CN113559054A - 活性氧清除/响应变构自组装水凝胶及其应用 - Google Patents
活性氧清除/响应变构自组装水凝胶及其应用 Download PDFInfo
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- CN113559054A CN113559054A CN202110529137.6A CN202110529137A CN113559054A CN 113559054 A CN113559054 A CN 113559054A CN 202110529137 A CN202110529137 A CN 202110529137A CN 113559054 A CN113559054 A CN 113559054A
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Abstract
本发明公开了一种活性氧清除/响应变构自组装水凝胶及其应用,属于药物制剂技术领域。本发明的水凝胶由小分子凝胶因子在水溶液中自组装形成,所述小分子凝胶因子由封端基团、短肽序列和抗氧化基团连接组成。本发明通过将具有抗氧化能力的基团引入小分子凝胶因子的设计中,构建出具有活性氧清除/响应变构能力的小分子水凝胶作为药物控释载体。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种活性氧清除/响应变构自组装水凝胶及其应用及其制备方法和应用。
背景技术
水凝胶是具有三维网状结构,含有大量水分的半固体制剂。小分子水凝胶通常是由分子量小于2000的凝胶因子的亲水/疏水基团通过非共价键相互作用,如氢键、范德华力、π-π堆积等,发生有序排列进而形成具有特殊结构的聚集体。小分子水凝胶的骨架材料通常由短肽构成,具有良好的生物相容性和生物降解性,并且小分子水凝胶在成胶后仍具有可注射性,在体外条件下即可制备同时实现对药物的包载,从而有效降低原位凝胶在体内成胶过程中的突释。因此小分子水凝胶被视为药物,特别是生物药物的理想的缓控释载体。
近年来研究表明,体内产生的活性氧簇 (reactive oxygen species, ROS) 在多种细胞信号传导通路中均发挥着重要的作用。ROS主要包括超氧化物(O2 •−)、羟基自由基(OH•)、过氧化氢(H2O2)和单线态氧。在生理条件下,低水平ROS的生成被认为是信号分子。另一方面,ROS的过度产生,促细胞炎症与凋亡,可氧化信号分子、核酸、糖类、蛋白质、脂类等,使之受损。ROS的过度产生参与多种疾病的发生发展,包括心血管疾病,获得性免疫缺陷综合症,中风、衰老等。
因此,本发明设计将具有抗氧化能力的基团引入小分子凝胶因子中,构建出具有活性氧清除/响应变构能力的小分子水凝胶作为药物控释载体。
发明内容
本发明的目的是提供一种活性氧清除/响应变构自组装水凝胶及其应用,通过将具有抗氧化能力的基团引入小分子凝胶因子中,构建得到具有活性氧清除/响应变构能力的小分子水凝胶,该小分子水凝胶可作为药物控释载体,与活性氧清除剂协同,产生更好的治疗效果。
为了实现上述发明目的,本发明采用以下技术方案:
活性氧清除/响应变构自组装水凝胶及其应用,由小分子凝胶因子在水溶液中自组装形成,所述小分子凝胶因子由封端基团、短肽序列和抗氧化基团连接组成;
所述封端基团选自芴甲氧羰基、萘基、苄氧羰基或硝基苯并呋喃;
所述短肽序列选自苯丙氨酸-苯丙氨酸、苯丙氨酸-苯丙氨酸-苯丙氨酸、甘氨酸-苯丙氨酸-苯丙氨酸、苯丙氨酸-酪氨酸-酪氨酸、酪氨酸-酪氨酸-酪氨酸、甘氨酸-苯丙氨酸-苯丙氨酸-酪氨酸、苯丙氨酸-苯丙氨酸-酪氨酸-甘氨酸、苯丙氨酸-苯丙氨酸-苯丙氨酸-精氨酸;
抗氧化基团选自多巴(3,4-二羟基苯丙氨酸),2,3,4-三羟基苯甲醛(2,3,4-三羟基苯甲醛),没食子酸(3,4,5-三羟基苯甲酸),川芎嗪(2,3,5,6-四甲基吡嗪),咖啡酸(β-(3,4-二羟苯基)丙烯酸),阿魏酸(4-羟基-3-甲氧基肉桂酸),姜黄素((E,E)-1,7-双(4-羟基-3-甲氧基苯基)-1,6-庚二烯-3,5-二酮),丁香酚(4-烯丙基-2-甲氧基苯酚),丁香酸(3,5-二甲氧基-4-羟基苯甲酸),芥子酸(3,5-二甲氧基-4-羟基肉桂酸),抗坏血酸(2,3,4,5,6-五羟基-2-己烯酸-4-内酯),间羟胺(α-(1-氨乙基)-3-羟基苯甲醇),绿原酸(3-(3,4-二羟基肉桂酰基)奎宁酸)。
进一步地,所述小分子凝胶因子采用固相肽合成法制备得到。
上述水凝胶的制备方法,是将小分子凝胶因子溶解在水溶液中,经自组装形成。
上述水凝胶可用于制备药物控释制剂,如癌症、动脉粥样硬化、关节炎、心机梗塞、肝炎、胃炎、结肠炎、皮肤损伤、帕金森、阿尔茨海默病、系统性红斑狼疮、高血压、充血性心力衰竭、肝肾损伤、糖尿病并发症等疾病的治疗药物;也可用于制备伤口修复产品或组织工程产品。
本发明通过将具有抗氧化能力的基团引入小分子凝胶因子的设计中,构建出具有活性氧清除/响应变构能力的小分子水凝胶作为药物控释载体。如图1所示,该自组装小分子水凝胶系统具备的三维网状结构有利于药物的包载。经病灶部位直接注射,小分子水凝胶可长时间滞留在给药部位,小分子凝胶因子中的抗氧基团可以消耗炎症部位产生的大量ROS,减缓过量ROS对组织的损伤,同时在ROS作用下,具有抗氧化能力的基团被氧化生成新的化学结构,改变了原有小分子水凝胶之间的非共价键作用力,导致水凝胶向溶液转变,从而释放出荷载的药物,与活性氧清除剂协同,产生更好的治疗效果。在心血管疾病,获得性免疫缺陷综合症,中风、衰老等疾病方面有很大的应用前景。
附图说明
图1为本发明水凝胶的释药示意图。
图2为水凝胶Fmoc-GFF-DOPA、Fmoc-FFF-DOPA、Nap-GFF-DOPA、Nap-FFF-DOPA、Cbz-FFF-DOPA的超氧阴离子自由基清除实验结果。
图3为水凝胶Fmoc-FFFK-Gallic、Nap-FFFK-Gallic、Caffeic-FFF、Fmoc-FFFK-Caffeic、Fmoc-FFFK-Ferulic、Nap-FFFK-Ferulic的超氧阴离子自由基清除实验结果。
图4为凝胶因子Fmoc-GFF-DOPA的水凝胶电镜图。
图5为凝胶因子Fmoc-FFF-DOPA的水凝胶电镜图。
图6 为凝胶因子Nap-GFF-DOPA的水凝胶电镜图。
图7为凝胶因子Cbz-FFF-DOPA的水凝胶电镜图。
图8为Nap-GFF-DOPA水凝胶的体外PTIO•共孵育变构实验结果。
图9为荷载免疫球蛋白G的Nap-GFF-DOPA水凝胶的体外释放实验结果。
具体实施方式
以下实施例进一步说明本发明的内容,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改和替换,均属于本发明的范围。若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例1-11
通过固相肽合成的方法获得了11条不同的凝胶因子序列,分别为:芴甲氧羰基-甘氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Fmoc-GFF-DOPA)、芴甲氧羰基-苯丙氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Fmoc-FFF-DOPA)、萘基-甘氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Nap-GFF-DOPA)、萘基-苯丙氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Nap-FFF-DOPA)、苄氧羰基-苯丙氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Cbz-FFF-DOPA)、芴甲氧羰基-苯丙氨酸-苯丙氨酸-苯丙氨酸-精氨酸-没食子酸(Fmoc-FFFK-Gallic)、萘基-苯丙氨酸-苯丙氨酸-苯丙氨酸-精氨酸-没食子酸(Nap-FFFK-Gallic)、咖啡酸-苯丙氨酸-苯丙氨酸-苯丙氨酸(Caffeic-FFF)、芴甲氧羰基-苯丙氨酸-苯丙氨酸-苯丙氨酸-精氨酸-咖啡酸(Fmoc-FFFK-Caffeic)、芴甲氧羰基-苯丙氨酸-苯丙氨酸-苯丙氨酸-精氨酸-阿魏酸(Fmoc-FFFK-Ferulic)、萘基-苯丙氨酸-苯丙氨酸-苯丙氨酸-精氨酸-阿魏酸(Nap-FFFK-Ferulic)。
通过标准的固相肽合成方法合成Fmoc-GFF-DOPA,2-氯三苯甲基氯树脂作为不溶性的固相载体。具体地:先将氨基被芴甲氧羰基保护的二羟苯丙氨酸共价连接在固相载体上,在三氟乙酸的作用下,脱去芴甲氧羰基;然后将芴甲氧羰基保护的苯丙氨酸的羧基活化,再与二羟苯丙氨酸的氨基反应形成肽键;接着依次连接苯丙氨酸和甘氨酸,再将肽链和固相载体之间的酯键水解,就得到了Fmoc-GFF-DOPA,之后使用高效液相色谱进行纯化。其他序列用同样的方法合成获得。
小分子水凝胶的制备:将20mM的凝胶因子溶于2mL的双蒸水,调节pH至溶解后,加热冷却至室温,30min后倒置没有重力流动,即形成水凝胶。
下面将上述制得的水凝胶进行体外抗氧化能力测定、微观结构观察和体外变构能力检测。
1、体外抗氧化能力测定
采用超氧化物歧化酶(SOD)检测试剂盒(Solarbio,BC0170)检测其超氧阴离子清除活性。通过黄嘌呤与黄嘌呤氧化酶反应体系生成超氧阴离子,超氧阴离子能使硝基-蓝四唑还原生成蓝色的甲瓒,并在560nm处被吸收。因此,560nm处的吸光度下降反映了超氧阴离子的清除能力。将不同水凝胶浓度(5、10和15 mM)的样品各90 μL加入黄嘌呤、黄嘌呤氧化酶和硝基蓝四唑的工作溶液中。37℃孵育30 min后,用酶标仪(BioTek, PowerWave XS)测定560nm处吸光度。
结果如图2和图3所示,所有凝胶因子序列均具有O2 •−清除能力,表明凝胶因子中引入抗氧基团可以很好的发挥抗氧作用。
2、透射电镜观察微观结构
将镀碳的铜格网垂直插入小分子水凝胶中5-10 s后轻轻取出,置于干燥箱中过夜,次日用透射电镜进行观察,样品室电压为80 kV。
如图4-7所示,采用芴甲氧羰基-甘氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Fmoc-GFF-DOPA)、芴甲氧羰基-苯丙氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Fmoc-FFF-DOPA)、萘基-甘氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Nap-GFF-DOPA)、苄氧羰基-苯丙氨酸-苯丙氨酸-苯丙氨酸-二羟苯丙氨酸(Cbz-FFF-DOPA)制备的水凝胶中形成纤维状结构。
3、体外变构能力考察
采用Nap-GFF-Dopa验证本发明水凝胶对ROS的敏感性,水凝胶样品分别被放置于含有或不含8mMPTIO•的磷酸盐缓冲溶液中,在37℃下孵育观察样品的形态变化,并每天拍照记录。
如图8所示,在含有PTIO•的磷酸盐缓冲溶液中样品的体积随着孵育时间增加而逐渐变小,在第十天体积有明显的变小,而不含有PTIO•的磷酸盐缓冲溶液中随着时间的推移样品的大小基本不变,表明Nap-GFF-Dopa小分子水凝胶对活性氧簇具有特定的响应变构性。
4、载药活性氧清除/响应性变构的水凝胶的制备
将20mM的凝胶因子分别溶于2mL的双蒸水,调节pH至溶解,加热冷却至室温,将IgG和凝胶因子溶液混合均匀后静置,30min后倒置没有重力流动,即形成载药水凝胶。
5、体外释放行为研究
选择FITC goat anti-rat IgG(Thermo Fisher Scientific,31629)作为模型药物,然后将其包载于Nap-GFF-Dopa水凝胶中。将制备好的载药水凝胶分别置于含有或不含8mMPTIO•的磷酸盐缓冲溶液中,在200rpm、37℃的条件下持续震荡,每天同一时间点取样1mL,同时补充1mL新鲜缓冲介质,连续取样15天。通过荧光酶标仪分析并计算拟合出Nap-GFF-Dopa水凝胶在不同缓冲介质中的体外释放行为。
Claims (6)
1.活性氧清除/响应性变构自组装水凝胶,由小分子凝胶因子在水溶液中自组装形成,其特征在于:所述小分子凝胶因子由封端基团、短肽序列和抗氧化基团连接组成;
所述封端基团选自芴甲氧羰基、萘基、苄氧羰基或硝基苯并呋喃;
所述短肽序列选自苯丙氨酸-苯丙氨酸、苯丙氨酸-苯丙氨酸-苯丙氨酸、甘氨酸-苯丙氨酸-苯丙氨酸、苯丙氨酸-酪氨酸-酪氨酸、酪氨酸-酪氨酸-酪氨酸、甘氨酸-苯丙氨酸-苯丙氨酸-酪氨酸、苯丙氨酸-苯丙氨酸-酪氨酸-甘氨酸、苯丙氨酸-苯丙氨酸-苯丙氨酸-精氨酸;
抗氧化基团选自3,4-二羟基苯丙氨酸、2,3,4-三羟基苯甲醛、没食子酸、川芎嗪、咖啡酸、阿魏酸、姜黄素、丁香酚、丁香酸、芥子酸、抗坏血酸、间羟胺或绿原酸。
2.根据权利要求1所述的活性氧清除/响应性变构的水凝胶,其特征在于:所述小分子凝胶因子采用固相肽合成法制备得到。
3.权利要求1所述水凝胶的制备方法,其特征在于:将小分子凝胶因子溶解在水溶液中,经自组装形成。
4.权利要求1所述水凝胶在制备药物控释制剂中的应用。
5.权利要求1所述水凝胶在制备伤口修复产品中的应用。
6.权利要求1所述水凝胶在制备组织工程产品中的应用。
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