CN110217801B - 硫辛酸功能化的介孔氧化硅纳米材料及其制备方法与应用 - Google Patents
硫辛酸功能化的介孔氧化硅纳米材料及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供一种硫辛酸功能化的介孔氧化硅纳米材料及其制备方法与应用。本发明选用硫辛酸在介孔氧化硅材料表面进行抗氧化修饰,将硫辛酸通过酰胺化反应共价修饰到介孔氧化硅的表面,可有效降低介孔氧化硅材料作为药物载体对于生物体的毒性作用,并进一步提高其生物相容性。研究表明,硫辛酸修饰介孔氧化硅纳米材料对小鼠大脑神经具有保护作用,有效降低了静脉注射介孔氧化硅材料后引起的小鼠社交能力和认知功能的异常,从而降低介孔硅的神经毒性。
Description
技术领域
本发明涉及生物医药领域,具体地说,涉及一种硫辛酸功能化的介孔氧化硅纳米材料及其制备方法与应用。
背景技术
介孔氧化硅纳米材料作为一种优良的药物载体,具有介孔材料和纳米材料的双重特性。具有生物相容性好,比表面积大,孔径和孔容可调,孔道均匀,表面易于功能化修饰等优点,在药物递送、疾病诊断以及生物成像等领域具有巨大的潜在应用价值。
虽然介孔氧化硅作为纳米载体已经有广泛研究,但是介孔氧化硅的安全性仍然存在隐患。由于介孔氧化硅材料表面存在大量的硅羟基,进入细胞后会产生大量的活性氧,造成细胞和组织氧化损伤。介孔氧化硅会引起红细胞溶血,影响其在静脉给药方面的应用。此外,介孔氧化硅经皮下注射和肌肉注射给小鼠,会引起注射部位炎症反应。因此,仍需对介孔氧化硅的毒性进行系统研究。
硫辛酸是一种在线粒体中天然存在的抗氧化剂,具备优良的抗氧化性质。硫辛酸及其还原型二氢硫辛酸可以清除几乎所有种类的自由基,发挥抗氧化作用。硫辛酸还可以鳌合金属离子,清除自由基。硫辛酸通过激活Nrf2通路,增加II相代谢酶基因的表达,起到抗氧化作用。最重要的是,硫辛酸作为一种重要的线粒体辅助因子,可以抑制线粒体的衰老以及氧化应激引起的线粒体功能障碍,改善因线粒体的衰老以及功能障碍引起的神经功能受损包括记忆缺失和认识功能障碍。
发明内容
本发明的目的是提供一种硫辛酸功能化的介孔氧化硅纳米材料及其制备方法与应用。通过在介孔氧化硅表面共价修饰硫辛酸,使其能够降低介孔硅材料的毒性,降低其静脉注射后引起的小鼠社交能力和认知功能的异常,从而降低介孔硅的神经毒性。
为了实现本发明目的,第一方面,本发明提供一种硫辛酸功能化的介孔氧化硅纳米材料的制备方法,包括以下步骤:
1)以十六烷基三甲基溴化铵为模板剂,在碱性条件下使正硅酸乙酯与(3-巯基丙基)三甲氧基硅烷进行共缩聚反应,得到巯基功能化的介孔氧化硅;除去产物中的模板剂;
2)以无水短链醇为反应溶剂,使(3-氨丙基)三甲氧基硅烷与步骤1)所得巯基功能化的介孔氧化硅表面的硅羟基发生水解缩聚进行后嫁接,得到氨基功能化的介孔氧化硅;
3)在氮气保护的条件下,使步骤2)所得氨基功能化的介孔氧化硅与N,N’-羰基二咪唑活化的硫辛酸发生酰胺化反应,得到以酰胺键共价连接的硫辛酸功能化的介孔氧化硅纳米材料。
前述的方法,步骤1)所述共缩聚反应在水中进行。
所述共缩聚反应的反应温度为65-95℃,反应时间为1-4h,优选80℃反应2h。
所述碱性条件的pH值为10-11,优选pH值11。
步骤1)所述共缩聚反应中,十六烷基三甲基溴化铵、正硅酸乙酯、(3-巯基丙基)三甲氧基硅烷和水的摩尔比分别为1:8.5-10.3:2.0-3.0:9000-11000,优选1:9.3:2.6:9697。
步骤1)除去模板剂的方法为萃取法;萃取所用溶剂为质量浓度为35%-37%的盐酸溶液和无水甲醇按体积比1:30-1:50(优选1:50)形成的混合液。
步骤2)中所述反应溶剂为无水乙醇或无水甲醇等。
步骤2)的反应条件为:常温反应24~48h。
步骤2)中(3-氨丙基)三甲氧基硅烷和巯基功能化介孔氧化硅的质量比为1:0.2-0.5,优选1:0.3。
步骤3)中氨基功能化的介孔氧化硅、N,N’-羰基二咪唑和硫辛酸的质量比分别为1:1.02-1.50:1.02-1.53,优选2.5:2.6:3。
在本发明的一个具体实施方式中,所述硫辛酸功能化的介孔氧化硅纳米材料的制备方法如下:
(1)取0.3g十六烷基三甲基溴化铵溶解于144mL蒸馏水中,加入2mol/L的NaOH溶液1mL,调节温度至80℃,再加入1.5mL正硅酸乙酯、0.4mL(3-巯基丙基)三甲氧基硅烷,在80℃、1500rpm条件下搅拌反应2h;2h后自然冷却,4℃、10000rpm离心30min,收集沉淀,依次用无水乙醇和水洗涤沉淀,然后于80℃真空干燥48h,得白色粉末;将白色粉末用滤纸包住放入索氏提取器,向烧瓶中加入7mL浓度为37.0%的盐酸和350mL无水甲醇,回流反应36h,脱除十六烷基三甲基溴化铵;然后4℃、10000rpm离心10min,收集沉淀,用无水乙醇洗涤沉淀,80℃真空干燥48h,即得巯基功能化的介孔氧化硅(MSN-SH);
(2)取步骤(1)所得0.3g巯基功能化的介孔氧化硅,用60mL无水乙醇溶解,然后逐滴加入1mL(3-氨丙基)三甲氧基硅烷,室温搅拌24h,然后用无水乙醇离心洗涤,真空干燥得到氨基功能化的介孔氧化硅(MSN-SH-NH2);
(3)取100mL三颈圆底烧瓶,一口插反口塞,反口塞上插针头用作出气口,一口通入氮气,一口密闭;烧瓶中先加入3~4mL无水甲苯,氮气吹扫5min,然后向所述三颈圆底烧瓶中加入0.3g硫辛酸,再加入20mL无水甲苯使其充分溶解,将0.26g N,N’-羰基二咪唑用3mL无水氯仿溶解,加入到所述三颈圆底烧瓶中;混合物在室温氮气氛围下搅拌1h,作为A液,将A液转移到恒压漏斗中;然后,向所述三颈圆底烧瓶中加入步骤(2)所得0.25g氨基功能化的介孔氧化硅,用30mL无水甲苯分散,用恒压漏斗逐滴将A液加入所述三颈圆底烧瓶中,在室温氮气氛围下反应6h,然后关闭氮气,室温反应过夜;最后用无水乙醇离心洗涤,真空干燥,即得硫辛酸功能化的介孔氧化硅纳米材料(MSN-LA)。
本发明中使用的介孔氧化硅纳米材料(MSNs)可按照常规合成方法制得。
第二方面,本发明提供按照上述方法制备的硫辛酸功能化的介孔氧化硅纳米材料。
所述纳米材料呈球形,平均粒径为80~120nm左右(优选80nm左右),且表面具有六方孔道的规则结构;所述纳米材料表面硫辛酸的修饰量为2.0×10-3~4.0×10-3mol/g(优选2.0×10-3mol/g)。
第三方面,本发明提供所述硫辛酸功能化的介孔氧化硅纳米材料的以下任一应用:
1)用于制药;
2)用作药物递送载体。
所述纳米材料在应用时,可以用5%葡萄糖溶液为分散介质,配成混悬液,通过静脉注射给药。
第四方面,本发明提供含有所述硫辛酸功能化的介孔氧化硅纳米材料的药物或组合物。
借由上述技术方案,本发明至少具有下列优点及有益效果:
本发明有效降低了介孔氧化硅材料作为药物载体对于生物体的毒性作用,并进一步提高其生物相容性。选用硫辛酸在介孔氧化硅材料表面进行抗氧化修饰,将硫辛酸通过酰胺化反应共价修饰到介孔氧化硅的表面,并与未经修饰的介孔硅材料(MSNs)进行对比,结果表明硫辛酸修饰介孔氧化硅纳米材料对小鼠大脑神经起到保护作用。例如,将修饰后的纳米材料(MSN-LA)经尾静脉注射进C57BL/6N小鼠体内,可降低介孔硅材料引起的神经毒性,降低介孔硅材料引起的小鼠社交能力和认知功能的异常。
附图说明
图1为本发明无修饰的介孔氧化硅纳米材料(A)以及实施例2中硫辛酸修饰的介孔氧化硅纳米材料MSN-LA(B)的透射电镜照片。
图2为本发明实施例2中介孔氧化硅对C57BL/6N小鼠社交能力和认知能力的影响,三箱交流实验(A、C、D、E)和新物体识别实验(B、F)。其中,NS表示无统计学差异,*表示P﹤0.05,**表示P﹤0.01。
图3为本发明实施例2中介孔氧化硅对C57BL/6N小鼠血脑屏障的影响。其中,A:小鼠脑照片,B:EB含量检测统计结果。NS表示无统计学差异,*表示P﹤0.05。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。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,所用原料均为市售商品。
实施例1硫辛酸功能化的介孔氧化硅纳米材料的制备方法
本实施例提供的硫辛酸功能化的介孔氧化硅纳米材料按如下方法制备得到:
(1)巯基功能化的介孔氧化硅的制备:取0.3g十六烷基三甲基溴化铵溶解于144mL蒸馏水中,加入2mol/L的NaOH溶液1mL,调节温度至80℃,再加入1.5mL正硅酸乙酯、0.4mL(3-巯基丙基)三甲氧基硅烷,在80℃、1500rpm条件下搅拌反应2h;2h后自然冷却,4℃、10000rpm离心30min,收集沉淀,依次用无水乙醇和水洗涤沉淀,然后于80℃真空干燥48h,得白色粉末;将白色粉末用滤纸包住放入索氏提取器,向圆底烧瓶中加入7mL浓度为37.0%的盐酸和350mL无水甲醇,回流反应36h,脱除十六烷基三甲基溴化铵;然后4℃、10000rpm离心10min,收集沉淀,用无水乙醇洗涤沉淀,80℃真空干燥48h,即得MSN-SH;
(2)氨基功能化的介孔氧化硅的制备:取步骤(1)所得0.3g巯基功能化的介孔氧化硅,用60mL无水乙醇溶解,然后逐滴加入1mL(3-氨丙基)三甲氧基硅烷,室温搅拌24h,然后用无水乙醇离心洗涤,真空干燥得到氨基功能化的介孔氧化硅MSN-SH-NH2;
(3)硫辛酸功能化的介孔氧化硅纳米材料的制备:取100mL三颈圆底烧瓶,一口插反口塞,反口塞上插针头用作出气口,一口通入氮气,一口密闭;烧瓶中先加入3~4mL无水甲苯,氮气吹扫5min,然后向所述三颈圆底烧瓶中加入0.3g硫辛酸,再加入20mL无水甲苯使其溶解,将0.26g N,N’-羰基二咪唑用3mL无水氯仿溶解,加入到所述三颈圆底烧瓶中;混合物在室温氮气氛围下搅拌1h,作为A液,将A液转移到恒压漏斗中;然后,向所述三颈圆底烧瓶中加入步骤(2)所得0.25g氨基功能化的介孔氧化硅,用30mL无水甲苯溶解,用恒压漏斗逐滴将A液加入所述三颈圆底烧瓶中,在室温氮气氛围下反应6h,然后关闭氮气,室温反应过夜;最后用无水乙醇离心洗涤,真空干燥,即得MSN-LA。该纳米材料呈球形,平均粒径约80nm,表面具有六方孔道的规则结构;该纳米材料表面硫辛酸的修饰量为2.0×10-3mol/g。MSN-LA的透射电镜照片见图1-B。
实施例2硫辛酸功能化的介孔氧化硅纳米材料的体内生物评价
对实施例1制得的MSN-LA样品进行体内生物评价。本实施例中使用的无修饰的介孔氧化硅(MSNs组)的合成方法为:取0.3g十六烷基三甲基溴化铵,用144mL蒸馏水溶解,搅拌加热到80℃;向上述溶液中加入2mol/L的NaOH溶液1mL,80℃加热搅拌1h。然后逐滴加入正硅酸乙酯1.50mL,搅拌2h。离心,弃上清,沉淀用蒸馏水离心洗涤2次,用无水乙醇离心洗涤2次。将所得产物转移到滤纸中,包裹好放入索氏提取器中,配制提取液无水甲醇:37%盐酸=50:1(v:v),将提取液加入圆底烧瓶中回流提取36h,取出滤纸中的产物转移到离心管中,然后用无水乙醇超声分散离心洗涤,真空干燥,所得介孔氧化硅纳米材料的透射电镜照片见图1-A。
为了使介孔氧化硅载体材料能够很快在体内分布,将介孔氧化硅MSN-LA紫外灭菌后加入5%葡萄糖溶液配成2.5mg/mL的溶液,用超声波清洗仪使其分散均匀,现配现用。给小鼠(C57BL/6N,体重20g,雄性)尾静脉注射所述混悬液0.2mL/只,给药14d,每天给一次,利用三箱交流试验和新物体识别实验(图2)观测给药后介孔氧化硅在小鼠社交能力和认知功能的异常,然后进行伊文思蓝染色检测血脑屏障的完整性(图3)。三箱交流试验和新物体识别实验的具体实验方法参见Mu Yang,Jill L.Silverman,and Jacqueline N.Crawley,Curr Protoc Neurosci,2011,chapter 8。
图2为小鼠的行为学测试结果。其中,A为三箱交流试验示意图。C为以空笼子和陌生鼠为对象,检测小鼠对二者的社会交流行为。D为以模型假鼠和陌生鼠为对象,检测小鼠对二者的社会交流行为。E为以可动的模型假鼠和陌生鼠为对象,检测小鼠对二者的社会交流行为。B为新物体识别实验示意图。F为利用新物体识别实验检测小鼠的认知能力。如图所示,表面无修饰的介孔氧化硅MSNs组,小鼠对新物体的识别行为以及社会交流行为均减少,表明小鼠的认知能力以及社会交流能力均明显下降。而修饰了硫辛酸的介孔氧化硅MSN–LA组,小鼠的认知能力以及社会交流能力下降程度降低。并且小鼠的认知能力与正常葡萄糖对照组无统计学差异。小鼠行为学测试结果表明,无修饰的介孔氧化硅可引起严重的脑损伤,使小鼠的脑功能紊乱,介孔氧化硅表面硫辛酸的修饰,可以起到明显的神经保护的作用。
图3为小鼠的血脑屏障伊文思蓝染色结果图。其中,A为尾静脉注射伊文思蓝半小时后,经心内灌注后取脑拍摄的照片。B为紫外检测脑中伊文思蓝含量的统计图,结果显示,在5%葡萄糖组,小鼠的血脑屏障完整性良好,脑中伊文思蓝含量较低;与对照组相比,无修饰的介孔氧化硅MSNs组,小鼠脑中伊文思蓝的含量明显升高,表明血脑屏障的完整性丧失,伊文思蓝透过血脑屏障进入到脑实质中;而修饰了硫辛酸的介孔氧化硅MSN–LA组,与对照组相比,小鼠脑中伊文思蓝的含量变化不明显,血脑屏障的完整性变化不明显,血脑屏障功能比较完好。
通过小鼠行为学测试发现给药无修饰介孔硅MSNs后,小鼠社交能力和认知功能异常,表现明显的神经毒性。而表面硫辛酸功能化的介孔硅MSN–LA,由于硫辛酸的抗氧化作用,小鼠社交能力和认知功能异常的情况明显改善。
通过血脑屏障伊文思蓝染色结果发现,无修饰的介孔硅MSNs破坏了血脑屏障的功能,造成血脑屏障完整性丧失,进而引发了小鼠脑功能异常。而表面硫辛酸功能化的介孔硅MSN–LA给药小鼠后,小鼠血脑屏障的完整性相对良好,所以其行为异常情况改善,证明硫辛酸的修饰可以起到神经保护的作用。
由此可见,本发明提供的硫辛酸功能化纳米材料生物相容性提高,生物毒性降低,提高了介孔硅的临床应用安全性。
实施例3硫辛酸功能化的介孔氧化硅纳米材料的体外毒性评价
选用人神经母细胞瘤SH-SY5Y细胞作为细胞模型。取生长处于对数期的细胞,采用胰酶消化,离心(1500rpm,3min),弃上清,加培养基吹打分散,稀释计数,按每孔5×103个细胞接种到96孔板中,其中一列只加入培养基作为空白对照组,四周后加PBS,保持细胞生长所需的湿润环境,37℃,5%CO2培养箱中培养。待96孔板中细胞贴壁后开始给药,给药浓度分别为0,1,10,25,50,75,100,200和400μg/mL,每组6个复孔。给药24h后,每孔加入20μLMTT(5mg/mL),孵育4h后,吸去上清,每孔加100μL DMSO,用振板器震荡15min,在490nm波长处用酶标仪检测吸光度值。细胞抑制率=1-(给药组OD值-空白组OD值)/(不给药组OD值-空白组OD值)。IC50值为细胞抑制率50%时的给药浓度。所得抑制率数据用Origin软件拟合得到IC50值,结果见表1。
表1介孔氧化硅材料的IC50值
由表1数据可以看出,介孔氧化硅MSNs对细胞的毒性较大,其IC50值为30μg/mL;而修饰了硫辛酸的介孔硅材料MSN-LA对细胞毒性较小,在最高检测浓度400μg/mL时未观察到明显的细胞毒性。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之做一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (7)
1.硫辛酸功能化的介孔氧化硅纳米材料的制备方法,其特征在于,包括以下步骤:
1)以十六烷基三甲基溴化铵为模板剂,在碱性条件下使正硅酸乙酯与(3-巯基丙基)三甲氧基硅烷进行共缩聚反应,得到巯基功能化的介孔氧化硅;除去产物中的模板剂;
2)以无水短链醇为反应溶剂,使(3-氨丙基)三甲氧基硅烷与步骤1)所得巯基功能化的介孔氧化硅表面的硅羟基发生水解缩聚进行后嫁接,得到氨基功能化的介孔氧化硅;
3)在氮气保护的条件下,使步骤2)所得氨基功能化的介孔氧化硅与N,N’-羰基二咪唑活化的硫辛酸发生酰胺化反应,得到以酰胺键共价连接的硫辛酸功能化的介孔氧化硅纳米材料。
2.根据权利要求1所述的方法,其特征在于,步骤1)所述共缩聚反应在水中进行;和/或
所述共缩聚反应的反应温度为65-95℃,反应时间为1-4h;和/或
所述碱性条件的pH值为10-11。
3.根据权利要求2所述的方法,其特征在于,步骤1)所述共缩聚反应中,十六烷基三甲基溴化铵、正硅酸乙酯、(3-巯基丙基)三甲氧基硅烷和水的摩尔比分别为1:8.5-10.3:2.0-3.0:9000-11000。
4.根据权利要求1所述的方法,其特征在于,步骤1)除去模板剂的方法为萃取法;萃取所用溶剂为质量浓度为35%-37%的盐酸溶液和无水甲醇按体积比1:30-100形成的混合液。
5.根据权利要求1所述的方法,其特征在于,步骤2)中所述反应溶剂为无水乙醇或无水甲醇;和/或
反应条件为:常温反应24~48h。
6.根据权利要求1所述的方法,其特征在于,步骤2)中(3-氨丙基)三甲氧基硅烷和巯基功能化介孔氧化硅的质量比为1:0.2-0.5;和/或
步骤3)中氨基功能化的介孔氧化硅、N,N’-羰基二咪唑和硫辛酸的质量比分别为1:1.02-1.50:1.02-1.53。
7.根据权利要求1-6任一项所述的方法,其特征在于,包括以下步骤:
(1)取0.3g十六烷基三甲基溴化铵溶解于144mL蒸馏水中,加入2mol/L的NaOH溶液1mL,调节温度至80℃,再加入1.5mL正硅酸乙酯、0.4mL(3-巯基丙基)三甲氧基硅烷,在80℃、1500rpm条件下搅拌反应2h;2h后自然冷却,4℃、10000rpm离心30min,收集沉淀,依次用无水乙醇和水洗涤沉淀,然后于80℃真空干燥48h,得白色粉末;将白色粉末用滤纸包住放入索氏提取器,向烧瓶中加入7mL浓度为37%的盐酸和350mL无水甲醇,回流反应36h,脱除十六烷基三甲基溴化铵;然后4℃、10000rpm离心10min,收集沉淀,用无水乙醇洗涤沉淀,80℃真空干燥48h,即得巯基功能化的介孔氧化硅;
(2)取步骤(1)所得0.3g巯基功能化的介孔氧化硅,用60mL无水乙醇溶解,然后逐滴加入1mL(3-氨丙基)三甲氧基硅烷,室温搅拌24h,然后用无水乙醇离心洗涤,真空干燥得到氨基功能化的介孔氧化硅;
(3)取100mL三颈圆底烧瓶,一口插反口塞,反口塞上插针头用作出气口,一口通入氮气,一口密闭;烧瓶中先加入3~4mL无水甲苯,氮气吹扫5min,然后向所述三颈圆底烧瓶中加入0.3g硫辛酸,再加入20mL无水甲苯使其充分溶解,将0.26gN,N’-羰基二咪唑用3mL无水氯仿溶解,加入到所述三颈圆底烧瓶中;混合物在室温氮气氛围下搅拌1h,作为A液,将A液转移到恒压漏斗中;然后,向所述三颈圆底烧瓶中加入步骤(2)所得0.25g氨基功能化的介孔氧化硅,用30mL无水甲苯分散,用恒压漏斗逐滴将A液加入所述三颈圆底烧瓶中,在室温氮气氛围下反应6h,然后关闭氮气,室温反应过夜;最后用无水乙醇离心洗涤,真空干燥,即得硫辛酸功能化的介孔氧化硅纳米材料。
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