CN114539490B - 一种两亲性过渡型高分子及其制备方法和应用 - Google Patents
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Abstract
本发明属于两亲性高分子技术领域,具体涉及一种两亲性过渡型高分子及其制备方法和应用。本发明所提供的两亲性过渡型高分子包括依次键连的亲水嵌段、过渡嵌段和疏水嵌段。该两亲性过渡型高分子较现有的两亲性嵌段聚合物稳定性得到了提高。并且,其可通过RAFT聚合法合成得到,具有可应用于生物体内、合成成功率高、便于设计、具有工业化前景等优点。
Description
技术领域
本发明属于两亲性高分子技术领域,具体涉及一种两亲性过渡型高分子及其制备方法和应用。
背景技术
两亲性聚合物由疏水链段和亲水链段组成。疏水链段中,水溶性较差的药物可以被包裹在疏水性的核中,增加其水溶性,同时降低了其在血液循环中发生降解的可能性;亲水链段中,亲水性的壳可增强胶束的稳定性,提高胶束穿透网状内皮组织体系的渗透性,延长药物在体内的循环时间。从整体来看,胶束呈球形纳米结构,聚合物胶束的粒径一般在100-200nm范围左右,能够增加药物的穿透性。两亲性聚合物在纳米器件、高分子表面活性剂、药物等领域均具有广阔的应用前景。近年来,随着可控/活性自由基聚合的发展,两亲性聚合物的合成、自组装以及相关的应用研究都取得了长足的进步。在生物医药领域,由两亲性嵌段聚合物自组装成的胶束因其良好的生物相容性、较高的载药率和靶向功能,成为目前最受关注的载药体系之一。
目前,比较成功的活性自由基聚合主要包括以下三种:氮氧稳定自由基聚合(NMP)、原子转移自由基聚合(ATRP)和可逆加成-断裂链转移聚合(RAFT)。NMP可用于制备分子量分布较窄的均聚物和嵌段共聚物,但可适用的单体种类少,大多限于苯乙烯类和丙烯酸酯类。ATRP可适用的单体范围广且可在较温和的条件下进行反应,近年来得到了快速发展。但原子转移自由基聚合本身也存在着明显的缺陷,如作为非均相催化系统,其环境稳定性较差,所采用的卤化物具有毒性、产物有毒性残留等。相较于其他的活性自由基聚合,RAFT聚合发现的时间最晚,但是由于它具有适用反应条件温和、聚合方法多样化、单体范围广且结构多样化等优点,目前已成为发展速度最快的活性自由基聚合。
目前两亲性三嵌段(A-b-B-b-C型或A-b-B-b-A型)聚合物主要采用ATRP聚合法合成,但有环境稳定性较差、聚合速度慢等问题存在。而RAFT聚合大多用来合成两亲性两嵌段(A-b-B型或A-b-A型)聚合物,但具有反应条件温和、便于设计、适用单体范围广等优点。因此,有必要发展RAFT聚合法来制备两亲性三嵌段聚合物(A-b-B-b-C型)的技术方案。
发明内容
为解决现有技术的不足,本发明提供了一种两亲性过渡型高分子及其制备方法和应用。
本发明所提供的技术方案如下:
一种两亲性过渡型高分子,包括依次键连的亲水嵌段、过渡嵌段和疏水嵌段。
本发明所提供的两亲性三嵌段过渡型高分子因具有过渡嵌段和聚合方法的改变,较现有的两亲性嵌段聚合物稳定性得到了提高,zeta电位绝对值可达到30mV以上。
具体的,两亲性过渡型高分子具有如下通式:
其中:
-A-为2个碳的直链或支链烷基;
-B-为1或2个碳的直链或支链烷基;
-C-为3或4或5个碳的直链或支链烷基;
k值为2~10;
n值为5~12;
m值为3~35。
基于上述技术方案:
1)可应用于生物体内:各嵌段可通过RAFT聚合得到相对安全的两亲性过渡型高分子,而其他聚合方法,例如ATRP法聚合过程中过渡金属络合物的用量大,且在聚合过程中不消耗,难以去除,残留在聚合物中容易导致聚合物老化。
2)合成成功率高:ATRP的反应条件较为严苛,特别是对除氧的要求极高。而本合成全程需在无水无氧条件下进行反应,RAFT聚合法反应条件较为温和,降低了合成难度,更容易实现。
3)便于设计:在合成嵌段共聚物时可以通过共价键修饰RAFT端基的方法,先在端基上接入一个嵌段序列,再通过逐步加料的RAFT聚合合成多嵌段共聚物。
优选的,两亲性过渡型高分子具有如下通式:
优选的,k为3~8;n为7~10;m为4~30。
本发明还提供了一种两亲性过渡型高分子的制备方法,包括以下步骤:
1)将RAFT试剂与过渡单体进行聚合,得到具有过渡嵌段的第一中间聚合物;
2)将步骤1)得到的第一中间聚合物与疏水单体进行聚合,得到具有过渡嵌段和疏水嵌段的第二中间聚合物;
3)将步骤2)得到的第二中间聚合物与亲水单体在引发剂的条件下进行RAFT聚合,得到第三中间聚合物;
4)将步骤3)得到的第三中间聚合物与偶氮二异丁腈进行聚合,通过取代脱除三硫代碳硫酯基团,得到具有亲水嵌段、过渡嵌段和疏水嵌段的两亲性过渡型高分子。
上述制备方法基于RAFT聚合,因而具有以下方面的优点:
1)可应用于生物体内:各嵌段可通过RAFT聚合得到相对安全的两亲性过渡型高分子,而其他聚合方法,例如ATRP法聚合过程中过渡金属络合物的用量大,且在聚合过程中不消耗,难以去除,残留在聚合物中容易导致聚合物老化。
2)合成成功率高:ATRP的反应条件较为严苛,特别是对除氧的要求极高。而本合成全程需在无水无氧条件下进行反应,RAFT聚合法反应条件较为温和,降低了合成难度,更容易实现。
3)便于设计:在合成嵌段共聚物时可以通过共价键修饰RAFT端基的方法,先在端基上接入一个嵌段序列,再通过逐步加料的RAFT聚合合成多嵌段共聚物。
4)具有工业化前景:简单易行、条件温和、便于设计的特点使RAFT比ATRP更容易实现工业化生产。
具体的:
RAFT试剂为4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇;
过渡单体为:L-丙交酯或乙交酯;
疏水单体为:丁内脂、戊内脂、ε-己内脂;
亲水单体为:聚乙二醇甲基丙烯酸酯。
优选的:
过渡单体为L-丙交酯(LLA);
疏水单体为ε-己内酯(CL);
亲水单体为聚乙二醇甲基丙烯酸酯(PEGMA);
引发剂为偶氮二异丁腈。
两亲性过渡型高分子的制备方法具体的包括如下步骤:
1)向无水甲苯中按照摩尔比为1:(180-220)加入4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇和L-丙交酯,催化剂为辛酸亚锡,并将反应混合物在N2气氛下于(75-85)℃搅拌反应20-28小时,优选为24小时,然后将所得产物缓慢滴在石油醚中沉淀,进行两次沉淀后得到纯净产物,真空烘箱中干燥,得到所述的第一中间聚合物;
2)将步骤1)得到的所述第一中间聚合物与ε-己内酯按照摩尔比为1:(1~4)溶解在无水甲苯中,以辛酸亚锡为催化剂,在N2氛围中(75-85)℃下反应20-28小时,优选为24小时,然后将所得产物缓慢滴在石油醚中沉淀,进行两次沉淀后得到纯净产物,真空烘箱中干燥,得到所述的第二中间聚合物;
3)再将步骤2)得到的所述第二中间聚合物产物和聚乙二醇甲基丙烯酸酯溶解在无水甲苯中,二者摩尔比为(1~4):(1:2),再加入引发剂偶氮二异丁腈,在N2氛围下以(75-85)℃的条件进行反应,反应时间为20-28小时,优选为24小时,然后将所得产物缓慢滴在石油醚中沉淀,进行两次沉淀后得到纯净产物,真空烘箱中干燥,得到所述的第三中间聚合物;
4)再将步骤3)得到的所述第三中间聚合物产物和微量偶氮二异丁腈溶解在无水甲苯中,全程在N2氛围下,以(75-85)℃的温度进行油浴反应,20-28小时后反应完毕,优选为24小时,然后将所得产物缓慢滴在石油醚中沉淀,进行两次沉淀后抽滤得到纯净产物,真空烘箱中干燥,得到最终产物,即过渡型两亲性高分子。
反应机理如下:
本发明还提供了两亲性过渡型高分子的应用,用于制备胶束,可用于负载阿霉素等药物。一个具体的制备方法如下:
将5mg阿霉素与80mg两亲性过渡型高分子聚合物一起溶解在80ml DMSO中,在室温下超声30min,得到均一、稳定的胶束溶液。然后将此溶液置于分子量截止值为3500Da的透析袋中,在水中透析2天,每隔6小时换一次溶液,即可得到负载着阿霉素的胶束。
附图说明
图1是本发明所提供的两亲性过渡型高分子的傅里叶变换红外光谱。
图2是本发明所提供的两亲性过渡型高分子所形成的胶束的SEM图。
图3是本发明所提供的两亲性过渡型高分子所形成的胶束的界面张力曲线图。
具体实施方式
以下对本发明的原理和特征进行描述,所举实施例只用于解释本发明,并非用于限定本发明的范围。
试剂与仪器
4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇,分析纯,探索平台;丙交酯,化学纯,成都麦克林生物科技有限公司;ε-己内酯,分析纯,北京化工厂;甲苯,分析纯,天津市富宇精细化工有限公司;偶氮二异丁腈,分析纯,北京化学试剂公司;辛酸亚锡,分析纯,北京化学试剂公司;聚乙二醇甲基丙烯酸酯,分析纯,阿拉丁;石油醚,分析纯,北京化工厂;乙酸乙酯,分析纯,川东化学化工试剂厂;正庚烷,分析纯,成都麦克林生物科技有限公司。
Nicolet 6700型傅里叶变换红外光谱仪,赛默飞世尔科技、Inspect F50扫描电子显微镜、CA-100C型接触角公司测量仪,上海盈诺精密仪器有限公司;Malvern 200型湿法激光粒度仪,英国马尔文公司;高温凝胶色谱仪,上海月旭科技股份有限公司。
实施例1
1)所有玻璃器皿在100℃下干燥12小时。在合成中,将少许Na溶解在无水甲苯(100ml)中,并在真空条件下完全蒸馏出甲苯,以除去溶剂中可能存在的少许水分。向上述混合物中加入RAFT试剂和LLA,二者摩尔比例为1:200,并将反应混合物在N2气氛下于80℃油浴搅拌24小时。然后将所得产物缓慢滴在石油醚中沉淀,沉淀进行两次后得到纯净产物。最终获得的产品在40℃的真空烘箱中干燥。
2)将第一步得到的这种基于聚左旋丙交酯(PLLA)的新型大分子与CL完全溶解在甲苯中,二者摩尔比例为1:1、1:2、1:4,以辛酸亚锡(Sn(Oct)2)为催化剂,N2气体吹扫烧瓶30分钟,在N2氛围中80℃下油浴反应24小时,后续处理步骤同上。
3)再将第二步所得产物和PEGMA完全溶解在甲苯中,二者摩尔比为1:1、2:1。在80℃下向烧瓶中加入AIBN引发剂之前,用N2气体吹扫烧瓶30分钟,在N2氛围中80℃下油浴反应24小时,直到单体完全转化,后续处理步骤同上。
4)最后将第三步所得产物和微量偶氮二异丁腈完全溶解在甲苯中,N2氛围下油浴反应24小时,反应完成后,将烧瓶冷却至室温,用冰冷的石油醚沉淀粗产物2次,再将产物置于分子量截止值为3500Da的透析袋中,在乙酸乙酯环境中透析2天,每隔6小时换一次溶液,得到两亲性过渡型高分子。
对最终产物进行数据表征,结果和分析如下:
傅里叶变换红外光谱(FTIR)分析:聚合物红外光谱采用溴化钾压片法制样,样品质量与无水溴化钾质量比为1:100,使用Nicolet 6700型傅里叶变换红外光谱仪对样品进行定性分析。
凝胶渗透色谱(GPC)测试:合成聚合物的数均分子量、重均分子量、Z均分子量和多分散性(Mw/Mn)通过凝胶渗透色谱法进行表征。
图1是不同比例的PEGMA-b-PLLA-PCL的红外谱图,可以看到4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇引发L-丙交酯的开环聚合后1750cm-1处出现了明显的羰基伸缩振动峰,这证实了聚乳酸链段的存在。2300cm-1处的峰微弱,但经局部放大可知,有较为明显的氰基峰,这是4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇所产生的红外吸收。此外,在3500cm-1处的羟基的伸缩振动峰也显著增强,这验证了PLLA中大量羟基的引入。研究结果表明,红外谱图具备特征吸收峰,红外谱图的变化符合聚合物链的变化,成功合成此种两亲性过渡型高分子聚合物。
表1不同配比聚合物的分子量
表1是不同分子结构的聚合物的分子量情况,从表中可以看出,随着n(PCL):n(PEGMA)与n(PEGMA):n(PCL)的增大,聚合物分子量也随之增加,聚合物数均分子量的范围在1446~4199之间,分子量分布较窄。
应用例1
使用溶剂切换法获得胶束:将共聚物溶解在微量的良好溶剂二甲基亚砜(DMSO)中,然后在超声波条件下,用水非常缓慢地稀释并用水透析以产生胶束。
对其进行DLS、SEM、界面张力方面的性能测试,结果如下:
粒径的测定:称量一定量的共聚物,用少量二甲基亚砜分散,再加入去离子水配置成0.5wt%质量分数的共聚物水溶液即胶束,用于DLS粒度分析。使用Malvern 2000型湿法激光粒度仪(英国马尔文,马尔文,Malvern Panalytic)在25℃下120s内评估粒径,每个程序测试3遍取平均值。
SEM测试:铜网置于滤网上,滴一滴胶束溶液于铜网上,待样品干燥后可重复滴加多次,送样进行测试。结果图2所示。
界面张力测试:传统用芘测CMC的方法复杂且有毒性,本发明采用了另一种测定方法。配置七种不同浓度的两亲性嵌段共聚物溶液,超声30min,准备向装有三分之二正庚烷溶剂的自制5×5×5的正方体透明玻璃容器内滴入,缓慢加液使液滴变大,在液滴滴落前的瞬间测量界面张力,将得到的数据进行origin画图,若出现明显平台期,则可反推出CMC值。具体如图3所示。
实施例得到的两亲性过渡型高分子的各项测试结果如表2所示:
表2两亲性过渡型高分子的性能表征
上述稳定性检测结果标准说明:
表征聚合物稳定性的因素有很多,如:粒度大小、Zeta电位、PH值、温度、产物配比等,而Zeta电位是样品稳定性比较直观的一个参数,它的数值与胶态分散的稳定性相关。分子或分散粒子越小,Zeta电位的绝对值越高,体系越稳定,即溶解或分散可以抵抗聚集。Zeta电位(绝对值)与体系稳定性之间的关系如下:Zeta电位为0到5mV时,胶体快速凝结或凝聚;Zeta电位为10到30mV时,体系开始变得不稳定;Zeta电位为30到40mV时,体系稳定性一般;Zeta电位为40到60mV时体系有较好的稳定性;Zeta电位超过61mV时,体系稳定性极好。
以上研究结果证明,以上说明本发明实施例制备得到的两亲性过渡型高分子分布均匀、稳定,无大颗粒固体或凝聚。根据界面张力的平台期可反推出此种两亲性过渡型高分子的CMC值约为1.667×10-3g/mL。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种两亲性过渡型高分子,其特征在于,具有如下通式:
其中:
-A-为2个碳的直链或支链烷基;
-B-为1或2个碳的直链或支链烷基;
-C-为3或4或5个碳的直链或支链烷基;
k值为2~10;
n值为5~12;
m值为3~35。
2.根据权利要求1所述的两亲性过渡型高分子,其特征在于,具有如下通式:
3.根据权利要求2所述的两亲性过渡型高分子,其特征在于:k为3~8;n为7~10;m为4~30。
4.一种根据权利要求1至3任一所述的两亲性过渡型高分子的制备方法,其特征在于,包括以下步骤:
1)将RAFT试剂与过渡单体进行聚合,得到具有过渡嵌段的第一中间聚合物;
2)将步骤1)得到的第一中间聚合物与疏水单体进行聚合,得到具有过渡嵌段和疏水嵌段的第二中间聚合物;
3)将步骤2)得到的第二中间聚合物与亲水单体在引发剂的条件下进行RAFT聚合,得到第三中间聚合物;
4)将步骤3)得到的第三中间聚合物与偶氮二异丁腈进行聚合,通过取代脱除三硫代碳硫酯基团,得到具有亲水嵌段、过渡嵌段和疏水嵌段的两亲性过渡型高分子。
5.根据权利要求4所述的两亲性过渡型高分子的制备方法,其特征在于:
RAFT试剂为4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇;
过渡单体为:L-丙交酯或乙交酯;
疏水单体为:丁内酯、戊内酯、ε-己内酯;
亲水单体为:聚乙二醇甲基丙烯酸酯。
6.根据权利要求5所述的两亲性过渡型高分子的制备方法,其特征在于:
过渡单体为L-丙交酯;
疏水单体为ε-己内酯;
亲水单体为聚乙二醇甲基丙烯酸酯;
引发剂为偶氮二异丁腈。
7.根据权利要求6所述的两亲性过渡型高分子的制备方法,其特征在于,包括以下步骤:
1)向无水甲苯中按照摩尔比为1:(180-220)加入4-氰基-4-[(十二烷基硫烷基硫代羰基)硫烷基]戊醇和L-丙交酯,催化剂为辛酸亚锡,并将反应混合物在N2气氛下于(75-85)℃搅拌反应20-28小时,然后将所得产物缓慢滴在石油醚中沉淀,进行两次沉淀后得到纯净产物,真空烘箱中干燥,得到所述的第一中间聚合物;
2)将步骤1)得到的所述第一中间聚合物与ε-己内酯按照摩尔比为1:(1~4)溶解在无水甲苯中,以辛酸亚锡为催化剂,在N2氛围中(75-85)℃下反应20-28小时,然后将所得产物缓慢滴在石油醚中沉淀,进行两次沉淀后得到纯净产物,真空烘箱中干燥,得到所述的第二中间聚合物;
3)再将步骤2)得到的所述第二中间聚合物产物和聚乙二醇甲基丙烯酸酯溶解在无水甲苯中,二者摩尔比为(1~4):(1~2),再加入引发剂偶氮二异丁腈,在N2氛围下以(75-85)℃的条件进行反应,反应时间为20-28小时,然后将所得产物缓慢滴在石油醚中沉淀,进行两次沉淀后得到纯净产物,真空烘箱中干燥,得到所述的第三中间聚合物;
4)再将步骤3)得到的所述第三中间聚合物产物和微量偶氮二异丁腈溶解在无水甲苯中,全程在N2氛围下,以(75-85)℃的温度进行油浴反应,20-28小时后反应完毕,然后将所得产物缓慢滴在石油醚中沉淀,进行两次沉淀后抽滤得到纯净产物,真空烘箱中干燥,得到最终产物,即过渡型两亲性高分子。
8.一种根据权利要求1至3任一所述的两亲性过渡型高分子的应用,其特征在于:用于制备胶束。
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