CN112438961A - 一种具有温度敏感性的聚多巴胺双载药纳米材料的制备方法 - Google Patents
一种具有温度敏感性的聚多巴胺双载药纳米材料的制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有温度敏感性的聚多巴胺双载药纳米材料的制备方法，属于纳米材料自组装技术领域。通过分子间Π‑Π堆积的非共价相互作用，构建了一个双载药聚多巴胺纳米颗粒。随后，我们通过酰胺化反应在多巴胺表面引入了温敏性物质甘氨酰胺，得到一个具有温度敏感性的聚多巴胺双载药纳米材料。本发明制备方法温和简单、无污染。可广泛应用于材料学、生物学、医学等领域，既可以显著地抑制肿瘤细胞的生长，又可以作为细胞内荧光定位实现可视化检测。
Description
技术领域
本发明属于纳米材料自组装技术领域，采用简单的“纳米沉淀法”，通过多巴胺自聚形成核壳结构，利用Π-Π堆积作用加载双药物，进而采用酰胺化反应在聚多巴胺外壳上接入甘氨酰胺，从而形成具有温度敏感性的聚多巴胺双载药纳米粒子的制备方法。
背景技术
自组装(self-assembly)，是指基本结构单元(分子，纳米材料，微米或更大尺度的物质)自发形成有序结构的一种技术。在自组装的过程中，基本结构单元在基于非共价键的相互作用下自发地组织或聚集为一个稳定、具有一定规则几何外观的结构。分子自组装涉及非共价或弱共价相互作用，例如：范德华、静电和疏水相互作用、相互作用、氢和配位键。
采用简单的“纳米沉淀法”，利用多巴胺自聚形成核壳结构，其组合了纳米粒与胶束的优势，而且可对外壳材料进行特定改造。聚多巴胺纳米粒不仅具有高光热转换效率和优秀的生物相容性，几乎无细胞毒性的生物特性使其作为首选的药物载体。通过Π-Π堆积作用将疏水化疗药物阿霉素和光热试剂花菁类染料Cypate制备成抗肿瘤药物纳米材料，能显著提高双药物的载药率。利用酰胺化反应在多巴胺核上接入温敏性物质，当肿瘤部位经过近红外照射，温度升高，纳米材料膨胀崩解，导致药物的释放。大大提高了抗肿瘤疗效的同时降低了单一化疗药物的毒副作用。
发明内容
本发明的目的是针对上述技术分析，提供一种具有抗癌特性和体内成像的自组装纳米材料的制备方法，该制备方法工艺简单、成本低廉且易于实施。
本发明的技术方案：
一种具有温度敏感性的聚多巴胺双载药纳米材料的制备方法，所述自组装纳米材料为以聚多巴胺为基础高分子，以Π-Π堆积的方式加载疏水阿霉素和花菁染料Cypate，进而通过酰胺化反应接入温敏性物质甘氨酰胺，制备步骤如下:
1)将疏水阿霉素和Cypate分别溶于1,3-二氧环戊烷和无水甲醇中得到母液，分别取阿霉素溶液和Cypate溶液放于无菌去离子水中，搅拌混合均匀后，连续通入氮气以除去有机溶剂；
2)往溶液中加入多巴胺的Tris溶液和甘氨酰胺盐酸盐水溶液，分别敞口和密闭反应1小时；
3)取所得溶液放于离心机中，离心所得沉淀加水溶解，冻干后得到DOX/Cypate@PDA-GA纳米药物。
进一步的，所述为聚多巴胺经过甘氨酰胺修饰的温敏性聚多巴胺纳米材料。
进一步的，步骤2)中多巴胺和甘氨酰胺盐酸盐的摩尔比为3：1。
进一步的，步骤3)中所得溶液于4℃下，20000转，离心20分钟。
本发明的优点是：该温敏性纳米材料通过分子间Π-Π堆积构建具有温敏性的聚多巴胺双载药纳米颗粒。载药率高，同时，通过酰胺化反应在聚多巴胺表面引入了温敏性物质甘氨酰胺。
本发明制备方法温和简单、无污染。可广泛应用于材料学、生物学、医学等领域，既可以显著地抑制肿瘤细胞的生长，又可以作为细胞内荧光定位实现可视化检测。
附图说明
图1为自组装温敏性聚多巴胺双载药纳米材料的设计和作用机理；
图2为扫描电镜图和粒径分布图；
图3为温敏性曲线；
图4为红外图。
具体实施方式
下面结合附图对本发明做进一步说明。
附图1给出了自组装温敏性聚多巴胺双载药纳米材料的设计和作用机理，由附图1可知，
本发明所述自组装纳米材料为是以多巴胺作为基本骨架，通过自聚作用形成聚多巴胺，然后通过Π-Π堆积作用加载双药物，同时，利用酰胺化反应，接入温敏性物质甘氨酰胺，即可得到自组装纳米材料(DOX/Cypate@PDA-GA)。
下面给出本发明具体实例阐述：
将疏水阿霉素和Cypate分别溶于1,3-二氧环戊烷和无水甲醇中得到母液。分别取100μL阿霉素溶液和Cypate溶液混合后，注射到1mL无菌去离子水中，搅拌30秒以混合均匀后，连续通入氮气65分钟以除去1,3-二氧环戊烷和无水甲醇有机溶剂。
然后称量多巴胺盐酸盐0.2mg，溶于75mL的10mmol Tris溶液，随后加入上述溶液中，搅拌1小时。再称量甘氨酰胺盐酸盐配成50mg/mL的母液，取10μL加入反应液中，继续密闭反应1小时。
取所得溶液放于离心机中，4℃下，20000转，离心20分钟，取沉淀加等量水溶解，冻干后得到DOX/Cypate@PDA-GA纳米药物。
图2为本发明扫描电镜图和粒径分布图，该图说明：扫描电镜图可以看出，DOX/Cypate@PDA-GA的直径为201±7.4nm，且呈较为均匀的球形(图2)。与粒径分布图数据基本一致。
图3为纳米药物的粒径随温度变化图。该图表示温度越高，粒径越大，证明该纳米药物具有温敏性。
图4FT-IR光谱中1650cm-1处和1540cm-1的酰胺键峰证实了酰胺化反应的顺利发生，证实了温敏性物质甘氨酰胺顺利接上，证实得到了温敏性材料DOX/Cypate@PDA-GA的成功构建。
需要说明的是，以上所述实施方式仅为本发明优选实施例，仅仅用于对本发明做进一步说明，并非因此限制本发明保护范围。对属于本发明技术构思而仅仅显而易见的改动，同样在本发明保护范围之内。
Claims (4)
1.一种具有温度敏感性的聚多巴胺双载药纳米材料的制备方法，其特征是所述自组装纳米粒子为以多巴胺为载体，通过Π-Π堆积作用加载疏水化疗药物阿霉素和光热试剂花菁类染料Cypate，然后通过酰胺化反应在聚多巴胺表面引入温敏性物质甘氨酰胺，制备步骤如下：
1)将阿霉素和Cypate分别溶于1,3-二氧环戊烷和无水甲醇中得到母液，分别取阿霉素溶液和Cypate溶液置于无菌去离子水中，搅拌混合均匀后，连续通入氮气以除去有机溶剂；
2)往溶液中加入多巴胺的Tris溶液和甘氨酰胺盐酸盐水溶液，分别敞口和密闭反应1小时；
3)取所得溶液放于离心机中，离心所得沉淀加水溶解，冻干后得到DOX/Cypate@PDA-GA纳米药物。
2.根据权利要求1所述的一种具有温度敏感性的聚多巴胺双载药纳米材料的制备方法，其特征是：所述为聚多巴胺经过甘氨酰胺修饰的温敏性聚多巴胺纳米材料。
3.根据权利要求1所述的一种具有温度敏感性的聚多巴胺双载药纳米材料的制备方法，其特征是：步骤2)中多巴胺和甘氨酰胺盐酸盐的摩尔比为3：1。
4.根据权利要求1所述的一种具有温度敏感性的聚多巴胺双载药纳米材料的制备方法，其特征是：步骤3)中所得溶液于4℃下，20000转，离心20分钟。
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