CN114306572A - 转运抗菌肽的介孔纳米载体 - Google Patents
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Abstract
本发明涉及一种介孔纳米药物载体，材料选择具有良好生物相容性的二氧化硅、碳酸钙、磷酸钙等实现对抗菌肽的负载和口服给药。本发明设计合成了转运抗菌肽的介孔纳米载体，将介孔纳米载体的表面和介孔孔道表面设计成疏水性结构，并通过吸附、门禁等方式完成对抗菌肽的负载。通过纳米颗粒表面修饰靶向剂、荧光基团，合成具有靶向性/可视化/良好生物相容性的多功能纳米生物复合载体，运用靶向、门禁环境条件释放和压力释放等方法使抗菌肽达到在肠道内或结肠内释放的效果。
Description
技术领域
本发明涉及纳米药物载体，尤其涉及负载抗菌肽的可实现口服给药的介孔纳米药物转运载体。
背景技术
抗菌肽作为有抗细菌、抗病毒和抗真菌活性的小蛋白质，已经越来越广泛的作为生物抗生素使用。抗菌肽一般包含20-50个氨基酸残基，分子量在1-50kD之间，带有正电荷并呈现两亲性，但整体上抗菌肽的疏水性更强，这些特点都与化学小分子药物不同。抗菌肽在体内的转运过程和吸收过程都具有独特性。目前已经发现了7000余种的抗菌肽，抗菌肽抗菌谱广，抑菌活性强，对多重耐药菌具有良好的杀伤作用，对某些包膜病毒有直接的杀伤作用，抗菌肽除了抗菌作用以外还有促进细胞增殖与迁移的作用，抗菌肽的使用可以大大减少抗生素的使用。
纳米药物载体作为生物医药领域中较为活跃的一个分支，近些年来也被广泛研究和应用。纳米药物载体可以跨过生物屏障靶向地控释在目的组织与细胞中，解决了很多药物的转运和释放问题。纳米生物复合材料在纳米载体、纳米医药及纳米生物组织工程等方面得到越来越多的研究和应用。介孔纳米载体由于比表面积大，孔容大等优势在药物转运载体领域占有一席之地。
发明内容
本发明的目的是，针对抗菌肽的口服制剂、抗菌肽的负载与控制释放，设计合成转运抗菌肽的介孔纳米载体，将介孔纳米载体的表面和介孔孔道表面设计成疏水性结构，通过靶向、门禁和压力控释的方法，使抗菌肽达到在肠道内和结肠内释放的效果。
对上述设计做出进一步的说明：
所述的转运抗菌肽介孔纳米载体，颗粒尺寸介于20-950nm之间，载体的形态包括但不限于实心纳米球状颗粒、棒状纳米颗粒、中空的薄壳介孔纳米颗粒等；
所述的转运抗菌肽介孔纳米载体，其材质包括但不限于二氧化硅纳米颗粒、有机硅纳米颗粒、碳酸钙纳米颗粒、磷酸钙纳米颗粒；
所述的转运抗菌肽介孔纳米载体，将载体的表面和介孔孔道表面设计成疏水性结构，具体方法包括但不限于通过煅烧使表面基团脱落形成疏水性结构、表面修饰上长碳链或芳香基团等疏水性结构、表面修饰上短肽等疏水性基团等方法；
所述的转运抗菌肽介孔纳米载体，介孔孔道介于2-50nm之间，其介孔孔道类型包括但不限于二维孔道、相互连通的三维孔道等；
所述的转运抗菌肽介孔纳米载体，其介孔孔道进行门禁修饰，其修饰的分子在酸性条件下是封堵状态，在中性或偏碱性条件下封堵的连接键断裂或封堵分子本身形态结构改变，使负载的抗菌肽释放出来；
所述的转运抗菌肽介孔纳米载体，在纳米颗粒表面修饰上靶向基团，使载体靶向到肠道上表皮或者结肠位置；
所述的转运抗菌肽介孔纳米载体，其中薄壳介孔纳米结构，在结肠内可实现压力控释；
所述的转运抗菌肽介孔纳米载体，在纳米颗粒表面或孔道内修饰以荧光基团，用于对载体的转运过程进行全程监控的可视化治疗与研究；荧光基团包括但不限于碳量子点、半导体量子点和有机荧光素等。
附图说明
图1通过门禁方式对抗菌肽进行负载的带量子点的介孔纳米载体设计合成示意图
具体实施方式
转运抗菌肽介孔纳米载体制备的实例一
1)利用嵌段共聚物P123、硅酸四乙酯、十六烷基三甲基溴化铵，盐酸、水、无水乙醇和氟化胺合成具有六方有序排列，孔径在5.0nm的介孔纳米颗粒。
2)通过550℃煅烧6-10h的方式，去除介孔表面和孔道内表面大部分基团。
3)配制pH值为6.8的缓冲液，将分子量为35kD的抗菌肽溶解。
4)通过浴式吸附的形式，使介孔纳米颗粒负载上抗菌肽。
5)对上述的转运抗菌肽介孔纳米载体的介孔孔道进行门禁修饰，其门禁的连接键在酸性条件下为封堵状态，在弱碱性或中性条件下门禁连接键断裂，介孔孔道呈打开状态，释放出抗菌肽。
6)对抗菌肽介孔纳米材料载体外表面修饰肠道上表皮细胞靶向剂。
转运抗菌肽介孔纳米载体制备的实例二
1)利用嵌段共聚物F127，水、无水乙醇、氨水、十六烷基三甲基溴化铵、硅酸四乙酯合成包括两个相互独立的旋转三维孔道系统，孔径在2.5nm的介孔纳米颗粒。
2)通过硅烷化试剂，使介孔纳米颗粒孔道内表面带有芳香基团。
3)配制pH值为7.0的缓冲液，将分子量为5kD的抗菌肽溶解。
4)通过固定床式吸附的形式，使介孔纳米颗粒负载上抗菌肽。
5)对上述的转运抗菌肽介孔纳米载体的介孔孔道进行门禁修饰，其门禁连接键所连接的门禁分子在pH值为酸性条件下结构稳定，为封堵状态，在偏碱性条件下结构发生变形，门禁分子不再对孔道形成封堵状态，抗菌肽得以释放。由于纳米颗粒表面的疏水基团的存在，其抗菌肽的释放过程是缓慢释放。介孔纳米载体整体达到靶向控制释放的应用效果。
抗菌肽介孔纳米载体制备的实例三
1)配制pH 7.4的缓冲液，将分子量为1.4kD的抗菌肽溶解。
2)在溶液中利用嵌段共聚物P123，硅酸四乙酯、盐酸和水合成薄壳型抗菌肽介孔纳米载体，载体内部携带抗菌肽。
3)对上述转运抗菌肽介孔纳米载体外表面修饰碳量子点。
4)利用上述转运抗菌肽介孔纳米载体，进行可视化监测控制释放，在监测载体-抗菌肽复合物到达结肠部位时，在结肠部位进行压力控释的同时进行外部超声等方式实现结肠靶向释放。
Claims (9)
1.一种转运抗菌肽的介孔纳米载体，用于对抗菌肽进行负载、转运和控制释放。
2.根据权利要求书1所述的一种转运抗菌肽介孔纳米载体，其特征在于颗粒尺寸介于20-950nm之间，载体的形态包括但不限于实心纳米球状颗粒、棒状纳米颗粒、中空的薄壳介孔纳米颗粒等。
3.根据权利要求书1所述的一种转运抗菌肽介孔纳米载体，其特征在于：合成的转运抗菌肽介孔纳米载体的介孔孔道介于2-50nm之间，其介孔孔道类型包括但不限于二维孔道、相互联通的三维孔道等。
4.根据权利要求书1所述的一种转运抗菌肽介孔纳米载体，其特征在于：合成的转运抗菌肽介孔纳米载体的材质包括但不限于二氧化硅纳米颗粒、有机硅纳米颗粒、碳酸钙纳米颗粒、磷酸钙纳米颗粒。
5.根据权利要求书1所述的一种转运抗菌肽介孔纳米载体，其特征在于：合成的转运抗菌肽介孔纳米载体，其颗粒表面或介孔孔道表面设计成疏水性结构，具体方法包括但不限于通过煅烧使表面基团脱落形成疏水性结构、表面修饰上长碳链或芳香基团等疏水性结构、表面修饰上短肽等疏水性基团等方法。
6.根据权利要求书1所述的一种转运抗菌肽介孔纳米载体，其特征在于：其介孔孔道进行门禁修饰，门禁分子在酸性条件下是封堵状态，在中性或偏碱性条件下封堵的连接键断裂或封堵分子本身形态结构改变，使负载的抗菌肽释放出来。
7.根据权利要求书1所述的一种转运抗菌肽介孔纳米载体，其特征在于：在纳米颗粒表面修饰上靶向基团，使载体可以靶向到肠道上表皮或者结肠位置。
8.根据权利要求书2所述的一种转运抗菌肽介孔纳米载体，其特征在于：中空的薄壳介孔纳米结构在结肠内可进行压力控释。
9.根据权利要求书1所述的一种转运抗菌肽介孔纳米载体，其特征在于：在纳米颗粒表面或孔道内修饰以荧光基团，用于对载体的转运过程进行全程监控的可视化治疗与研究；荧光基团包括但不限于碳量子点、半导体量子点和有机荧光素等。
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