CN111333840B - 一种具有本征自修复性氨基酸类聚合物及其制备方法 - Google Patents
一种具有本征自修复性氨基酸类聚合物及其制备方法 Download PDFInfo
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- CN111333840B CN111333840B CN202010262159.6A CN202010262159A CN111333840B CN 111333840 B CN111333840 B CN 111333840B CN 202010262159 A CN202010262159 A CN 202010262159A CN 111333840 B CN111333840 B CN 111333840B
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Abstract
本发明公开了一种具有本征自修复性氨基酸类聚合物及其制备方法。本发明采用聚琥珀酰亚胺作为材料主体,选择嘧啶化合物、氨基酸、胺类化合物对聚琥珀酰亚胺进行开环反应和交联反应,制备本征自修复性氨基酸类聚合物材料。本发明所设计的本征自修复性氨基酸类聚合物具有自修复性能好、生物降解性和较好的生物相容性,且具有制备方法简便、制备成本低等优势。材料结构和调控,可将其应用于水凝胶敷料、药物缓释、护肤品、水处理、血液净化等领域。
Description
技术领域
本发明涉及氨基酸类聚合物及其制备领域,具体涉及一种具有本征自修复性氨基酸类聚合物及其制备方法。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
水凝胶是一种三维交联网络,其具有较好的生物相容性和宽松的网状结构,从而使其广泛应用于生物医药、柔性电子皮肤等领域的研究。迄今为止,水凝胶正在以极快的速度发展并逐渐应用于生物和医疗、及柔性电子领域中。
然而,目前水凝胶仍存在一些问题,一方面,如变形易破碎,破坏不可恢复,寿命较短;另一方面,水凝胶大都采用不可生物降解的主链段,无法应用于需生物降解的特殊应用领域,这些问题极大限制了水凝胶的应用。开发具有自修复功能和生物降解功能性的水凝胶成为了新的研究方向。然而,这种具有自修复性和降解性的水凝胶还存在一些难以忽视的问题,比如自修复性能差、制备方法不够简便、制备成本比较高等。如现有水凝胶分子结构中常采用引入的基于脲基嘧啶酮单元UPy的四重氢键单元,其引入方式和制备过程复杂繁琐、成本高。
聚天冬氨酸类高分子材料具有可生物降解、生物相容性好、毒性低、合成方便、易与药物键合等优点,被认为是一类相当有应用前景的生物医用高分子。国内外学者对这类材料进行了许多研究。相比于其它可降解的高分子材料,聚琥珀酰亚胺(PSI)通过L-天冬氨酸的热缩聚制备获得,通过选择不同的亲核试剂对PSI进行开环反应,可以制备一系列侧链官能团修饰的聚天冬氨酸的衍生物。聚合物的主链为聚氨基酸,这从根本上保证材料良好的生物可降解性和生物相容性。其次,L-天冬氨酸原料易得,可再生性好。而且通过改变PSI开环试剂的种类和比例,可以对聚合物的结构和性质进行调控和设计,以实现不同的用途目的。
发明内容
本发明要解决的技术问题在于,提供一种具有自修复功能和生物降解性的本征自修复性氨基酸类聚合物,可将其应用于水凝胶敷料、药物缓释、护肤品、水处理、血液净化等领域。本发明所设计的本征自修复性氨基酸类聚合物具有自修复性能好、制备方法简便、制备成本低等优势。
为了实现本发明的目的,本发明提供的一种具有本征自修复性氨基酸类聚合物,所述具有本征自修复性氨基酸类聚合物是利用嘧啶化合物、氨基酸、胺类化合物对聚琥珀酰亚胺进行开环反应得到;
所述嘧啶化合物为5-甲基胞嘧啶、胞嘧啶、6-甲基异胞嘧、2-氨基-4-羟基-6-甲基嘧啶、5-氮胞嘧啶、5-氨基嘧啶、2-氨基-4-甲基嘧啶、2-巯基胞嘧啶、4,6-二氨基嘧啶、2-氨基-4-羟基-6-甲基嘧啶、5-氨基尿嘧啶、2,4-二氨基-6-羟基嘧啶、4-氨基-5-氰基嘧啶、6-氨基尿嘧啶、2,4-二氨基嘧啶、4,5-二氨基-2-硫脲嘧啶、2-氨基-4-甲氧基-6-甲基嘧啶、异胞嘧啶、4-氨基-6-羟基-2-巯基嘧啶的至少一种;
所述氨基酸为甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、酪氨酸、天冬氨酸、天冬酰胺、谷氨酸、组氨酸、赖氨酸、谷氨酰胺、甲硫氨酸、丝氨酸、苏氨酸、半胱氨酸、脯氨酸、精氨酸的至少一种;
所述胺类化合物为乙醇胺、二乙醇胺、异丙基胺、N,N-二甲基-1,3-丙二胺、牛磺酸、苯丙氨酸甲酯盐酸盐、聚乙烯亚胺(PEI)、乙二胺、二乙烯三胺、三乙烯四胺和四乙烯五胺、多乙烯多胺的至少一种;
所述聚琥珀酰亚胺的平均分子量为1000~100000;
本发明采用聚琥珀酰亚胺作为材料主体,选择嘧啶化合物、氨基酸、胺类化合物对聚琥珀酰亚胺进行开环反应和交联反应,制备本征自修复性氨基酸类聚合物材料。一方面,材料主体为聚氨基酸,这从根本上保证材料良好的生物可降解性和生物相容性;另一方面,在材料上复合嘧啶化合物、氨基酸、胺类化合物等分子结构,利用聚琥珀酰亚胺开环后主链上的酰胺结构、嘧啶化合物的氢键供体和受体、氨基酸的氢键供体和受体、胺类化合物的氢键供体和受体等互相之间的氢键作用,以及氨基酸结构之间呈现的静电作用,可赋予材料较好的自修复功能。
以精氨酸和5-甲基胞嘧啶对聚琥珀酰亚胺开环反应为例,其反应原理如附图2所示。 以精氨酸和5-甲基胞嘧啶对聚琥珀酰亚胺开环反应,所得到的氨基酸类聚合物材料内部存在 不同分子结构间的氢键作用和静电作用,如下所示,从而赋予了材料较好的自修复功能,如 附图3所示。
同样,采用其他嘧啶化合物、氨基酸、胺类化合物对聚琥珀酰亚胺进行开环反应和交联反应,制备本征自修复性氨基酸类聚合物材料,可赋予材料具有较好的自修复功能和可降解功能。
本发明的另一目的,提供一种本征自修复性氨基酸类聚合物的制备方法。该制备方法简便、制备成本低。
为了实现本发明的目的,本发明所述的一种具有本征自修复性氨基酸类聚合物的制备方法,包括如下步骤:
(A)将聚琥珀酰亚胺、嘧啶化合物、氨基酸、胺类化合物、溶剂A混合,在0~30℃条件下搅拌溶解,混合均匀得到反应相;
所述溶剂A为二甲基甲酰胺、二甲基亚砜的至少一种;
所述聚琥珀酰亚胺、嘧啶化合物、氨基酸、胺类化合物、溶剂A的质量比为100:(1~200):(1~200):(1~200):(100~2000);
(B)将反应相在搅拌状态下,升温至40~120℃反应1~20h,得到反应物溶液;
(C)将反应物溶液加入到溶剂B中,沉淀洗涤,过滤;再用溶剂C在30~100℃下搅溶解均匀后,再加入到溶剂B中,沉淀洗涤;重复该流程1~10次,得到具有本征自修复性氨基酸类聚合物;
所述溶剂B为***、丙酮、石油醚、环己烷、正己烷、环戊烷、戊烷、正庚烷、正辛烷、异辛烷的至少一种;
所述溶剂C为甲醇、乙醇、乙酸乙酯、二甲基甲酰胺、二甲基亚砜的至少一种。
本发明所述具有本征自修复性氨基酸类聚合物可应用在水凝胶敷料、药物缓释、护肤品、水处理、血液净化等领域。
由于胺类基团易阳离子化,可通过静电作用,与带负电的物质相互作用,起到吸附作用。本发明在生物相容性的水凝胶材料上引入适量的含易阳离子化的胺类基团,可以用于血液净化中,吸附人体内内源性和外源性的带有负电特性的毒素,如胆红素、胆汁酸、蛋白结合毒素(硫酸吲哚酚IS、硫酸对甲酚PCS等)、内毒素等。另外,通过静电作用,本发明带有胺类基团亦可用于药物释放领域。除此之外,由于胺类基团不仅与金属阳离子有螯合作用,也能通过静电作用或氢键吸附金属负离子,从而对重金属具有很强的吸附能力。故本发明在生物相容性的水凝胶微球上引入适量的含易阳离子化的胺类基团,可用于重金属去除领域,包括水处理和人体皮肤重金属去除的护肤领域。
相对于现有技术,本发明具有如下优点和有益效果:
1、本发明通过对聚琥珀酰亚胺进行开环和交联反应接枝嘧啶化合物和氨基酸等基团,赋予新型氨基酸水凝胶材料较好的自修复功能和可降解性;
2、该两性离子水凝胶具有自修复功能、生物降解性和较好的生物相容性;
3、在高分子链段中引入氢键基团过程简单,制备方法简易,成本低;
4、材料结构和调控,可以满足不同的领域要求。
附图说明
图1为实施例1中本征自修复性氨基酸类聚合物水凝胶的自修复愈合过程图;图2为 以精氨酸和5-甲基胞嘧啶对聚琥珀酰亚胺开环反应的原理示意图;图3为以精氨酸和5-甲基 胞嘧啶对聚琥珀酰亚胺开环反应,所得到的氨基酸类聚合物材料内部存在不同分子结构间的 氢键作用和静电作用的示意图。
具体实施方式
下面结合附图和实施例子对本发明的具体实施方式作进一步详细的说明,但本发明的实施方式不限于此。
实施例1
(A)将100g的聚琥珀酰亚胺(平均分子量约为7000g/mol)、30g的5-甲基胞嘧啶、40g的组氨酸、5g的乙醇胺、600g的二甲基甲酰胺混合,在20℃条件下搅拌溶解,混合均匀得到反应相;
(B)将反应相在搅拌状态下,升温至60℃反应20h,得到反应物溶液;
(C)将反应物溶液加入到丙酮中,沉淀洗涤,过滤;再用甲醇在70℃下搅溶解均匀后,再加入到丙酮中,沉淀洗涤;重复该流程2次,得到具有本征自修复性氨基酸类聚合物。
将所得到的得到具有本征自修复性氨基酸类聚合物溶胀在水中,得到本征自修复性氨基酸类聚合物水凝胶。如附图1所示,将所得到的水凝胶材料切开,并重新接触,水凝胶材料在5秒之内即可愈合修复,并可进行拉伸。可见,在短时间的室温接触后,即可实现高效愈合修复。
经检测,将本发明本征自修复性氨基酸类聚合物置于室外环境中3个月,能够最终降解。
通过蛋白吸附、细胞毒性和抗细菌粘附等评价实施例所制备的水凝胶的生物相容性。采用静态蛋白吸附实验评价所制备的本征自修复性氨基酸类聚合物水凝胶材料的抗蛋白吸附能力,选取牛血清蛋白(BSA,5mg/ml),计算样品单位面积吸附量及抗蛋白吸附能力,结果发现,本发明的水凝胶的蛋白质吸附量为0.01μg/mm2,显著低于玻璃对照样的吸附量(1.2μg/mm2)。根据ISO10993-5 2009细胞毒性的要求,本发明采用CCK-8法对水凝胶的体外细胞毒性进行评价。结果发现,本实施例水凝胶毒性等级为1级,无细胞毒性。采用体外细菌粘附评价所制备的本征自修复性氨基酸类聚合物水凝胶材料的抗细菌粘附能力。以大肠杆菌和金黄色葡萄球菌作为测试细菌,将水凝胶材料置于细菌悬浮液培养4h,结果发现,相比较空白玻璃样,本实施例水凝胶表面的细菌粘附量极少,细菌数量减少至空白玻璃对比样表面细菌数量的0.4%。可见本实施例的水凝胶材料体现出较好的抗细菌粘附功能。
实施例2
(A)将100g的聚琥珀酰亚胺(平均分子量约为20000g/mol)、30g的6-甲基异胞嘧、20g的半胱氨酸、4g的N,N-二甲基-1,3-丙二胺、800g的二甲基甲酰胺混合,在30℃条件下搅拌溶解,混合均匀得到反应相;
(B)将反应相在搅拌状态下,升温至80℃反应5h,得到反应物溶液;
(C)将反应物溶液加入到石油醚中,沉淀洗涤,过滤;再用乙醇在60℃下搅溶解均匀后,再加入到石油醚中,沉淀洗涤;重复该流程4次,得到具有本征自修复性氨基酸类聚合物;
将所得到的得到具有本征自修复性氨基酸类聚合物溶胀在水中,得到本征自修复性氨基酸类聚合物水凝胶。将所得到的水凝胶材料切开,并重新接触,水凝胶材料在10秒之内即可愈合修复,并可进行拉伸。可见,在短时间的室温接触后,即可实现高效愈合修复。
经检测,所制备的本征自修复性氨基酸类聚合物水凝胶,对各种重金属离子(如Cd2+,Hg2+,Pb2+等)具有较好的选择性吸附性能,去除率能达到90%以上。试验发现,所制备的本征自修复性氨基酸类聚合物水凝胶对重金属的吸附速率非常快,吸附动力学非常好,基本上在10min之内就可以达到平衡。
为了确认本发明本征自修复性氨基酸类聚合物水凝胶对人体皮肤重金属离子的去除效果,将本发明所制备的本征自修复性氨基酸类聚合物水凝胶碎颗粒化并添加在市售软膏制品中,制备成可去除皮肤表面有害重金属离子的护肤软膏,用于下面的实验。在20人次志愿者中,随机分成未添加水凝胶碎颗粒的市售软膏对照组和实验组。在双盲状态下,每人每天使用一次软膏并在面部停留30分钟。连续处理30天后,收集志愿者皮肤角质层细胞并用原子吸收光谱法测定皮肤样品中重金属离子的含量。实验结果显示,实验组中志愿者皮肤表面的Pb离子比未添加水凝胶碎颗粒的市售软膏对照组中志愿者的低10倍,达到了较好的清除有毒重金属离子的效果。
实施例3
(A)将100g的聚琥珀酰亚胺(平均分子量约为10000g/mol)、30g的2-氨基-4-甲基嘧啶、10g的精氨酸、5g的乙二胺、1000g的二甲基甲酰胺混合,在20℃条件下搅拌溶解,混合均匀得到反应相;
(B)将反应相在搅拌状态下,升温至70℃反应5h,得到反应物溶液;
(C)将反应物溶液加入到正己烷中,沉淀洗涤,过滤;再用甲醇在100℃下搅溶解均匀后,再加入到正己烷中,沉淀洗涤;重复该流程3次,得到具有本征自修复性氨基酸类聚合物;
将所得到的得到具有本征自修复性氨基酸类聚合物溶胀在水中,得到本征自修复性氨基酸类聚合物水凝胶。将所得到的水凝胶材料切开,并重新接触,水凝胶材料在1秒之内即可愈合修复,并可进行拉伸。可见,在短时间的室温接触后,即可实现高效愈合修复。
根据ISO10993-5 2009细胞毒性的要求,本发明采用CCK-8法对水凝胶的体外细胞毒性进行评价。结果发现,本实施例水凝胶毒性等级为1级,无细胞毒性。
实施例4
(A)将100g的聚琥珀酰亚胺(平均分子量约为1000g/mol)、20g的5-氨基尿嘧啶、20g的氨基酸、10g的二乙烯三胺、500g的二甲基甲酰胺混合,在10℃条件下搅拌溶解,混合均匀得到反应相;
(B)将反应相在搅拌状态下,升温至60℃反应9h,得到反应物溶液;
(C)将反应物溶液加入到环己烷中,沉淀洗涤,过滤;再用甲醇在30℃下搅溶解均匀后,再加入到环己烷中,沉淀洗涤;重复该流程2次,得到具有本征自修复性氨基酸类聚合物;
将所得到的得到具有本征自修复性氨基酸类聚合物溶胀在水中,得到本征自修复性氨基酸类聚合物水凝胶。将所得到的水凝胶材料切开,并重新接触,水凝胶材料在3秒之内即可愈合修复,并可进行拉伸。可见,在短时间的室温接触后,即可实现高效愈合修复。
根据ISO10993-5 2009细胞毒性的要求,本发明采用CCK-8法对水凝胶的体外细胞毒性进行评价。结果发现,本实施例水凝胶毒性等级为1级,无细胞毒性。
实施例5
(A)将100g的聚琥珀酰亚胺(平均分子量约为100000g/mol)、10g的5-氮胞嘧啶、10g的赖氨酸、8g的乙醇胺、1000g的二甲基甲酰胺混合,在20℃条件下搅拌溶解,混合均匀得到反应相;
(B)将反应相在搅拌状态下,升温至40℃反应10h,得到反应物溶液;
(C)将反应物溶液加入到石油醚中,沉淀洗涤,过滤;再用乙酸乙酯在60℃下搅溶解均匀后,再加入到石油醚中,沉淀洗涤;得到具有本征自修复性氨基酸类聚合物;
将所得到的得到具有本征自修复性氨基酸类聚合物溶胀在水中,得到本征自修复性氨基酸类聚合物水凝胶。将所得到的水凝胶材料切开,并重新接触,水凝胶材料在60秒之内即可愈合修复,并可进行拉伸。可见,在短时间的室温接触后,即可实现高效愈合修复。
根据ISO10993-5 2009细胞毒性的要求,本发明采用CCK-8法对水凝胶的体外细胞毒性进行评价。结果发现,本实施例水凝胶毒性等级为1级,无细胞毒性。
实施例6
(A)将100g的聚琥珀酰亚胺(平均分子量约为7000g/mol)、200g的5-甲基胞嘧啶、200g的丙氨酸、200g的牛磺酸、100g的二甲基亚砜混合,在0℃条件下搅拌溶解,混合均匀得到反应相;
(B)将反应相在搅拌状态下,升温至40℃反应20h,得到反应物溶液;
(C)将反应物溶液加入到***中,沉淀洗涤,过滤;再用乙醇在100℃下搅溶解均匀后,再加入到***中,沉淀洗涤;重复该流程5次,得到具有本征自修复性氨基酸类聚合物;
将所得到的得到具有本征自修复性氨基酸类聚合物溶胀在水中,得到本征自修复性氨基酸类聚合物水凝胶。将所得到的水凝胶材料切开,并重新接触,水凝胶材料在2秒之内即可愈合修复,并可进行拉伸。可见,在短时间的室温接触后,即可实现高效愈合修复。
根据ISO10993-5 2009细胞毒性的要求,本发明采用CCK-8法对水凝胶的体外细胞毒性进行评价。结果发现,本实施例水凝胶毒性等级为1级,无细胞毒性。
实施例7
(A)将100g的聚琥珀酰亚胺(平均分子量约为5000g/mol)、1g的6-甲基异胞嘧、1g的异丙基胺、1g的乙醇胺、2000g的二甲基亚砜混合,在30℃条件下搅拌溶解,混合均匀得到反应相;
(B)将反应相在搅拌状态下,升温至120℃反应1h,得到反应物溶液;
(C)将反应物溶液加入到丙酮中,沉淀洗涤,过滤;再用甲醇在30℃下搅溶解均匀后,再加入到丙酮中,沉淀洗涤;重复该流程10次,得到具有本征自修复性氨基酸类聚合物;
将所得到的得到具有本征自修复性氨基酸类聚合物溶胀在水中,得到本征自修复性氨基酸类聚合物水凝胶。将所得到的水凝胶材料切开,并重新接触,水凝胶材料在120秒之内即可愈合修复,并可进行拉伸。可见,在短时间的室温接触后,即可实现高效愈合修复。
根据ISO10993-5 2009细胞毒性的要求,本发明采用CCK-8法对水凝胶的体外细胞毒性进行评价。结果发现,本实施例水凝胶毒性等级为1级,无细胞毒性。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (4)
1.一种具有本征自修复性氨基酸类聚合物,其特征在于:所述具有本征自修复性氨基酸类聚合物是利用嘧啶化合物、氨基酸、胺类化合物对聚琥珀酰亚胺进行开环反应得到;
所述嘧啶化合物为5-甲基胞嘧啶、胞嘧啶、2-氨基-4-羟基-6-甲基嘧啶、5-氮胞嘧啶、5-氨基嘧啶、2-氨基-4-甲基嘧啶、2-巯基胞嘧啶、4 ,6-二氨基嘧啶、5-氨基尿嘧啶、2,4-二氨基-6-羟基嘧啶、4-氨基-5-氰基嘧啶、6-氨基尿嘧啶、2,4-二氨基嘧啶、4,5-二氨基-2-硫脲嘧啶、2-氨基-4-甲氧基-6-甲基嘧啶、异胞嘧啶、4-氨基-6-羟基-2-巯基嘧啶的至少一种;
所述氨基酸为甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、酪氨酸、天冬氨酸、天冬酰胺、谷氨酸、组氨酸、赖氨酸、谷氨酰胺、甲硫氨酸、丝氨酸、苏氨酸、半胱氨酸、脯氨酸、精氨酸的至少一种;
所述胺类化合物为乙醇胺、二乙醇胺、异丙基胺、N,N-二甲基-1,3-丙二胺、牛磺酸、苯丙氨酸甲酯盐酸盐、聚乙烯亚胺(PEI)、乙二胺、二乙烯三胺、三乙烯四胺和四乙烯五胺、多乙烯多胺的至少一种;
所述聚琥珀酰亚胺的平均分子量为1000~100000;
所述聚琥珀酰亚胺、嘧啶化合物、氨基酸、胺类化合物的质量比为100:(1~200):(1~200):(1~200)。
2.根据权利要求1所述的一种具有本征自修复性氨基酸类聚合物的制备方法,其特征在于,包括如下步骤:
(A)将聚琥珀酰亚胺、嘧啶化合物、氨基酸、胺类化合物、溶剂A混合,在0~30℃条件下搅拌溶解,混合均匀得到反应相;
所述溶剂A为二甲基甲酰胺、二甲基亚砜的至少一种;
所述聚琥珀酰亚胺、嘧啶化合物、氨基酸、胺类化合物、溶剂A的质量比为100:(1~200):(1~200):(1~200):(100~2000);
(B)将反应相在搅拌状态下,升温至40~120℃反应1~20h,得到反应物溶液;
(C)将反应物溶液加入到溶剂B中,沉淀洗涤,过滤;再用溶剂C在30~100℃下搅溶解均匀后,再加入到溶剂B中,沉淀洗涤;重复该流程1~10次,得到具有本征自修复性氨基酸类聚合物;
所述溶剂B为***、丙酮、石油醚、环己烷、正己烷、环戊烷、戊烷、正庚烷、正辛烷、异辛烷的至少一种;
所述溶剂C为甲醇、乙醇、乙酸乙酯、二甲基甲酰胺、二甲基亚砜的至少一种。
3.根据权利要求1所述具有本征自修复性氨基酸类聚合物在护肤品、水处理领域的应用。
4.根据权利要求1所述具有本征自修复性氨基酸类聚合物在制备水凝胶敷料的应用。
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