CN103603079B - 一种用于抗癌药物传输的响应型纳米纤维的制备方法 - Google Patents
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Abstract
本发明利用静电纺丝的方法成功制备了一种刺激响应型纳米纤维。本发明以嵌段共聚物(聚(N-异丙基丙烯酰胺-丙烯酰胺-乙烯吡咯烷酮)，P(NIPAAM-AAm-VP)为制备材料，制备了阿霉素负载纳米纤维膜。本发明制备的载有额阿霉素的纳米纤维膜非常稳定，即使是在细胞孵化之后仍旧能保持它们的形貌。本发明涉及的纳米纤维中能够有效利用纳米纤维的大的表面积和孔隙率，具有在抗癌药物传输领域的应用前景。
Description
技术领域
本发明涉及一种基于静电纺丝的纳米纤维制备方法，尤其涉及一种用于抗癌药物传输的刺激响应型纳米纤维的制备方法。
背景技术
可控释放药物治疗技术一般会包括在特定的时间内对特定药物的特定行为的控制，可控释放系统的目的就是建立有效的药物医疗体系。静电纺丝技术制备的纳米纤维构建了一种新颖的药物传输系统(DDSs)，许多天然和合成的聚合物已经被制备成几十到几百纳米的纳米纤维，可以化学治疗和放射治疗的效率、减低抗癌药物的副作用，以达到稳定的储藏性和选择靶向性。
聚异丙基丙烯酰胺(PNIPAAm)是一种智能聚合物，当其具有大的可调的表面积和孔隙率时，能够对环境中微小的变化如温度和pH，作出响应。这种聚合物可通过静电纺丝的方法来制备，但静电纺NIPAAm纳米纤维均聚物在水中是不稳定的，很容易分散。另一方面，水溶性聚合物的静电纺纳米纤维的亲水性会限制其应用，亲水性聚合物的交联是制备不溶性纤维的非常好的方法。交联反应可以通过很多方法实现，如螯合交联、热处理、氧化交联、辐射交联和物理交联；物理交联通过离子或疏水性作用实现。由于不会造成污染，物理交联比其它的交联更具有优势。
药物／聚合物／溶剂系统中药物的溶解性和生物相容性是静电纺纤维制备的决定因素。在许多应用，如组织工程、生物医学、农业，中，有机溶剂的毒性都是非常关键的。然而，有机溶剂都是有毒的，用没有毒性的水溶液体系在生物医学应用领域就更可取。静电纺纳米纤维的直径可以通过控制静电纺丝的参数(如聚合物性质、纺丝过程和环境)来实现。溶液参数：如粘度、导电性、纺丝距离、接收端的几何形状、温度和适度等，都会影响纤维的形成和形貌。
因此，一种位点和靶向药物传输系统在癌症治疗中需解决以下问题：1、响应型共聚物在水中的稳定性；2、亲水性聚合物的交联方式；3、静电纺纳米纤维的形貌与直径等物理性能。
发明内容
本发明涉及一种利用静电纺丝技术制备用于抗癌药物传输的刺激响应型纳米纤维的制备方法。
具体步骤如下：
(1)聚合物的制备：将预先定量的聚异丙基丙烯酰胺(NIPAAm)、AAm和VP按照分子比20：10：1～1：5：10溶解到含有过硫酸铵的蒸馏水中，混合物磁力搅拌然后用氩气脱气处理60～90min；然后加入N，N，N，N，N-三甲基乙烯二胺(TEDA)作为加速剂，聚合反应在室温下进行24～36h，期间一直鼓入氩气，得到的反应混合物用截留分子量为2000的透析膜透析7天，每天水溶液都用新鲜的替换；聚合物溶液加热析出，得到的凝胶在45～60℃下真空干燥36～48h后立即用液氮冷冻处理，然后再在45～60℃下真空干燥36～48h。
(2)静电纺丝：P(NIPAAM-AAm-VP)溶解到蒸馏水中，然后在5～9℃下搅拌18～22h制成15～20wt％的溶液，将得到的溶液装入注射器中进行静电纺丝。喷丝头的直径为0.2mm，纺丝电压为15～20kV，溶液推进速度为2～10mL／h，纺丝距离为7～15cm；所有的静电纺丝实验的温度控制在25℃，接收装置为一个直径为5cm的金属转筒，转速为500～900rpm，得到的纤维支架室温真空干燥168～180h以彻底去除多余的溶剂。
本发明利用静电纺丝的方法成功制备了一种刺激响应型纳米纤维。嵌段共聚物(聚(N-异丙基丙烯酰胺-丙烯酰胺-乙烯吡咯烷酮)，P(NIPAAM-AAm-VP)用作制备材料，制备了阿霉素负载纳米纤维膜。这种新型的纳米纤维将刺激响应的特征整合到纳米纤维中能够有效利用纳米纤维大的表面积和孔隙率，且非常稳定，在释放媒介(pH=7.4，37℃)的条件下，即使是在细胞孵化之后仍旧能保持它们的形貌。
试管细胞毒性检测表明P(NIPAAM-AAm-VP)纳米纤维本身不能影响A549细胞的生长。纯的阿霉素会在实验进行48h后消失，但是负载到纳米纤维上后在整个实验的过程中其抗癌活性会一直保持；在这些体系中药物的释放是零级，药物的释放速率与药物／聚合物的比例没有关系。
具体实施方式
为了加深对本发明的理解，下面结合具体实例做进一步的详述。
(1)聚合物的制备：将预先定量的NIPAAm、AAm、和VP(分子比为20：3：1)溶解到含有过硫酸铵的蒸馏水中，混合物磁力搅拌然后用氩气脱气处理80min，然后加入N，NN，N，N-三甲基乙烯二胺作为加速剂，聚合反应在室温下进行30h，其中一直鼓入氩气，得到的反应混合物用截留分子量为2000的透析膜透析5天，每天水溶液都用新鲜的替换；聚合物溶液加热析出，得到的凝胶在46℃下真空干燥40h后立即用液氮冷冻处理，然后再在46℃下真空干燥40h。
(2)静电纺丝：P(NIPAAM-AAm-VP)溶解到蒸馏水中，然后在8℃下搅拌20h制成15wt％的溶液，将得到的溶液装入注射器中进行静电纺丝；喷丝头的直径为0.2mm，纺丝电压为17kV，溶液推进速度为5mL／h，纺丝距离为14cm，所有的静电纺丝实验的温度控制在25℃，接收装置为一个直径为5cm的金属转筒，转速为800rpm，得到的纤维支架室温真空干燥168h以彻底去除多余的溶剂。
Claims (4)
1.一种用于抗癌药物传输的响应型纳米纤维的制备方法，其步骤如下：
(1)聚合物的制备：
将预先定量的聚异丙基丙烯酰胺(PNIPAM)、AAm和VP按照分子比20:10:1～1:5:10溶解到含有过硫酸铵的蒸馏水中，混合物磁力搅拌然后用氩气脱气处理60～90min，然后加入N,N,N,N,N-三甲基乙烯二胺(TEDA)作为加速剂，聚合反应在室温下进行24～36h，期间一直鼓入氩气，得到的反应混合物用截留分子量为2000的透析膜透析7天，每天水溶液都用新鲜的替换，聚合物溶液加热析出，得到的凝胶在45～60℃下真空干燥36～48h后立即用液氮冷冻处理，然后再在45～60℃下真空干燥36～48h；
(2)静电纺丝：
P(NIPAM-AAm-VP)溶解到蒸馏水中，然后在5～9℃下搅拌18～22h制成15～20wt％的溶液，将得到的溶液装入注射器中进行静电纺丝，喷丝头的直径为0.2mm，纺丝电压为15～20kV，溶液推进速度为2～10mL/h，纺丝距离为7～15cm；所有的静电纺丝实验的温度控制在25℃，接收装置为一个直径为5cm的金属转筒，转速为500～900rpm，得到的纤维支架室温真空干燥168～180h以彻底去除多余的溶剂。
2.如权利要求1所述的响应型纳米纤维的制备方法，其特征在于：所述P(NIPAM-AAm-VP)溶解到蒸馏水制得溶液的浓度为20wt％。
3.如权利要求1所述的响应型纳米纤维的制备方法，其特征在于：所述静电纺丝电压为18kV。
4.如权利要求1所述的响应型纳米纤维的制备方法，其特征在于：所述溶液推进速度为5mL/h。
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| CN1816357A (zh) * | 2003-04-30 | 2006-08-09 | 德崇大学 | 用于生物材料应用的热凝胶化的聚合物共混物 |
| EP1216042B1 (en) * | 1999-09-23 | 2006-12-13 | Dabur Pharma Ltd. | Formulations of paclitaxel entrapped into nanoparticles of polymeric micelles |
| CN102718928A (zh) * | 2012-07-04 | 2012-10-10 | 天津工业大学 | 一种细胞片层智能脱附水凝胶及其应用 |
| US8299178B2 (en) * | 2009-03-25 | 2012-10-30 | National Tsing Hua University | Stable micelles formed with diblock copolymers of critical micelle concentration copolymer and temperature-sensitive copolymer |
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| EP1216042B1 (en) * | 1999-09-23 | 2006-12-13 | Dabur Pharma Ltd. | Formulations of paclitaxel entrapped into nanoparticles of polymeric micelles |
| CN1816357A (zh) * | 2003-04-30 | 2006-08-09 | 德崇大学 | 用于生物材料应用的热凝胶化的聚合物共混物 |
| US8299178B2 (en) * | 2009-03-25 | 2012-10-30 | National Tsing Hua University | Stable micelles formed with diblock copolymers of critical micelle concentration copolymer and temperature-sensitive copolymer |
| CN102718928A (zh) * | 2012-07-04 | 2012-10-10 | 天津工业大学 | 一种细胞片层智能脱附水凝胶及其应用 |
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