CN106883360A - 可功能化的刺激响应性聚合物及其制备方法 - Google Patents
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Abstract
本发明涉及一种可功能化的刺激响应性聚合物及其制备方法。该聚合物由含烷氧链的亲水单体VBOEG与含胆固醇基元的单体通过两种自由基可控聚合而得。得到的双亲嵌段聚合物末端具有可功能化修饰的呋喃官能团、主链带有可还原响应的二硫键。由此聚合物制备的纳米材料的亲水壳的外层可通过Diels‑Alder反应进行原位多功能化修饰,疏水核与亲水壳间具有还原响应能力的二硫键连接,可在还原试剂存在下实现其纳米结构的解离。此聚合物材料在药物智能递送领域具有巨大的潜在应用价值。
Description
技术领域
本发明涉及一种可功能化的刺激响应性聚合物及其制备方法。
背景技术
智能聚合物材料是二十一世纪飞速发展起来的一类新型材料。由于其模仿生命***,当感知到外部环境的物理、化学乃至生物刺激信号的变化时,聚合物自身的某种性质如形状、水合状态、表面能、渗透速率或识别能力等会发生响应的改变。结合纳米科技技术的发展,综合聚合物智能的响应行为以及纳米级尺寸材料的特性而构建的聚合物智能纳米材料更是近年来发展最快的高新尖端功能材料之一,在生物医药、光电、绿色储能材料等领域有着广泛的应用潜力,尤其是在药物智能递送等领域具有不可估量的前景。借助聚合物纳米材料作为治疗用有效成分的载体,实现输送有机分子类药物,负载特异性蛋白,基因药物等已经不再是不可能的事情。以往作为载体类聚合物纳米材料的要求比较简单,只需无毒、生物相容性好及具有简单包覆有效成分能力即可。随之科学的发展,人们对聚合物纳米材料的设计越来越要求高,智能化、多功能化的方向发展已成主流的研究及应用方向。而实现纳米聚合物载体的智能化主要在以下两个方面考虑:
1.表面可功能化修饰。在包覆有效成分的聚合物纳米材料表面可有效引入具有不同功能性质的物质,例如靶向分子、蛋白、抗体等,以此来实现载药体系的多种功能化应用,增强智能递送效果的同时扩展其应用领域。
2. 赋予聚合物纳米材料智能响应的能力。通过外加刺激触发聚合物材料的智能响应,从而实现定时、定点及定量的可控递送有效成分的目的。在制备具有刺激响应的聚合物纳米材料领域,以发展除针对不同刺激源的进行响应的多种聚合物纳米材料。例如温度响应、pH响应、光响应、还原响应等等。其中,还原响应聚合物纳米载药体系可根据人体内的不同环境(细胞内外)还原性物质谷胱甘肽的浓度差异而做出不同的变化,实现选择性细胞内给药,因此此类材料被视为未来可大规模实际应用的聚合物载体材料之一。
常见的聚合物载体类纳米材料往往仅具有单一的刺激响应性能,而要真正实现纳米聚合物纳米材料的智能递送性能,必须将可功能化修饰及刺激响应性能有机结合在一起,从而发挥纳米聚合物纳米材料在药物智能递送/释放等领域中真正的应用价值。
发明内容
本发明的目的之一在于提供一种可功能化的刺激响应性聚合物。该聚合物是末端带有呋喃官能团,主链带有二硫键的双亲嵌段聚合物。
本发明的目的之二在提供一种该聚合物纳米材料的制备方法。
为了实现以上发明目的,本发明的双亲嵌段聚合物由含有聚乙二醇短链的苯乙烯类单体(VBOEG)与含有胆固醇基元的单体通过两种活性可控聚合联用进行合成,其中VBOEG单体通过可逆加成链转移聚合(Reversible Addition-Fragmentation Chain TransferPolymerization,RAFT)聚合得到亲水嵌段聚合物,通过末端功能化修饰引入含有双硫键的原子转移自由基聚合(Atom Transfer Radical Polymerization,ATRP)引发基团,实现含有胆固醇基元的丙烯酸酯单体通过ATRP聚合得到目标双亲嵌段聚合物。在此基础上,通过溶剂置换方法制备聚合物球状纳米材料,具体反应式为:
根据上述反应机理,本发明采用如下技术方案如下:
一种可功能化的刺激响应性聚合物,其特征在于该聚合物的结构式为:
其中m=10~30;n=10~90。
一种制备上述的可功能化的刺激响应性聚合物的方法,其特征在于该方法的具体步骤为:
a. 将链转移剂、含有聚乙二醇短链的苯乙烯类单体和偶氮二异丁腈按1:(20~50):(0.1~0.3)摩尔比溶于二氧六环中,密封后,进行除水除氧操作,再在60~80℃温度下搅拌反应12~36小时,反应结束后,溶剂,***中沉淀纯化,得到亲水嵌段聚合物PVBOEG。
b. 将步骤a所得PVBOEG和正己胺按1:(5~50)的摩尔比溶于二氯甲烷中,进行除水除氧操作,室温下搅拌反应10~24小时,反应结束后,除去溶剂,***中沉淀纯化,得到末端带巯基的聚合物产物PVBOEG-SH。
c. 将上述产物PVBOEG-SH和含有双硫键的ATRP小分子引发剂按1:10~50的摩尔比溶于甲醇中,室温搅拌反应16~24小时后,在***中沉淀纯化,得到目标ATRP大分子引发剂PVBOEG-SS-Br。
d. 在惰性气氛下,将步骤c所得PVBOEG-SS-Br、溴化亚铜、含胆固醇基元的单体和五甲基二乙烯三胺按1:(2~5):(20~100):(2~5)的摩尔比溶于甲苯中,进行除水除氧操作后,在70~80℃温度下,搅拌反应18~48小时;反应结束完后除去产物中的铜盐。在甲醇中沉淀纯化,真空干燥后得到目标聚合物可功能化的刺激响应性聚合物。
所述的链转移剂的结构式为:;含有聚乙二醇短链的苯乙烯类单体的化学结构式如下:;含有双硫键的ATRP小分子引发剂的化学结构式如下:;所述含胆固醇基元的单体的化学结构式如下:。
采用本发明的可功能化的刺激响应性聚合物制备得到的聚合物纳米材料,其粒径在30~500 nm之内,且分布均一、形状规整。其制备方法的具体步骤为:将上述可功能化的刺激响应性聚合物溶解在一定量的四氢呋喃中,配成0.1wt%-1wt%的溶液,将1-3倍体积量的去离子水缓慢滴加至聚合物溶液中。然后通过透析袋(截留分子量3500 Da)透析。最后得到聚合物球状纳米材料的水溶液。
本发明的可功能化的刺激响应性聚合物末端带有特定的可功能化修饰的呋喃官能团,亲水嵌段与疏水嵌段之间以还原响应性双硫键连接。因此同时具有可功能化修饰能力与还原刺激响应能力于同一聚合物体系。通过溶剂置换法制备得到的聚合物纳米材料,其表面可根据需要进行多种功能化修饰,作为有效成分载体材料亦具有智能响应释放能力,此聚合物材料在药物智能递送领域具有巨大的潜在应用价值。
附图说明
图1为本发明的嵌段聚合物PVBOEG-SS-PAChol的1HNMR谱图。
图2为本发明的嵌段聚合物PVBOEG-SS-PChol的与二硫苏糖醇作用不同时间后的分子量变化的GPC曲线图。
图3为由本发明的嵌段聚合物PVBEOG-SS-PAChol制备的球状纳米材料的TEM照片。
具体实施方式
本发明的优选实施例详述如下:
实施例一:
(1)在干燥的25 mL Schlenk反应瓶中加入含有聚乙二醇短链的苯乙烯类单体(3.65g)、Furan-RAFT试剂(95.5 mg)、偶氮二异丁腈(8.8 mg)和5 mL的二氧六环。用橡胶塞密封好后,经过除水除氧操作后将反应瓶浸入预热好的65oC油浴锅中,加热搅拌反应24小时。反应完后,旋转蒸发除去溶剂,在40 mL***中沉淀纯化,得到产物PVBOEG。
(2)将PVBOEG(700 mg),正己胺(90 mg),3 mL的二氯甲烷加入到10 mL反应瓶中,经过除水除氧操作后。搅拌24小时。旋转蒸发除去溶剂后, 在40 mL***沉淀三次,得到产物PVBOEG-SH。将PVBOEG-SH和小分子ATRP引发剂,3 mL甲醇加入到10 mLSchlenk反应瓶中。搅拌24小时后,旋转蒸发除去溶剂,在40 mL***中沉淀三次纯化,真空干燥后得到目标大分子引发剂PVBOEG-SS-Br。
(3)将PVBOEG-SS-Br(60 mg)、溴化亚铜(3.2 mg)、含胆固醇基元的单体(373 mg)加入到干燥的10 mLSchlenk反应管中,氮气保护下,将五甲基二乙烯三胺(5.2 mg)的甲苯的溶液(0.6 mL)加入反应管。经过除水除氧操作后,将反应管浸入预热好的80oC油浴锅中,搅拌24小时。反应结束完后过碱性氧化铝柱子以除去产物中的铜盐。在甲醇中沉淀纯化,真空干燥后得到目标聚合物。核磁参见图1。
实施例二:
在本实施例中,选用二硫苏糖醇作为还原剂,来探究嵌段聚合物的还原响应能力。具体实施过程如下:嵌段聚合物(2 mg)与二硫苏糖醇(2.5 mg)溶在二氯甲烷(1 mL)中。体系除氧后开始搅拌反应。分别在反应开始后24小时和8小时取样通过四氢呋喃相的凝胶渗透色谱进行分子量测试。参见图2。与原始聚合物对比, PVBOEG-SS-PAChol与二硫苏糖醇反应24小时后,出峰时间延后,双硫键发生断裂导致聚合物分子量降低。当反应48小时后,聚合物分子量降低程度加剧,嵌段聚合物分解为两种均聚物。由此证明了该嵌段聚合物中具有对还原环境响应的能力。
实施例三:
一种通过溶剂置换法制备聚合物球状纳米材料。具体实施过程如下:将上述双亲嵌段聚合物(0.5 mg)溶解在四氢呋喃(1 mL)中,配成溶液,以10 μL /min的滴加速度将的去离子水(1 mL)加入聚合物溶液中。滴加的过程中,不停震荡使溶液混合均匀,直至去离子水滴加完毕。然后通过透析袋(截留分子量3500 Da)透析,最后得到聚合物球状纳米材料的水溶液。通过透射电子显微镜对聚合我纳米材料微观形貌进行观测,参见图3,其形貌为尺寸在60-100 nm之间球状,尺寸比较一致,分布均匀。
实施例四:
在本实施例中,选用荧光素5-马来酰亚胺作为表面修饰的模型分子对聚合物纳米材料表面进行原位功能化修饰。具体实施过程如下:取荧光素5-马来酰亚胺(0.5 mg)溶解在DMF(30 μL)中,与上述纳米球状材料的水溶液进行混合,12小时后,通过透析的方法除去未反应的模型分子。对比反应前后,反应后的组装体溶液明显带有荧光颜色,证明此聚合物纳米材料具有表面可原位修饰功能化物质的能力。带有这种表面修饰的聚合物载体在实现载药体系的靶向递送方面上将大有应用前景。
上面结合附图对本发明实施例进行了说明,但本发明不限于上述实施例,还可以根据本发明的发明创造目的做出多种变化,凡依据本发明技术方案的精神实质和原理做的改变、修饰、替代、组合、简化,均应为等效的置换方式,只要符合本发明的发明目的,只要不背离本发明嵌段聚合物的合成方法及球状纳米材料的制备方法和应用的技术原理和发明构思,都属于本发明的保护范围。
Claims (4)
1.一种可功能化的刺激响应性聚合物,其特征在于该聚合物的结构式为:
其中m=10~30;n=10~90。
2.一种制备根据权利要求1所述的可功能化的刺激响应性聚合物的方法,其特征在于该方法的具体步骤为:
a. 将链转移剂、含有聚乙二醇短链的苯乙烯类单体和偶氮二异丁腈按1:(20~50):(0.1~0.3)摩尔比溶于二氧六环中,密封后,进行除水除氧操作,再在60~80℃温度下搅拌反应12~36小时,反应结束后,溶剂,***中沉淀纯化,得到产物PVBOEG;
b. 将步骤a所得PVBOEG和正己胺按1:(5~50)的摩尔比溶于二氯甲烷中,进行除水除氧操作,室温下搅拌反应10~24小时,反应结束后,除去溶剂,***中沉淀纯化,得到产物PVBOEG-SH;
c. 将上述产物PVBOEG-SH和含有双硫键的ATRP小分子引发剂按1:10~50的摩尔比溶于甲醇中,室温搅拌反应16~24小时后,在***中沉淀纯化,得到目标ATRP大分子引发剂PVBOEG-SS-Br;
d. 在惰性气氛下,将步骤c所得PVBOEG-SS-Br、溴化亚铜、含胆固醇基元的单体和五甲基二乙烯三胺按1:(2~5):(20~100):(2~5)的摩尔比溶于甲苯中,进行除水除氧操作后,在70~80℃温度下,搅拌反应18~48小时;反应结束完后除去产物中的铜盐,在甲醇中沉淀纯化,真空干燥后得到目标聚合物可功能化的刺激响应性聚合物。
3.一种聚合物球状纳米材料,根据权利要求1所述的嵌段聚合物为原料制备得到,其特征在于该纳米微球的大小在30-500 nm之间;纳米微球亲水壳与疏水核之间以二硫键连接,纳米微球表面带有可功能化修饰的呋喃基团。
4.一种根据权利要求3所述的纳米微球的制备方法,其特征在于该方法的具体步骤为:将双亲嵌段聚合物溶解在四氢呋喃中,配成0.1 wt%-1 wt%的溶液,将1-3倍体积量的去离子水缓慢滴加到聚合物溶液中;经过去离子水透析后,制备得到聚合物球状纳米材料。
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