CN106729976A - 一种pelcl/聚己内酯‑redv电纺纤维膜及制备方法 - Google Patents

一种pelcl/聚己内酯‑redv电纺纤维膜及制备方法 Download PDF

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CN106729976A
CN106729976A CN201611268210.4A CN201611268210A CN106729976A CN 106729976 A CN106729976 A CN 106729976A CN 201611268210 A CN201611268210 A CN 201611268210A CN 106729976 A CN106729976 A CN 106729976A
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caprolactone
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袁晓燕
周芳
任丽霞
赵蕴慧
崔策
文美玲
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Abstract

本发明涉及一种聚乙二醇‑b‑聚(L‑丙交酯‑co‑ε‑己内酯)/聚ε‑己内酯‑REDV共混超细电纺纤维膜及制备方法。以低分子量聚ε‑己内酯偶联REDV小肽，制备聚ε‑己内酯‑g‑REDV，并与高分子量聚乙二醇‑b‑聚(L‑丙交酯‑co‑ε‑己内酯)一起溶解在氯仿和N,N‑二甲基甲酰胺的混和溶剂中，通过电纺方法制备得到超细纤维膜。该电纺纤维膜由直径为400～1000nm的超细纤维构成,厚度为50～200μm。本发明的电纺超细纤维膜，表面含有REDV小肽，具有促进血管内皮细胞粘附和生长的功能；同时超细纤维膜用于包载核酸、蛋白、药物等生物活性物质，具有控制释放生物活性物质的能力。用于生物医用材料。

Description

一种PELCL/聚己内酯-REDV电纺纤维膜及制备方法
技术领域
本发明涉及了一种聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(PELCL)/聚己内酯-REDV电纺超细纤维膜及制备方法，属于组织工程和生物医用材料领域。
背景技术
采用静电纺丝技术在组织工程支架中负载基因蛋白等生物活性物质，可以调控细胞的粘附、增殖和迁移，有利于组织的修复和再生。生物降解性聚丙交酯共聚物聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(PELCL)、聚ε-己内酯(聚己内酯，PCL)等生物相容性好，力学性能优良。采用静电纺丝技术,制备出超细纤维膜,模拟细胞外基质结构,可作为组织重建的支架材料。精氨酸-谷氨酸-天冬氨酸-缬氨酸(Arg-Glu-Asp-Val,REDV)存在于纤维连接蛋白的III-CS区域，含有该序列的合成肽能够特异性地粘附血管内皮细胞，而较少粘附平滑肌细胞和成纤维细胞，在血管组织工程支架功能化中具有重要的应用价值。
为促进血管组织工程支架材料表面形成内皮细胞层，一般采用纤维膜表面物理或者化学修饰的方法，在纤维膜表面偶联REDV和RGD等小肽(Ren X,Feng Y,Guo J,Wang H,LiQ,Yang J,Hao X,Lv J,Ma N,Li W.Surface modification and endothelialization ofbiomaterials as potential scaffolds for vascular tissue engineeringapplications.Chemical Society Reviews 2015,44:5680-5742)。例如，通过表面浸涂的方式在PCL电纺纤维膜表面修饰RGD小肽，可提高细胞在纤维膜表面的粘附和铺展(Wang Z,Wang H,Zheng W,Zhang J,Zhao Q,Wang S,Yang Z,Kong D.Highly stable surfacemodifications of poly(ε-caprolactone)(PCL)films by molecular self-assembly topromote cells adhesion and proliferation.Chemical Communications 2011,47:8901-8903)。我们前期研究发现，在PELCL电纺纤维膜表面通过EDS/NHS活化的方法偶联具有特异粘附作用的REDV小肽,可以促进血管内皮细胞的特异性粘附和生长(Zhou F,Jia X,Yang Y,Yang Q,Gao C,Zhao Y,Fan Y,Yuan X.Peptide-modified PELCL electrospunmembranes for regulation of vascular endothelial cells.Materials Science andEngineering C 2016,68:623-631)。然而通过表面化学修饰的方法，在包载生物活性物质的电纺纤维膜表面偶联小肽，比如酸、碱或氨解处理，可能会降低生物活性物质的活性，从而增加原料成本。因此，在电纺纤维膜表面改性的同时，保证包载的生物活性物质的活性是十分必要的。
发明内容
本发明的目的在于制备一种聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(PELCL)/聚ε-己内酯-REDV电纺超细纤维膜，该电纺纤维膜具有促进血管内皮细胞粘附和生长的功能，且电纺纤维膜释放的核酸、蛋白、药物等生物活性物质的活性较高。
本发明的技术方案如下：
一种聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜(一种PELCL/聚己内酯-REDV电纺纤维膜)，其特征在于该超细纤维膜由直径为400～1000nm的超细纤维构成,其厚度为50～200μm。
所述聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)数均分子量为(5～12)×104。
所述的聚ε-己内酯的数均分子量为(1～5)×104,所述聚ε-己内酯的分子式为：
式中，m＝70～420；R1为-CH3或-CH2O(COCH2CH2CH2CH2CH2O)mCO(CH2)5OH。
本发明的电纺超细纤维膜的制备方法,其包括以下过程:
(1)将一定量的聚ε-己内酯-REDV和聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)一起溶于氯仿和N,N-二甲基甲酰胺以体积比为(4～8):1的混和溶剂中,配制成浓度100～200mg/mL的电纺溶液；
(2)将按步骤(1)所得的聚合物溶液进行电纺,电纺条件为:溶液的流量为0.02～0.10mL/h,电纺的电压为12～20kV,接收距离是15～20cm,得到50～200μm厚度的电纺超细纤维膜。
聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)和聚ε-己内酯-REDV小肽的质量比为(5～1):1。
聚ε-己内酯-REDV的制备方法是：
(1)聚ε-己内酯的双键改性；
(2)聚ε-己内酯-REDV的制备。
上述的聚ε-己内酯-REDV，其制备方法特征包括以下步骤：
(1)聚ε-己内酯的双键改性：使用N,N’-羰基二咪唑(CDI)活化羟基基团，将聚ε-己内酯配成0.3～0.5g/mL的无水二氯甲烷溶液，按照摩尔比[单端羟基聚ε-己内酯]/[CDI]为1:1(或[双端羟基聚ε-己内酯]/[CDI]为1:2)加入CDI，在N2中室温下搅拌反应24h，然后加入过量丙烯酸羟乙酯和质量分数为2～4％的催化剂4-二甲基吡啶，室温下搅拌反应48h～72h，产物用过量的甲醇沉淀，真空干燥,得到白色聚ε-己内酯双键改性产物,其结构式为：
式中，m＝70～420；R1为-CH3或
-CH2O(COCH2CH2CH2CH2CH2O)mCO(CH2)5OCOO(CH2)2OCOC(CH3)＝CH2
(2)聚ε-己内酯-REDV的制备：将聚ε-己内酯的双键改性物配制为200～300mg/mL的二氯甲烷溶液,按照聚ε-己内酯的双键改性物含有的双键与REDV小肽中巯基的摩尔比1:1加入REDV小肽,再加入质量分数为0.2～1.0％的光催化剂2,2-二甲氧基-2-苯基苯乙酮,室温搅拌均匀，置于圆形培养皿中，在365nm的UV中光照10～15min，产物使用乙醇沉淀，得到聚ε-己内酯-REDV。
本发明的聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜用于纤维膜表面含有REDV，包载核酸和蛋白等生物活性物质的生物医用材料。
本发明的优点在于上述聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜,在电纺过程中，随着溶剂的挥发，低分子量的聚ε-己内酯-REDV小肽粘度低，分子量运动速度快，具有向纤维表面迁移的趋势。一方面，迁移到表面的聚ε-己内酯-REDV小肽具有促进血管内皮细胞粘附和生长的功能；另一方面，该纤维膜可用于包载核酸和蛋白等生物活性物质，包载生物活性物质后的纤维仍然具有良好的纤维形貌，释放的生物活性物质具有良好的生物活性。该发明可用于生物医用材料领域。
附图说明
图1：实施例1制备的聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜包载miRNA复合的纳米粒子的SEM照片。
具体实施方式
下面通过实施案例对本发明的技术方案作进一步的描述，以下实施案例是对本发明的进一步说明，并不限制本发明的适用范围。
聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜由直径为400～1000nm的超细纤维构成，其厚度为50～200μm。
聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV,其聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)的数均分子量为(7～20)×104。
聚ε-己内酯-REDV,其聚ε-己内酯的数均分子量为(1～5)×104，所述聚ε-己内酯的分子式为：
式中，m＝70～420；R1为-CH3或-CH2O(COCH2CH2CH2CH2CH2O)mCO(CH2)5OH
上述聚ε-己内酯-REDV，所述REDV小肽为精氨酸-谷氨酸-天冬氨酸-缬氨酸-半胱氨酸(REDV-Cys)及其他可以靶向内皮细胞的多肽。
上述的聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(PELCL)/聚ε-己内酯-REDV电纺超细纤维膜的制备方法，其特征在于包括以下过程:
(1)聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(PELCL)和聚ε-己内酯-REDV,一起溶于氯仿和N,N-二甲基甲酰胺以体积比为4:1～8:1的混和溶剂中，配制成浓度100～200mg/mL的电纺溶液，PELCL和聚ε-己内酯-REDV的质量比为(5～1):1；
(2)将按步骤(1)所得溶液进行电纺,电纺条件为:溶液的流量为0.02～0.10mL/h，电纺的电压为12～20kV,接收距离是15～20cm,得到50～200μm厚度的电纺纤维膜，即聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺纤维膜。
实施例1：
在装有磁力搅拌的三口瓶中,将3g聚ε-己内酯(双端羟基)溶解于10mL无水二氯甲烷中，按照摩尔比[双端羟基聚ε-己内酯]/[CDI]＝1:2加入CDI 74.5mg，在N2中室温下搅拌反应24h，然后加入0.52g的丙烯酸羟乙酯和0.1g的催化剂4-二甲基吡啶，室温下搅拌反应48h，产物用过量的甲醇沉淀,真空干燥24h,得到白色的聚ε-己内酯双键改性产物。
将聚ε-己内酯的双键改性物796mg溶解在3mL的二氯甲烷溶液,按照上述聚ε-己内酯的双键改性物中的双键与REDV小肽中的巯基摩尔比1:1加入REDV 40mg,再加入8.4mg的光催化剂2,2-二甲氧基-2-苯基苯乙酮,室温搅拌均匀,置于圆形培养皿中，在365nm的UV中光照10min，产物使用乙醇沉淀，得到聚ε-己内酯-REDV小肽。
所制得的聚ε-己内酯-REDV小肽和聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(LA:CL＝3:1,)共聚物按照质量比1:1，溶于氯仿和N,N-二甲基甲酰胺以体积比为8:1的混和溶剂中，配制成浓度为200mg/mL的电纺溶液。将上述溶液作为电纺溶液的油相，将溶度为0.3mg/mL的miRNA复合物溶液作为水相。并按照水油比1:25混和20min至均匀。电纺条件为：溶液的流量为0.04mL/h，电纺的电压为12kV,接收距离是15cm,电纺24h,得到厚度100μm的电纺纤维膜。所制得包载miRNA的聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜。该纤维膜的SEM照片如图1所示,其中超细纤维直径为900～1000nm。
实施例2：
在装有磁力搅拌的三口瓶中,将5g聚ε-己内酯(双端羟基)溶解于10mL无水二氯甲烷中，按照摩尔比[双端羟基聚ε-己内酯]/[CDI]＝1:2加入CDI 32.4mg，在N2中室温下搅拌反应24h，然后加入0.60g的丙烯酸羟乙酯和0.11g的催化剂4-二甲基吡啶，室温下搅拌反应60h，产物用过量的甲醇沉淀，真空干燥24h,得到白色的聚ε-己内酯双键改性产物。
将聚ε-己内酯的双键改性物600mg溶解在3mL的二氯甲烷溶液,按照上述聚ε-己内酯的双键改性物中的双键与REDV小肽中的巯基摩尔比1:1加入REDV-SH 15mg,再加入3.1mg的光催化剂2,2-二甲氧基-2-苯基苯乙酮,室温搅拌均匀，置于圆形培养皿中，在365nm的UV中光照15min，产物使用乙醇沉淀，得到聚ε-己内酯-REDV小肽。
所制得的聚ε-己内酯-REDV小肽和聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(LA:CL＝3:1,)共聚物按照质量比5:1，溶于氯仿和N,N-二甲基甲酰胺以体积比为6:1的混和溶剂中,配制成浓度150mg/mL的电纺溶液。电纺条件为：溶液的流量为0.1mL/h，电纺的电压为13～15kV,接收距离是15～20cm,电纺12h，得到50μm厚度的电纺超细纤维膜，超细纤维的直径为800～900nm。
实施例3：
在装有磁力搅拌的三口瓶中,将4g聚ε-己内酯(单端羟基)溶解于10mL无水二氯甲烷中，按照摩尔比[单端羟基聚ε-己内酯]/[CDI]＝1:1加入CDI 64.9mg，在N2中室温下搅拌反应24h，然后加入0.50g的丙烯酸羟乙酯和0.18g的催化剂4-二甲基吡啶，室温下搅拌反应72h，产物用过量的甲醇沉淀，真空干燥24h,得到白色的聚ε-己内酯双键改性产物。
将聚ε-己内酯的双键改性物900mg溶解在3mL的二氯甲烷溶液,按照上述聚ε-己内酯的双键改性物中的双键与REDV小肽中的巯基摩尔比1:1加入REDV-SH 55.8mg,再加入1.9mg的光催化剂2,2-二甲氧基-2-苯基苯乙酮,室温搅拌均匀，置于圆形培养皿中，在365nm的UV中光照12min，产物使用乙醇沉淀，得到聚ε-己内酯-REDV小肽。
所制得的聚ε-己内酯-REDV小肽和聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(LA:CL＝3:1,)共聚物按照质量比2:1，溶于氯仿和N,N-二甲基甲酰胺以体积比为4:1的混和溶剂中,配制成浓度100mg/mL的电纺溶液。电纺条件为：溶液的流量为0.02mL/h,电纺的电压为15～20kV,接收距离是15～20cm,电纺24h，得到100～200μm厚度的电纺超细纤维膜，超细纤维的直径为400～700nm。

Claims (10)

1.一种聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜,其特征在于该超细纤维膜由直径为400～1000nm的超细纤维构成,其厚度为50～200μm。
2.权利要求1所述的电纺超细纤维膜；其特征是聚乙二醇-b-(L-丙交酯-co-ε-己内酯)数均分子量为(7～20)×104。
3.权利要求1所述的细电纺纤维膜；其特征所述的聚ε-己内酯的数均分子量为(1～5)×104,所述聚ε-己内酯的分子式为：
式中m＝70～420；R1为-CH3或-CH2O(COCH2CH2CH2CH2CH2O)mCO(CH2)5OH。
4.权利要求1所述的电纺超细纤维膜的制备方法，其特征是包括以下过程:
(1)聚ε-己内酯-REDV和聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)一起溶于氯仿和N,N-二甲基甲酰胺以体积比为(4～8):1的混和溶剂中,配制成浓度100～200mg/mL的电纺溶液；
(2)将按步骤(1)所得溶液进行电纺,电纺条件为:流量为0.02～0.10mL/h,电压为12～20kV,接收距离为15～20cm,得到50～200μm厚度的电纺超细纤维膜。
5.权利要求1所述的电纺超细纤维膜的制备方法，其特征是聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)和聚ε-己内酯-REDV小肽的质量比为(5～1):1。
6.权利要求5所述的方法，其特征是聚ε-己内酯-REDV的制备方法是：
(1)聚ε-己内酯的双键改性；
(2)聚ε-己内酯-REDV的制备。
7.权利要求6所述的方法，其特征是聚ε-己内酯的双键改性是：使用N,N’-羰基二咪唑(CDI)活化羟基基团，将聚ε-己内酯配成0.3～0.5g/mL的无水二氯甲烷溶液，按照摩尔比[单端羟基聚ε-己内酯]/[CDI]为1:1(或[双端羟基聚ε-己内酯]/[CDI]为1:2)加入CDI，在N2中室温下搅拌反应24h，然后加入过量丙烯酸羟乙酯和质量分数为2～4％的催化剂4-二甲基吡啶，室温下搅拌反应48～72h，产物用过量的甲醇沉淀，真空干燥,得到白色聚ε-己内酯双键改性产物,其结构式为：
式中，m＝70～420；R1为-CH3或
-CH2O(COCH2CH2CH2CH2CH2O)mCO(CH2)5OCOO(CH2)2OCOC(CH3)＝CH2。
8.权利要求6所述的方法，其特征是聚ε-己内酯-REDV的制备是：将聚ε-己内酯的双键改性物配制为200～300mg/mL的二氯甲烷溶液,按照聚ε-己内酯的双键改性物含有的双键与REDV小肽中巯基的摩尔比1:1加入REDV小肽,再加入质量分数为0.2～1.0％的光催化剂2,2-二甲氧基-2-苯基苯乙酮,室温搅拌均匀，置于圆形培养皿中，在365nm的UV中光照10～15min，产物使用乙醇沉淀，得到聚ε-己内酯-REDV。
9.权利要求1的聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜表面含有REDV。
10.权利要求1的聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)/聚ε-己内酯-REDV电纺超细纤维膜，包载包括核酸、蛋白、药物的生物活性物质，具有控制释放生物活性物质的能力。
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