CN108517006B - 一种常温常压条件下改善碳纳米管在水中分散性的多肽材料及其应用 - Google Patents
一种常温常压条件下改善碳纳米管在水中分散性的多肽材料及其应用 Download PDFInfo
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Abstract
本发明公开了一种常温常压条件下显著改善碳纳米管在水中分散性的多肽材料，所述多肽以RADA16‑I为主干，在N端引入甘氨酸、含苯环的氨基酸或含咪唑基的氨基酸中的至少一种，在C端引入精氨酸‑异亮氨酸‑赖氨酸‑缬氨酸‑丙氨酸‑缬氨酸，以此形成可与碳纳米管相互作用的多肽序列。所述多肽材料在常温常压条件下，微量使用即可显著改善碳纳米管在水中的分散性，可方便快捷地制备碳纳米管的水分散液。利用本发明技术制备的碳纳米管水分散液具有更好的分散性，可长期稳定不分层、不团聚，并可进一步制备成负载有碳纳米管的水凝胶材料，在拓展碳纳米管材料应用方面具有非常广阔的应用前景和临床应用价值。
Description
技术领域
本发明属于生物材料技术领域。更具体地，涉及一种常温常压条件下改善碳纳米管在水中分散性的多肽材料及其应用。
背景技术
碳纳米管作为一维纳米材料，重量轻，比表面积大，高长径比，具有许多异常的力学、电学和化学性能，空腔管体可容纳生物特异性分子和药物，优良的细胞穿透性能使其作为载体运送生物活性分子及药物进入细胞或组织，在生物医学、组织工程学等研究领域应用愈发广泛，但原始的碳纳米管缺少活性基团，不溶解于任何溶剂，加之它巨大的比表面积和很高的长径比，导致分散性很差，极易团聚，大大限制了碳纳米管材料的应用。因此，碳纳米管的有效分散成了其实际应用的关键难题。
目前常用的碳纳米管分散手段有两类：第一类是由有机溶剂如三氯甲烷、丙酮与水组成的溶液，这类溶剂虽能分散碳纳米管，但分散溶液只能保留几个小时；第二类是由表面活性剂组成的分散剂，常用的有十二烷基苯磺酸钠（SDS）；另一种做法是对碳纳米管进行改性，包括共价功能化和非共价功能化两类。共价功能化如通过化学改性在碳纳米管表面接上诸如羧基、羟基等活性基团，或一些长链有机化合物使其具有更好的溶解性，尽管该方法可得到分散性良好的碳纳米管分散液，但往往不同程度地破坏了碳纳米管本身结构的完整性，对其原本具有的性能造成不利影响。非共价功能化多是利用碳纳米管表面的碳原子经sp2杂化形成的高度离域化π电子，这些π电子可与其他含有π电子的化合物通过π-π非共价键作用相结合。如使用一些表面活性剂、功能聚合物来制备碳纳米管分散液，常用的有十二烷基苯磺酸钠等，但这类表面活性剂在使用过程中多具有毒性、刺激性、致敏性和易燃易爆等缺陷。
发明内容
本发明所要解决的技术问题是克服现有碳纳米管及其分散手段存在的缺陷和不足，提供一种多肽材料，该材料可在常温常压条件下，制备分散性良好的碳纳米管分散液，而且制备过程快速简便，无毒无刺激，同时制备得到的碳纳米管分散液具有良好的生物相容性，并可进一步制备成负载有碳纳米管的水凝胶材料。
本发明的目的是提供一种常温常压条件下改善碳纳米管在水中分散性的多肽材料。
本发明的目的是提供上述多肽材料的应用。
本发明的上述目的是通过以下技术方案给予实现的：
一种常温常压条件下改善碳纳米管在水中分散性的多肽材料，所述多肽以RADA16-I为主干，在N端引入甘氨酸、含苯环的氨基酸或含咪唑基的氨基酸中的至少一种，在C端引入精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸。
本发明通过在（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4序列上通过化学共价键同时在N端连接甘氨酸、含苯环的氨基酸或含咪唑基的氨基酸中的至少一种氨基酸，C端连接精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸，最终合成得到需要的多肽序列，所述多肽溶于水后可显著改善碳纳米管在水中的分散性，并可长期稳定存放。所述多肽采用现有的接枝方法获得，优选为固相多肽合成方法。
优选地，所述含苯环的氨基酸为苯丙氨酸，含咪唑基的氨基酸为组氨酸。
具体地，所述多肽的序列如下所示：
序列1：（组氨酸-甘氨酸-苯丙氨酸）n-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列2：（组氨酸）n-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列3：（苯丙氨酸）n-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列4：（组氨酸-甘氨酸）n-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列5：（甘氨酸-苯丙氨酸）n-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；其中，n=1～3。
由于目前未有成型的理论支持何种改性（即接枝序列和接枝位置）能够获得真正在中性条件下合成的自组装多肽水凝胶，不同的序列排列方式不同，电荷分布也不同，同时结构内部自组装方式均会影响最终的接枝效果，因此，上述接枝物的具体接枝位点和接枝序列排布，对最终效果影响非常大。
本发明所述多肽材料可常温常压条件下改善碳纳米管在水中分散性，因此上述任一所述的多肽在制备碳纳米管水分散液中的应用亦在本发明保护范围内。
具体地，所述应用为将碳纳米管粉末加入上述多肽材料的水溶液中，超声处理，即得碳纳米管分散液。
本发明还提供一种碳纳米管复合自组装多肽水凝胶材料，所述多肽水凝胶包含上述多肽材料。
具体地，所述碳纳米管复合自组装多肽水凝胶材料是将上述添加有本发明多肽材料的碳纳米管分散液注入缓冲液后获得；所述缓冲液为PBS溶液或DMEM的中性溶液。
另外，所述碳纳米管复合自组装多肽水凝胶材料在细胞三维培养中的应用和在制备软骨、血管、神经或皮肤的再生和损伤修复材料中的应用均在本发明保护范围内
与现有技术相比，本发明具有以下有益效果：
本发明提供了一种在常温常压条件下，可方便快捷地制备具有良好生物相容性的碳纳米管水分散液的多肽材料。利用本发明技术制备的碳纳米管水分散液具有更好的分散性，可长期稳定不分层、不团聚，并可进一步制备成负载有碳纳米管的水凝胶材料，在拓展碳纳米管材料的应用方面具有非常广阔的应用前景及临床应用价值。
附图说明
图1为不同浓度本发明多肽材料制备的碳纳米管分散液与未加材料的碳纳米管分散液的效果对比图。从左至右浓度依次为10mg/ml、5mg/ml、1mg/ml，最右侧为未加本发明多肽材料的碳纳米管水分散液。经点超声1~2min，再高速离心(10000rps，10min)后，直观可见，加入本发明多肽材料的碳纳米管分散液样品，分散性显著改善。
图2为原子力显微镜下，碳纳米管水分散液的微观形貌对比。左图为碳纳米管在超纯水中经过超声后的分散液；右图为加入本发明多肽材料制备的碳纳米管水分散液。
图3为扫描电子显微镜下，碳纳米管水分散液的微观形貌对比。A图为碳纳米管在超纯水中经过超声后的分散液；B图为加入本发明多肽材料制备的碳纳米管水分散液。从图中可明显看出，加入本发明材料后，碳纳米管在水中不再像A图所示那样团聚严重，而是以单根的状态均匀的存在于分散液中，分散情况得到显著改善。
图4为本发明多肽材料制备的碳纳米管多肽水凝胶的宏观照片。
图5为本发明多肽材料制备的碳纳米管多肽水凝胶的流变测试结果图。
图6为神经干细胞在本发明多肽材料制备的碳纳米管多肽水凝胶中三维培养7天后的生长分化情况。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
实施例1 多肽序列合成
本实施例以（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4（RADA16-I）为主干，通过采用本领域常规的固相法合成要以下序列的多肽：
序列1：组氨酸-甘氨酸-苯丙氨酸-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列2：组氨酸-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列3：苯丙氨酸-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；。
序列4：组氨酸-甘氨酸-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列5：甘氨酸-苯丙氨酸-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列6：（组氨酸-甘氨酸-苯丙氨酸）2-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列7：（组氨酸）2-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列8：（苯丙氨酸）2-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；。
序列9：（组氨酸-甘氨酸）2-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列10：（甘氨酸-苯丙氨酸）2-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列11：（组氨酸-甘氨酸-苯丙氨酸）3-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列12：（组氨酸）3-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列13：（苯丙氨酸）3-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；。
序列14：（组氨酸-甘氨酸）3-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
序列15：（甘氨酸-苯丙氨酸）3-（精氨酸-丙氨酸-天冬氨酸-丙氨酸）4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸；
实施例2 碳纳米管分散液的制备
1、将实施例1中序列1～15所示的多肽分别溶于超纯水，即可得到相应的多肽水溶液。根据需要配置为不同浓度的多肽水溶液（10mg/mL、5mg/mL、1mg/mL），然后加入过量碳纳米管，点超声1～2min后，高速离心（10000rps，10min），去除底部过量的碳纳米管，即可得到所述碳纳米管分散液。
2、结果
序列1所示的不同浓度多肽材料加入碳纳米管后的分散液与未加多肽材料的碳纳米管分散液的效果对比图如图1所示，原子力显微镜结果如图2所示，扫描电子显微镜结果如图3所示，显示，加入上述多肽材料的碳纳米管分散液与未加上述多肽材料的碳纳米管分散液相比，碳纳米管的分散情况得到显著改善，而且制备全过程方便快捷，环保无毒，在拓展碳纳米管材料的应用方面具有广阔的应用前景和实际应用价值。同时，加入序列2～15所示多肽材料的碳纳米管分散液与未加上述多肽材料的碳纳米管分散液相比，碳纳米管的分散情况也得到显著改善。
实施例3 负载有碳纳米管的水凝胶材料的制备
1、将实施例1中序列1～15的多肽分别溶于超纯水，配置成不同浓度的多肽水溶液（10mg/mL、5mg/mL、1mg/mL），然后加入Tris-base溶液，Trsi-base溶液的浓度为0.1～1mol/mL，调节pH值至7～7.4，即得中性多肽水溶液。再加入过量碳纳米管，点超声1～2min后，高速离心（10000rps，10min），去除底部过量的碳纳米管，即得所述中性碳纳米管分散液。
2、将步骤1的中性碳纳米管分散液注入PBS或DMEM溶液中，静置迅速形成稳定凝胶（图4），即可投入使用。
图5为旋转流变仪测试结果，加入碳纳米管后凝胶强度得到加强，且强度值可通过调节多肽溶液浓度或多肽溶液与碳纳米管分散液的体积比来调控。
实施例4 碳纳米管多肽水凝胶用于神经干细胞三维培养
将实施例3所述中性多肽水溶液与中性碳纳米管分散液按体积比1：1混合，用所得混合液悬浮神经干细胞后注入神经干细胞分化培养基（分化培养基为DMEM/F12，1%双抗，1%B27（含VA），1%FBS）中，形成包裹有神经干细胞的水凝胶，即可用于神经干细胞的三维培养。
图6为采用本实施例水凝胶三维培养神经干细胞7天时，经免疫荧光染色后，在激光共聚焦显微镜下拍摄的神经干细胞生长分化情况。图中可见，神经干细胞成功分化为了星形胶质细胞（绿色）和神经元（红色），且细胞生长情况良好，证实本发明材料具有良好的生物相容性。
Claims (7)
1.一种常温常压条件下改善碳纳米管在水中分散性的多肽，其特征在于，所述多肽以RADA16-I为主干，序列为组氨酸-甘氨酸-苯丙氨酸-(精氨酸-丙氨酸-天冬氨酸-丙氨酸)4-精氨酸-异亮氨酸-赖氨酸-缬氨酸-丙氨酸-缬氨酸。
2.权利要求1所述的多肽在制备碳纳米管水分散液中的应用。
3.根据权利要求2所述的应用，其特征在于，所述应用具体为将碳纳米管粉末加入权利要求1所述多肽的水溶液中，超声处理，即得碳纳米管分散液。
4.一种碳纳米管复合自组装多肽水凝胶材料，其特征在于，包含权利要求1所述的多肽和碳纳米管。
5.根据权利要求4所述的水凝胶材料，其特征在于，将权利要求3所述分散液注入缓冲液后获得；所述缓冲液为PBS溶液或DMEM。
6.权利要求4或5所述的碳纳米管复合自组装多肽水凝胶材料在细胞三维培养中的应用。
7.权利要求4或5所述的碳纳米管复合自组装多肽水凝胶材料在制备软骨、血管、神经或皮肤的再生和损伤修复材料中的应用。
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