骤(4)产物和0.05份阿霉素溶解在1mL四氢呋喃溶液中,并以0.1mL/min的速率向该溶液中滴加10mL含有5-氟尿嘧啶的水溶液,搅拌2h;经旋蒸、过滤和离心处理,获得负载抗癌药物的绿光响应高分子纳米药物载体。
实施例2:
(1)呋喃衍生物的制备:将1.51g米氏酸或1,3-二甲基巴比妥酸和0.961g糠醛溶解在30mL水中,室温反应16h;反应完成后,经过滤、水洗处理,获得黄色固体;将黄色固体重新溶解在二氯甲烷中,依次使用饱和亚硫酸氢钠溶液、超纯水、饱和碳酸钠溶液和饱和氯化钠溶液进行洗涤;最后经无水硫酸镁干燥、过滤和旋蒸处理,获得呋喃衍生物;
(2)聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯)的制备:将5份2-(十二烷基三硫代碳酸酯基)-2-甲基丙酸聚乙二醇单甲醚酯、0.1份偶氮二异丁腈、5份甲基丙烯酸五氟苯酯、60份丙烯酸己酯溶解在5mL二恶烷中,75℃反应15h;反应完成后,经透析处理,获得聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯);
(3)烷基胺修饰的两亲高分子的制备:将5份步骤(2)产物、15份N-甲基-1,3-丙二胺和5mL三乙胺溶解在10mL四氢呋喃和10mL N,N-二甲基甲酰胺的混合溶液中,50℃下反应5天;经过滤、透析和旋蒸处理,获得烷基胺修饰的两亲高分子;
(4)绿光响应两亲高分子的制备:将3份步骤(3)产物和10份呋喃衍生物溶解在5mL四氢呋喃中,室温下反应4天;随后经透析处理,获得绿光响应两亲高分子;
(5)绿光响应高分子纳米药物载体的制备:将5份步骤(4)产物和0.1份紫杉醇溶解在5mL四氢呋喃溶液中,并以0.5mL/min的速率向该溶液中滴加40mL含有硫鸟嘌呤的水溶液,搅拌2h;经旋蒸、过滤和离心处理,获得负载抗癌药物的绿光响应高分子纳米药物载体。
实施例3:
(1)呋喃衍生物的制备:将1.51g米氏酸或1,3-二甲基巴比妥酸和0.961g糠醛溶解在30mL水中,室温反应16h;反应完成后,经过滤、水洗处理,获得黄色固体;将黄色固体重新溶解在二氯甲烷中,依次使用饱和亚硫酸氢钠溶液、超纯水、饱和碳酸钠溶液和饱和氯化钠溶液进行洗涤;最后经无水硫酸镁干燥、过滤和旋蒸处理,获得呋喃衍生物;
(2)聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯)的制备:将10份2-(十二烷基三硫代碳酸酯基)-2-甲基丙酸聚乙二醇单甲醚酯、0.2份偶氮二异丁腈、8份甲基丙烯酸五氟苯酯、80份丙烯酸己酯溶解在10mL二恶烷中,90℃反应30h;反应完成后,经透析处理,获得聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯);
(3)烷基胺修饰的两亲高分子的制备:将10份步骤(2)产物、30份N-甲基-1,3-丙二胺和10mL三乙胺溶解在20mL四氢呋喃和20mL N,N-二甲基甲酰胺的混合溶液中,80℃下反应10天;经过滤、透析和旋蒸处理,获得烷基胺修饰的两亲高分子;
(4)绿光响应两亲高分子的制备:将5份步骤(3)产物和20份呋喃衍生物溶解在10mL四氢呋喃中,室温下反应7天;随后经透析处理,获得绿光响应两亲高分子;
(5)绿光响应高分子纳米药物载体的制备:将10份步骤(4)产物和1份喜树碱溶解在10mL四氢呋喃溶液中,并以1mL/min的速率向该溶液中滴加60mL含有阿糖胞苷的水溶液,搅拌2h;经旋蒸、过滤和离心处理,获得负载抗癌药物的绿光响应高分子纳米药物载体。
Claims (4)
1.一种绿光响应高分子纳米药物载体,其制备方法包括如下步骤,所用物料的份数均为重量份数:
(1)呋喃衍生物的制备:将1.51 g米氏酸或1,3-二甲基巴比妥酸和0.961 g糠醛溶解在30 mL水中,室温反应16 h;反应完成后,经过滤、水洗处理,获得黄色固体;将黄色固体重新溶解在二氯甲烷中,依次使用饱和亚硫酸氢钠溶液、超纯水、饱和碳酸钠溶液和饱和氯化钠溶液进行洗涤;最后经无水硫酸镁干燥、过滤和旋蒸处理,获得呋喃衍生物;
(2)聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯)的制备:将1~10份2-(十二烷基三硫代碳酸酯基)-2-甲基丙酸聚乙二醇单甲醚酯、0.05~0.2份偶氮二异丁腈、4~8份甲基丙烯酸五氟苯酯、40~80份丙烯酸己酯溶解在1~10 mL二恶烷中,60~90 ℃反应2~30 h;反应完成后,经透析处理,获得聚乙二醇-b-聚(丙烯酸己酯-co-甲基丙烯酸五氟苯酯);
(3)烷基胺修饰的两亲高分子的制备:将1~10份步骤(2)产物、5~30份N-甲基-1,3-丙二胺和1~10 mL三乙胺溶解在1~20 mL四氢呋喃和1~20 mL N,N-二甲基甲酰胺的混合溶液中,30~80 ℃下反应1~10天;经过滤、透析和旋蒸处理,获得烷基胺修饰的两亲高分子;
(4)绿光响应两亲高分子的制备:将1~5份步骤(3)产物和1~20份呋喃衍生物溶解在1~10 mL四氢呋喃中,室温下反应1~7天;随后经透析处理,获得绿光响应两亲高分子,其化学结构式为:
其中x:y:z=50:100:1~10:10:1,x、y、z均为1~100的整数;
(5)绿光响应高分子纳米药物载体的制备:将1~10份步骤(4)产物和0.05~1份疏水性药物溶解在1~10 mL四氢呋喃溶液中,并以0.1~1 mL/min的速率向该溶液中滴加10~60 mL含有亲水性药物的水溶液,搅拌2 h;经旋蒸、过滤和离心处理,获得负载抗癌药物的绿光响应高分子纳米药物载体。
3.如权利要求1所述的一种绿光响应高分子纳米药物载体,其特征在于所用疏水性药物包括但不限于阿霉素、紫杉醇或者喜树碱中的一种或多种。
4.如权利要求1所述的一种绿光响应高分子纳米药物载体,其特征在于所用亲水性药物包括但不限于5-氟尿嘧啶、硫鸟嘌呤或者阿糖胞苷中的一种或多种。
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