CN114681610B - 可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法 - Google Patents
可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法 Download PDFInfo
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Abstract
本发明公开了一种可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法，包括：步骤一、称取二氯硅萘菁与对羟基苯磺酸钠，并与碱性还原剂溶于有机溶剂，惰性气体保护下回流，反应结束后减压蒸去溶剂，淋洗剂淋洗，柱层析提纯得到二‑对‑缩羟基苯磺酸钠‑硅萘菁；步骤二、将二‑对‑缩羟基苯磺酸钠‑硅萘菁溶于有机溶剂，缓慢加入表面活性剂的蒸馏水中，静置，透析纯化，得到二‑对‑缩羟基苯磺酸钠‑硅萘菁自组装纳米粒子。本发明还公开了一种萘菁自组装纳米粒光敏抗菌剂以及光敏抗菌药物。本发明方法简单、原料易得、成本低、制备的得到的萘菁自组装纳米粒子有效成分高，能够用于制备新型高效光敏抗菌药物。
Description
技术领域
本发明涉及医药技术领域。更具体地说，本发明涉及一种可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法。
背景技术
近年来，滥用抗生素加速了普通细菌的基因突变，诞生了具有多重耐药性的超级细菌(Superbug)。传统药物对这一类细菌已达不到良好的治疗效果，这使得细菌感染者的治疗难度大大增加，故有必要开发新型高效的治疗手段。光敏抗菌剂具有特殊的杀伤机制，不会因为单一用药、给药的浓度、曝光时间不足等因素产生耐药问题，对细菌的治疗有着巨大的优势。现有的方法制备萘菁纳米粒主要通过萘菁分子与其他高分子共沉淀得到，这种方法制备的萘菁纳米颗粒中含有较多无效成分，降低的纳米粒子的药效。
发明内容
本发明提供一种可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法，其方法简单、原料易得、成本低、制备的得到的萘菁自组装纳米粒子有效成分高，能够用于制备新型高效光敏抗菌药物。
为了实现根据本发明的这些目的和其它优点，提供了一种可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法，包括：
步骤一、称取摩尔比为1:2-10的二氯硅萘菁与对羟基苯磺酸钠，并与碱性还原剂溶于有机溶剂，惰性气体保护下回流24-72h，反应结束后减压蒸去溶剂，淋洗剂淋洗，柱层析提纯得到二-对-缩羟基苯磺酸钠-硅萘菁，结构式为式(I)：
步骤二、将二-对-缩羟基苯磺酸钠-硅萘菁溶于有机溶剂制备0.02-0.05μM的溶液，缓慢加入重量占比3％表面活性剂的蒸馏水中，静置24-72h，使用500-1000Da纤维素膜透析纯化，得到二-对-缩羟基苯磺酸钠-硅萘菁自组装纳米粒子。
优选的是，包括：
步骤一、称取摩尔比为1:2-10的二氯硅萘菁与对羟基苯磺酸钠，并与氢化钠溶于甲苯，氮气保护下回流24-72h，反应结束后减压蒸去溶剂，并用氯仿作为淋洗剂，过中性氧化铝层析柱提纯得到二-对-缩羟基苯磺酸钠-硅萘菁，结构式为式(I)：
步骤二、将二-对-缩羟基苯磺酸钠-硅萘菁溶于二甲基亚砜制备0.02-0.05μM的溶液，缓慢加入重量占比3％聚氧乙烯蓖麻油的蒸馏水中，静置24-72h，使用500-1000Da纤维素膜透析纯化，得到二-对-缩羟基苯磺酸钠-硅萘菁自组装纳米粒子。
优选的是，
步骤一、称取摩尔比为1:2的二氯硅萘菁与对羟基苯磺酸钠，并与氢化钠溶于甲苯，氮气保护下回流24h，反应结束后减压蒸去溶剂，并用氯仿作为淋洗剂，过中性氧化铝层析柱提纯得到二-对-缩羟基苯磺酸钠-硅萘菁，结构式为式(I)：
步骤二、将二-对-缩羟基苯磺酸钠-硅萘菁溶于二甲基亚砜制备0.05μM的溶液，缓慢加入重量占比3％聚氧乙烯蓖麻油的蒸馏水中，静置24h，使用500-1000Da纤维素膜透析纯化，得到二-对-缩羟基苯磺酸钠-硅萘菁自组装纳米粒子。
所述的制备方法得到的萘菁自组装纳米粒光敏抗菌剂。
光敏抗菌药物，其包括有治疗有效量的所述的萘菁自组装纳米粒光敏抗菌剂和药学上可接受的载体。
优选的是，药学上可接受的载体包括稀释剂、增溶剂、潜溶剂、崩解剂、分散剂、润滑剂、矫味剂、抗氧剂、粘合剂、吸收剂、湿润剂、缓冲剂、交联剂。
优选的是，所述药物被制成药学上允许的剂型。
优选的是，所述剂型包括注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂。
本发明至少包括以下有益效果：
本发明通过自组装制备纳米颗粒，方法简单、原料易得、成本低，制备的得到的萘菁自组装纳米粒子成分单一、有效成分高，光照前后纳米形貌发生变化，可通过光照调控纳米形貌，可用于制备治疗细菌感染的新型光敏药物，光敏抗菌作用极为显著，可制成注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂的形式使用。
本发明的其它优点、目标和特征将部分通过下面的说明体现，部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
附图说明
图1为本发明的步骤一的合成路线示意图；
图2为本发明实例3制备的萘菁纳米粒子的透射电镜图；
图3为本发明对比例1制备的萘菁纳米粒子的透射电镜图；
图4为本发明对比例2制备的萘菁纳米粒子的透射电镜图；
图5为本发明实例3制备的萘菁纳米粒子在光照前后的透射电镜图；
图6为本发明的实例3萘菁纳米粒子对金黄色葡萄球菌和大肠杆菌的抑制效果图；
图7为本发明的对比例1萘菁纳米粒子对金黄色葡萄球菌和大肠杆菌的抑制效果图；
图8为本发明的对比例2萘菁纳米粒子对金黄色葡萄球菌和大肠杆菌的抑制效果图。
具体实施方式
下面结合附图对本发明做进一步的详细说明，以令本领域技术人员参照说明书文字能够据以实施。
应当理解，本文所使用的诸如“具有”、“包含”以及“包括”术语并不排除一个或多个其它元件或其组合的存在或添加。
需要说明的是，下述实施方案中所述实验方法，如无特殊说明，均为常规方法，所述试剂和材料，如无特殊说明，均可从商业途径获得。
<实例1>
可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法，包括：
步骤一、称取二氯硅萘菁12.2mg对羟基苯磺酸钠25mg，氢化钙10mg溶于15mL丙酮，氩气保护下回流72小时，反应结束后减压蒸去溶剂，并用氯仿作为淋洗剂，过硅胶层析柱提纯得到产物二-对-缩羟基苯磺酸钠-硅萘菁；
步骤二、二-对-缩羟基苯磺酸钠-硅萘菁溶于二氯甲烷制备得到0.02μM的溶液，然后缓慢加入含3％聚氧乙烯蓖麻油(Cremophor EL)的蒸馏水中，静置72小时，使用500-1000Da纤维素膜透析纯化，得到二-对-缩羟基苯磺酸钠-硅萘菁自组装纳米粒子。
<实例2>
可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法，包括：
步骤一、称取二氯硅萘菁12.2mg与对羟基苯磺酸钠50mg，氢化钾8mg溶于30mL乙醚，氦气保护下回流48小时，反应结束后减压蒸去溶剂，并用二氯甲烷作为淋洗剂，过大孔树脂层析柱提纯得到产物二-对-缩羟基苯磺酸钠-硅萘菁；
步骤二、二-对-缩羟基苯磺酸钠-硅萘菁溶于二甲苯制备得到0.04μM的溶液，然后缓慢加入含3％聚氧乙烯蓖麻油(Cremophor EL)的蒸馏水中，静置48小时，使用500-1000Da纤维素膜透析纯化，得到二-对-缩羟基苯磺酸钠-硅萘菁自组装纳米粒子。
<实例3>
可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法，包括：
步骤一、称取二氯硅萘菁12.2mg与对羟基苯磺酸钠12.5mg，氢化钠5mg溶于8mL甲苯，氮气保护下回流24小时，反应结束后减压蒸去溶剂，并用氯仿作为淋洗剂，过中心氧化铝层析柱提纯得到产物二-对-缩羟基苯磺酸钠-硅萘菁；
步骤二、二-对-缩羟基苯磺酸钠-硅萘菁溶于DMSO制备得到0.05μM的溶液，然后缓慢加入含3％聚氧乙烯蓖麻油(Cremophor EL)的蒸馏水中，静置24小时，使用500-1000Da纤维素膜透析纯化，得到二-对-缩羟基苯磺酸钠-硅萘菁自组装纳米粒子。
<对比例1>
制备方法同实例3，不同的是，步骤二中加入0.4％聚氧乙烯蓖麻油(CremophorEL)。
<对比例2>
制备方法同实例3，不同的是，步骤二中加入1％聚氧乙烯蓖麻油(Cremophor EL)。
<对比例3>
制备方法同实例3，不同的是，步骤二中加入十二烷基苯磺酸钠。
<对比例4>
制备方法同实例3，不同的是，步骤二中加入乙二胺。
<对比例5>
制备方法同实例3，不同的是，不包括步骤二。
<萘菁自组装纳米粒子的微观结构检测>
图2示出了实例3制备得到的萘菁自组装纳米粒子透射电镜图，图3示出了对比例1(0.4％聚氧乙烯蓖麻油)制备得到的萘菁自组装纳米粒子透射电镜图，图4示出了对比例2(1％聚氧乙烯蓖麻油)制备得到的萘菁自组装纳米粒子透射电镜图，可以看出，图2中萘菁分子已经是形成直径为20nm左右的纳米颗粒，图3中萘菁分子并没有很好地形成纳米颗粒，而是形成直径为110nm的纳米片，图4中萘菁分子已经是形成直径为70nm左右的纳米颗粒，尺寸较大。对比例3-5添加不同的表面活性剂，或者不添加表面活性剂，均做不出来纳米颗粒，直接沉淀，因此也没有做电镜图。
另外，如图5所示，实例3制备得到的萘菁自组装纳米粒子在激光光照30min(780nm,0.2W·cm-2)后前后纳米形貌发生变化，这说明，该纳米颗粒可以通过光照调控纳米形貌。目前没见报道过此类材料，已公开的萘菁、酞菁类光敏抗菌剂均未见具有报道此类性质。
<萘菁自组装纳米粒子的光敏抗菌活性>
实例3、对比例1-2制备得到的萘菁自组装纳米粒子用超纯水配制0.5×10-6mol/L溶液，再用灭菌后的生理盐水稀释为数个梯度：0.2、0.8、1.6、3.2、12.8nmol/L。将培养好的细菌(1×108cfu/mL)先用营养肉汤稀释至OD＝0.5。各取10μL该菌液与90μL不同浓度的萘菁纳米粒子的溶液混合震荡后，激光光照30min(780nm,0.2W·cm-2)，非光照组则混合均匀后在黑暗条件下培养30min。光照结束后，取10μL混合溶液，用灭菌后的玻璃涂敷棒涂于固体培养基上在37℃的培养箱中培养，取出后对培养基上的菌落数进行统计。
从图6可知，用0.2、0.8、1.6、3.2、12.8nmol/L浓度的20nm萘菁纳米粒子琼脂平板处理(A)金黄色葡萄球菌和(B)大肠杆菌，(a)非光照，(b)光照30分钟(780nm,0.2W·cm-2)，该萘菁纳米粒子对金黄色葡萄球菌和大肠杆菌的最小抑制浓度仅为0.2nmol/L，在12.8nmol/L的浓度时，萘菁纳米粒子对金黄色葡萄球菌和大肠杆菌的抑制率分别为98.37％和100％，显示出优良的抗菌光活性。
从图7可知，用0.2、0.8、1.6、3.2、12.8nmol/L浓度的70nm萘菁纳米粒子琼脂平板处理(A)金黄色葡萄球菌和(B)大肠杆菌，(a)非光照，(b)光照30分钟(780nm,0.2W·cm-2)，该萘菁纳米粒子对金黄色葡萄球菌和大肠杆菌的最小抑制浓度仅为12.8nmol/L，在12.8nmol/L的浓度时，萘菁纳米粒子对金黄色葡萄球菌和大肠杆菌的抑制率分别为83.17％和84.83％，抗菌活性较差。
从图8可知，用0.2、0.8、1.6、3.2、12.8nmol/L浓度的110nm萘菁纳米粒子琼脂平板处理(A)金黄色葡萄球菌和(B)大肠杆菌，(a)非光照，(b)光照30分钟(780nm,0.2W·cm-2)，该萘菁纳米片对金黄色葡萄球菌和大肠杆菌的最小抑制浓度仅为12.8nmol/L，在12.8nmol/L的浓度时，萘菁纳米粒子对金黄色葡萄球菌和大肠杆菌的抑制率分别为82.35％和84.59％，抗菌活性较差。
这里说明的设备数量和处理规模是用来简化本发明的说明的。对本发明的应用、修改和变化对本领域的技术人员来说是显而易见的。
尽管本发明的实施方案已公开如上，但其并不仅仅限于说明书和实施方式中所列运用，它完全可以被适用于各种适合本发明的领域，对于熟悉本领域的人员而言，可容易地实现另外的修改，因此在不背离权利要求及等同范围所限定的一般概念下，本发明并不限于特定的细节和这里示出与描述的图例。
Claims (7)
1.可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法，其特征在于，包括：
步骤一、称取摩尔比为1:2-10的二氯硅萘菁与对羟基苯磺酸钠，并与氢化钠溶于甲苯，氮气保护下回流24-72h，反应结束后减压蒸去溶剂，并用氯仿作为淋洗剂，过中性氧化铝层析柱提纯得到二-对-缩羟基苯磺酸钠-硅萘菁，结构式为式(I)：
步骤二、将二-对-缩羟基苯磺酸钠-硅萘菁溶于二甲基亚砜制备0.02-0.05μM的溶液，缓慢加入重量占比3％聚氧乙烯蓖麻油的蒸馏水中，静置24-72h，使用500-1000Da纤维素膜透析纯化，得到二-对-缩羟基苯磺酸钠-硅萘菁自组装纳米粒子。
2.如权利要求1所述的可光照调控形貌的萘菁自组装纳米粒光敏抗菌剂制备方法，其特征在于，
步骤一、称取摩尔比为1:2的二氯硅萘菁与对羟基苯磺酸钠，并与氢化钠溶于甲苯，氮气保护下回流24h，反应结束后减压蒸去溶剂，并用氯仿作为淋洗剂，过中性氧化铝层析柱提纯得到二-对-缩羟基苯磺酸钠-硅萘菁，结构式为式(I)：
步骤二、将二-对-缩羟基苯磺酸钠-硅萘菁溶于二甲基亚砜制备0.05μM的溶液，缓慢加入重量占比3％聚氧乙烯蓖麻油的蒸馏水中，静置24h，使用500-1000Da纤维素膜透析纯化，得到二-对-缩羟基苯磺酸钠-硅萘菁自组装纳米粒子。
3.如权利要求1-2任一项所述的制备方法得到的萘菁自组装纳米粒光敏抗菌剂。
4.光敏抗菌药物，其特征在于，其包括有治疗有效量的权利要求3所述的萘菁自组装纳米粒光敏抗菌剂和药学上可接受的载体。
5.如权利要求4所述的光敏抗菌药物，其特征在于，药学上可接受的载体包括稀释剂、增溶剂、潜溶剂、崩解剂、分散剂、润滑剂、矫味剂、抗氧剂、粘合剂、吸收剂、湿润剂、缓冲剂、交联剂。
6.如权利要求4所述的光敏抗菌药物，其特征在于，所述药物被制成药学上允许的剂型。
7.如权利要求6所述的光敏抗菌药物，其特征在于，所述剂型包括注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂。
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| CN107915740A (zh) * | 2017-11-09 | 2018-04-17 | 福州大学 | 取代酞菁铜及其在光热材料和光热治疗领域的应用 |
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