CN108904469A - 一种dqa包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法 - Google Patents
一种dqa包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法 Download PDFInfo
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Abstract
本发明公开了一种DQA包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法。该方法为：先制备三维树状介孔二氧化硅纳米粒，通过超声，真空旋转和重结晶的方法将药物加载在孔中，然后与DQA单分子通过超声探针进行反应使DQA成功的将介孔二氧化硅包裹。介孔二氧化硅属于一种亲水性物质，有很好的生物相容性，能够将药物有效地递送到病灶部位。DQA对线粒体具有天然的亲和力，能够有助于将药物递送到线粒体中，有效地治疗与线粒体有关的疾病。使用DQA对载药的介孔二氧化硅进行包裹，一，可以有效地预防孔道中的药物提前泄露，降低药物的损失量；二，将药物有效地带入线粒体中，提高药效。
Description
技术领域
本发明属于生物材料技术领域，具体涉及一种DQA包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法。
背景技术
线粒体是细胞内能量合成的主要场所,对维持细胞正常生理功能起着重要作用。线粒体不仅做为体内的主要能量产出地,而且还与氧自由基的产生,细胞死亡进程的调控有关。
衰老是细胞清除代谢废物的功能降低，导致受损蛋白质和细胞器过度积累，从而使生命体的生存能力降低。衰老不仅是皮肤松弛出现各种皮肤问题，还会引起很多相关的疾病，如：心脑血管疾病、神经性疾病（帕金森）、糖尿病等。线粒体是产自由基的主要场所，并且线粒体自身也容易受到自由基攻击，使机体发生一系列病变。靶向抗氧化物载体制剂旨在可以准确的靶向到病变的线粒体中，对自由基进行有效地清除。并且作为化妆品的有效成分其载体材料可以在短期内被快速地降解，避免在肝脏中积累引起组织损伤。(介孔二氧化硅、DQA)。
DQA可以形成一种中间是亲脂两端亲水的化合物，可以将亲水性载体介孔二氧化硅包裹在中心，通过线粒体膜，通过离子置换介孔二氧化硅进入线粒体中，通过纳米粒的降解使药物释放出来。
具有离域正电荷的亲脂性分子可以通过OMM的高度负性膜电位通过静电相互作用进入线粒体。DQAsomes是一种线粒体型阳离子“脂肪球”囊泡，具有线粒体的亲和能力，可以将药物靶向的送至线粒体内，在内膜上大量的积累DQAsomes内吞吸收后，线粒体内膜上存在丰富的心磷脂，它是一种可以有效地将DQA包裹的介孔二氧化硅置换出来的阴离子。
二氧化硅纳米粒是介孔材料中做常用的一种，与有机高分子聚合物相比，有较大的比表面积，孔径和粒径容易调节，耐高温降解，当紫外照射时不会发生危险转化，性质稳定。该发明中的二氧化硅是使用十六烷基三甲基氯化铵作为模板剂，有机硅源单体为正硅酸乙酯，三乙胺作为催化剂，有机相分别为1-十八烯、十氢萘和环己烷，分为三个阶段反应，并且在反应过程中要确保水油两相不相互混合。在将5-HMF 等药物加载到孔道中。药物随着纳米粒的降解逐渐的释放出来，达到缓释的效果。
发明内容
该发明的目的之一是提供了一种线粒体靶向的载小分子药物的载体，二是提供这种载体的制备方法。
本发明技术方案如下。
一种DQA包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法，先制备三维树状介孔二氧化硅纳米粒，通过超声，真空旋转和重结晶的方法将药物加载在孔中，然后与DQA单分子通过超声探针进行反应使DQA成功的将介孔二氧化硅包裹。
一种DQA包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法，包括如下步骤：
（1）将20 ml~40 ml的十六烷基三甲基氯化铵(CTAC)和1g~2g三乙胺（TEA）,用十氢萘、环己烷混合加入到去离子水中，在60℃~70℃搅拌1~2h，加入TEOS 的1-十八烯溶液，搅拌6~24h，然后，将上层相1-十八碳烯溶液完全去除，并用TEOS的十氢化萘溶液代替以使第二维生长的相同反应条件再维持6~24h，然后将上油层改变为 TEOS-环己烷溶液，同时将反应条件保持在相同条件下 6~24h，得到三维树状介孔二氧化硅纳米粒载体；
（2）将载体与药物混合，通过超声将载体分散均匀，然后通过真空旋转、重结晶和磁力搅拌30~60min，使药物加载入孔道中；
（3）DQAsomes的制备：DQA-somes是用薄膜水合法制备的，将地喹氯铵（DQA）与载药后的介孔二氧化硅分散到甲醇中，然后经过旋转蒸发和真空处理得到薄膜，将薄膜进行去离子水水合和超声得到纳米粒，使用过滤器过滤除去没有包裹上的介孔二氧化硅，将产物进行冷冻干燥，4℃保存。
上述方法中，步骤（2）中，所述药物为：五羟甲基糠醛(5-HMF)、阿霉素（DOX）、DNA或姜黄素（Curcumin）。
上述方法中，步骤（2）中，所述载体与药物的添加量满足载体 的质量范围为0.5~1g,药物的质量范围为0.625~2g。
与现有技术相比，本发明的优势在于：
介孔二氧化硅属于一种亲水性物质，有很好的生物相容性，能够将药物有效地递送到病灶部位。DQA对线粒体具有天然的亲和力，能够有助于将药物递送到线粒体中，有效地治疗与线粒体有关的疾病。使用DQA对载药的介孔二氧化硅进行包裹，一，可以有效地预防孔道中的药物提前泄露，降低药物的损失量；二，将药物有效地带入线粒体中，提高药效。
附图说明
图1为实施例1所得产品的AFM图(三维图)；
图2为所得产品的AFM图(二维图)；
图3为实施例1所得产品的扫描电镜（SEM）图（200nm）；
图4为实施例1所得产品的扫描电镜（SEM）图（100nm）；
图5为实施例1所得产品的空白介孔二氧化硅，载药介孔二氧化硅和经DQA包载的载药介孔二氧化硅的红外图；
图6为DQA@MSN@5-HMF的结构图。
具体实施方式
下面结合具体实施例对本发明作进一步地具体详细描述，但本发明的实施方式不限于此，对于未特别注明的工艺参数，可参照常规技术进行。
实施例1
（1）将30ml CTAC 溶液和1.8 g TEA 加入到 50 ml 去了离子水中，并在 100 mL 圆底烧瓶中在 65 ℃ 下温和搅拌 2 h ；然后在水-CTAC-TEA 溶液中加入 20 ml 的 10 v/v %的TEOS 的1-十八烯溶液，并在磁力搅拌下保持在 60 ℃ 的油浴中。搅拌速率设定为〜150rpm ，然后将反应物保持恒温并连续搅拌 12 h以获得第一维产物；然后，将上层相1-十八碳烯溶液完全去除并用10 v / v％ TEOS的十氢化萘溶液代替以使第二维生长的相同反应条件再维持 12h；对于第三维，将上油层改变为 TEOS-环己烷溶液，同时将反应条件保持在相同条件下 12h。
（2）将载体与5-HMF以0.5:1（m/m）的比例混合，通过超声将载体分散均匀，然后通过真空旋转30 min、加等量的水重结晶，然后磁力搅拌24 h时间；
（3）将DQA与介孔二氧化硅以摩尔比1:2的比例分散到30ml的甲醇中，DQA的浓度至少要控制在6mg/ml，介孔二氧化硅质量取0.5g，根据两者的摩尔比5-HMF质量为1g。旋转蒸发30min，在80℃下真空处理10min。将得到的薄膜通过加入30ml去离子水进行水合，在80℃下混合2min，再使用超声探针出力20min。将得到的产物通过冷冻干燥后得到的粉末4℃下保存。
图1和图2是DQA包裹介孔二氧化硅载药纳米粒的AFM三维和二维图，可以清楚地看到，纳米粒的粒径在100nm左右；图3和图4是DQA包裹介孔二氧化硅载药纳米粒的SEM图，结果与AFM相吻合，可以看出纳米粒被成功制备，粒径稳定在100nm，分散均匀；图5为MSN、MSN@5-HMF和DQA@MSN@5-HMF的红外图谱，在3525cm-1,1648cm-1和970cm-1处观察到较强的峰，这可以归因于丰富的5-HMF分子的-OH基团（红线），表明药物的成功加载；图6是DQA的结构图，是由两个亚甲基连接的二喹啉鎓环组成的阳离子硼杂二聚体。
实施例2
（1）将20ml CTAC 溶液和1.5 g TEA 加入到 36 ml 去了离子水中，并在 100 mL 圆底烧瓶中在 65 ℃ 下温和搅拌 1.5 h ；然后在水-CTAC-TEA 溶液中加入 18 ml 的 10 v/v% 的TEOS 的1-十八烯溶液，并在磁力搅拌下保持在 60 ℃ 的油浴中。搅拌速率设定为〜150 rpm ，然后将反应物保持恒温并连续搅拌 24 h以获得第一维产物；然后，将上层相1-十八碳烯溶液完全去除并用10 v / v％ TEOS的十氢化萘溶液代替以使第二维生长的相同反应条件再维持 24h；对于第三维，将上油层改变为 TEOS-环己烷溶液，同时将反应条件保持在相同条件下 24h；
（2）将载体与姜黄素（Curcumin）以0.75:1（m/m）的比例混合，通过超声将载体分散均匀，然后通过真空旋转30 min、加等量的水重结晶，然后磁力搅拌24 h时间；
（3）将DQA与介孔二氧化硅以摩尔比1:3的比例分散到30ml的甲醇中，DQA的浓度至少要控制在8mg/ml，介孔二氧化硅质量取0.5g，根据两者的摩尔比姜黄素质量为0.625g。旋转蒸发30min，在80℃下真空处理10min。将得到的薄膜通过加入30ml去离子水进行水合，在80℃下混合2min，再使用超声探针出力20min。将得到的产物通过冷冻干燥后得到的粉末4℃下保存。
实施例3
（1）将40ml CTAC 溶液和2.0 g TEA 加入到 450 ml 去了离子水中，并在 100 mL 圆底烧瓶中在 65 ℃ 下温和搅拌 1 h ；然后在water-CTAC-TEA 溶液中加入 15 ml 的 10v/v % 的TEOS 的1-十八烯溶液，并在磁力搅拌下保持在 60 ℃ 的油浴中。搅拌速率设定为〜150 rpm ，然后将反应物保持恒温并连续搅拌 6 h以获得第一维产物；然后，将上层相1-十八碳烯溶液完全去除并用10 v / v％ TEOS的十氢化萘溶液代替以使第二维生长的相同反应条件再维持 6h；对于第三维，将上油层改变为 TEOS-环己烷溶液，同时将反应条件保持在相同条件下 6h；
（2）将载体与阿霉素（DOX）以0.8:1（m/m）的比例混合，通过超声将载体分散均匀，然后通过真空旋转30 min、加等量的水重结晶，然后磁力搅拌12 h时间；
（3）将DQA与载药介孔二氧化硅以摩尔比2:3的比例分散到30ml的甲醇中，DQA的浓度至少要控制在5mg/ml，介孔二氧化硅质量去0.5g，根据两者的摩尔比阿霉素质量为0.75g。旋转蒸发30min，在80℃下真空处理10min。将得到的薄膜通过加入30ml去离子水进行水合，在80℃下混合2min，再使用超声探针出力20min。将得到的产物通过冷冻干燥后得到的粉末4℃下保存。
本发明的上述实施例仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。
Claims (4)
1.一种DQA包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法，其特征在于，先制备三维树状介孔二氧化硅纳米粒，然后通过超声，真空旋转和重结晶的方法将药物加载在孔中，然后与DQA单分子通过超声探针进行反应使DQA成功的将介孔二氧化硅包裹。
2.根据权利要求1所述DQA包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法，其特征在于，包括如下步骤：
（1）将20 ml~40 ml的十六烷基三甲基氯化铵(CTAC)和1g~2g三乙胺（TEA）,用十氢萘、环己烷混合加入到去离子水中，在60℃~70℃搅拌1~2h，加入TEOS 的1-十八烯溶液，搅拌6~24h，然后，将上层相1-十八碳烯溶液完全去除，并用TEOS的十氢化萘溶液代替以使第二维生长的相同反应条件再维持6~24h，然后将上油层改变为 TEOS-环己烷溶液，同时将反应条件保持在相同条件下 6~24h，得到三维树状介孔二氧化硅纳米粒载体；
（2）将载体与药物混合，通过超声将载体分散均匀，然后通过真空旋转、重结晶和磁力搅拌30~60min，使药物加载入孔道中；
（3）DQAsomes的制备：DQA-somes是用薄膜水合法制备的，将地喹氯铵（DQA）与载药后的介孔二氧化硅分散到甲醇中，然后经过旋转蒸发和真空处理得到薄膜，将薄膜进行去离子水水合和超声得到纳米粒，使用过滤器过滤除去没有包裹上的介孔二氧化硅，将产物进行冷冻干燥，4℃保存。
3.根据权利要求1所述DQA包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法，其特征在于，步骤（2）中，所述药物为：五羟甲基糠醛(5-HMF)、阿霉素（DOX）、DNA或姜黄素（Curcumin）。
4.根据权利要求1所述DQA包载介孔二氧化硅载小分子药物靶向线粒体的载体的制备方法，其特征在于，步骤（2）中，所述载体与药物的添加量满足载体的质量范围为0.5~1g,药物的质量范围为0.625~2g。
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