CN110878203A - 一种纳米材料及其制备方法和应用 - Google Patents
一种纳米材料及其制备方法和应用 Download PDFInfo
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- CN110878203A CN110878203A CN201911171829.7A CN201911171829A CN110878203A CN 110878203 A CN110878203 A CN 110878203A CN 201911171829 A CN201911171829 A CN 201911171829A CN 110878203 A CN110878203 A CN 110878203A
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Abstract
本发明公开了一种纳米材料及其制备方法和应用。该方法是在纳米尺度下通过精确控制纳米颗粒表面反应的进行及配体修饰,实现该种具有特殊表面修饰纳米颗粒的可控制备,并可精细调控和优化该纳米材料的物理和化学性质。该纳米材料具有良好的生物相容性和无毒性,在水溶液中具有高度分散性,在药物研发、靶向治疗、生物传感及活体成像等许多领域具备广泛的应用前景,如其具备的极高的生物光敏性,在和生物分子或细胞作用后能够迅速地发生荧光的蓝移,在生物传感领域具有极大的应用潜力。
Description
技术领域
本发明涉及纳米材料领域,具体涉及一种纳米材料及其制备方法和应用。
背景技术
半导体纳米材料凭借其特别的生物无毒性,生物相容性在生物医药、靶向治疗、生物传感及活体成像等诸多领域中具有极大的应用前景。在半导体纳米晶首次应用在生物成像中的荧光探针上后,其他生物应用诸如DNA芯片技术、免疫荧光测定法和细胞生物动物学中也开始广泛应用半导体纳米晶。作为一种新的无同位素标记的具有极大潜力的荧光材料,半导体纳米晶在科学界以及生物工业界赢得了广泛的认同。生物应用所关注的性能是高亮度,光稳定性以及荧光发射的可调性。对于双光子共聚焦显微镜和深层成像应用,半导体纳米晶由于它较大的双光子吸收截面也被证明是绝佳的荧光探针材料。但是当与超灵敏显微镜技术相结合时,半导体纳米晶显示出了它们真正的潜力—使细胞转化的的可视化下降到分子水平。半导体纳米晶较强的光物理性质能够从空间、时间到结构上满足对于所有长度或尺寸(从整个生物体到纳米级别分辨率的单一探针)严苛的要求。
荧光半导体纳米材料通常通过胶体化学的方式在非极性溶剂中合成。对于生物应用通常需要额外的化学修饰使得纳米材料溶解在水溶液中。这可以通过表面活性剂交换,例如一种主要由质量作用驱动的过程,其中天然的疏水表面配体被双功能性的亲水配体取代,或者通过多功能的两亲性涂层将最初的疏水纳米材料表面隔离。但这样通常会引入复杂的有机物并引起在纳米材料表面有机的聚合。对纳米材料表面进行氨基或羧基的修饰也能够使得纳米材料在水溶液中的溶解性大大增加,但是氨基表面配体通常会带来较高的细胞毒性,而羧基表面修饰的纳米颗粒则有着荧光量子产率低,合成副反应多且不受控等缺点。
发明内容
鉴于目前的方法和体系很难直接将半导体纳米颗粒和生物分子进行连接同时保留纳米材料的光物理性质。因此,本发明公开一种二次表面功能化方法合成表面由共价键体系修饰的纳米材料,可用于生物活体成像及探测。通过这种方法可以将纳米材料和生物分子及生物体上的活性位点稳固结合,通过这种方法结合后纳米材料的光物理性质发生显著变化,并且大大提高了纳米材料在水系介质中的分散性。该方法为生物分子及化合物的纳米材料负载提供了非常有吸引力的选择,并且在生物成像及探测等领域具有非常大的应用潜力。具体技术方案如下:
一种纳米材料的制备方法,包括以下步骤:
1)将烷基化合物水解,制得纳米粒子前驱体;
2)通过固相还原反应将纳米粒子前驱体还原,制得包裹纳米粒子的基底复合物;
3)通过蚀刻反应去除基底复合物中的基底,制得表面具有活性端基修饰的纳米粒子I,所述蚀刻反应中的蚀刻液为乙醇、水和氢氟酸的混合液;
4)将表面具有活性端基修饰的纳米粒子I与不饱和醛或不饱和羧酸混合反应,并通过调控外界刺激响应,制得表面具有醛基修饰的纳米粒子II或具有羧基修饰的纳米粒子III。
其中,步骤4)后还包括步骤5),步骤5)的过程为以下任一种:
过程1:将纳米粒子II与一级胺混合反应,并通过调控外界刺激响应,制得纳米粒子IV;
过程2:在酸存在的条件下,将纳米粒子III与一级胺混合反应,并通过调控外界刺激响应,制得纳米粒子V。本发明首次采用二次双层功能化的表面配体修饰方法,在单层醛基功能团的基础上利用“席夫碱”合成方法制备出具有亚胺键结构的双层表面功能化配体修饰的纳米粒子。显著地影响了纳米粒子的生物应用及光物理性质。该方法简单高效,不需要苛刻的反应条件即可完成。通过这种策略可以使纳米粒子与具有活性氨基位点的生物分子相连接,可以负载药物进行药物运输及靶向治疗。
上述烷基化合物为硅烷化合物、锗烷化合物、硅-锗烷化合物中的至少一种,优选地,所述硅烷化合物为三甲氧基硅烷、四甲氧基硅烷、三乙氧基硅烷、四乙氧基硅烷、甲基三甲氧基硅烷、乙基三甲氧基硅烷中的至少一种。更为优选地的,硅烷化合物选择三甲氧基硅烷,水解更高效安全,形成的聚合物网络更致密,形成的硅纳米颗粒不含杂质。
所述不饱和羧酸为丙烯酸、戊烯酸、庚烯酸、十一烯酸中的至少一种;所述不饱和醛为丙烯醛、戊烯醛、庚烯醛、十一烯醛中的至少一种。使用具有双功能团的不饱和醛或羧酸作为配体,通过自由基引发共价键的断裂和形成合成表面醛基封端或羧基封端的纳米颗粒,使二次双层功能化得以实现,利用醛基或羧基表面修饰的纳米粒子进行细胞成像,可以通过显著的荧光颜色变化来判断纳米粒子是否进入细胞内部。
优选地,所述一级胺为丙胺、丁胺、苯乙胺、苄胺、烯丙基胺、甘氨酸、苏氨酸、精氨酸、半胱氨酸、组氨酸中的至少一种。
优选地,步骤4)和步骤5)的过程1中所述的外界刺激响应分别独立为光刺激、温度刺激、酸碱刺激、化学引发、催化刺激、电场刺激、磁场刺激、超声刺激和生物功能分子刺激中的至少一种;步骤5)的过程2中所述的外界刺激响应为光刺激、温度刺激、化学引发、催化刺激、电场刺激、磁场刺激、超声刺激、生物功能分子刺激中的至少一种。
当外界刺激响应为光刺激时,光刺激所采用的光源的波长为350~650nm,功率为1~100W;所述外界刺激响应为温度刺激时,温度刺激的温度为25~200℃;所述外界刺激为酸碱刺激时,所述酸碱刺激的pH为0.1~4或10~13;所述外界刺激为化学引发或催化刺激时,引发剂或催化剂为偶氮二异庚腈、偶氮二异丁腈、过氧化苯甲酰、过氧化环己酮、叔丁基过氧化氢、钯、铑中的至少一种。
其中,以烷基化合物为硅烷化合物作为实施方式时,步骤1)的具体过程为:在惰性气体的保护下,将硅烷化合物与甲醇、水和硝酸混匀搅拌至出现凝胶乃至完全凝固后,陈化2天后,在真空环境下干燥24h,制得富硅氧烷聚合物块状固体颗粒,即纳米粒子前驱体。步骤1)中水解反应的条件为:搅拌时间为2min~12h,pH为0.1~4或10~13;反应时间为30s~36h;反应温度为0~50℃。
步骤2)的具体过程为:将纳米粒子前驱体置于氢气和惰性气体的混合气体中加热进行还原,制得含有硅纳米颗粒的无定形氧化硅复合物,即包裹纳米粒子的基底复合物。步骤2)中的固相还原反应在氢气和惰性气体的混合气体中进行,反应温度为700~1400℃,反应时间为30min~24h,氢气的体积分数为1~10%。
步骤3)的具体过程为:将包裹纳米粒子的基底复合物研磨至60~120nm,然后分散于蚀刻液中,反应10min~2h后用甲苯萃取出氢键表面修饰的纳米粒子,离心去除甲苯、水和乙醇,制得表面具有活性端基修饰的纳米粒子Ⅰ。步骤3)中乙醇、水和氢氟酸的体积比为1:(1~3):1。
步骤4)的具体过程为:在惰性气体的保护下,将表面具有活性端基修饰的纳米粒子Ⅰ与极性有机溶剂混合,然后与化学引发或催化剂以及具有羰基的不饱和醛或具有羰基的不饱和酸混合,加热反应,干燥后制得表面具有醛基修饰的纳米粒子II或具有羧基修饰的纳米粒子Ⅲ;步骤4)中加热反应的温度为50℃,反应时间为3天,极性有机溶剂为甲醇、乙醇、丙酮、氯仿和乙腈中的至少一种。本步骤中优选使用偶氮二异庚腈作为化学引发剂,其结构中的-N=N-双键相比其他引发剂更容易断裂形成自由基,使得反应体系可以在较低的温度发生(40-60℃),大多数氢化反应都需要在很高的温度下(比如190度),或者在较高温度下(>60℃)使用贵金属催化剂或者低效率引发剂和复杂的光催化设备才能驱动反应的进行,这大大地限制了配体和溶剂的选择(高沸点)。
步骤5)的过程1的具体过程为:将纳米粒子II分散于有机溶剂中,加入一级胺,加热反应,制得纳米粒子IV;步骤5)的过程2的具体过程为:将纳米粒子III分散于有机溶剂中,加入一级胺,在酸的条件下加热反应,pH为0.1~4,制得纳米粒子V。
优选地,步骤5)的过程2中的酸为无机酸或乙酸。
根据上述的制备方法制得形貌为球状、棒状、板状、碟状或锥状的用于生物活体成像及探测的纳米材料,其粒径为1nm~1μm,可应用在药物研发、靶向治疗、生物传感及活体成像领域。
本发明的有益效果为:本发明是在纳米尺度下通过对纳米粒子表面进行精细的配体和基团调控及构筑,首先通过引入能与纳米粒子进行共价连接的双功能团配体,再利用配体的另一侧功能团,通过精确控制不同反应的进行实现和不同种类的氨基化合物的连接。该方法合成的功能化纳米粒子在生物医药开发,靶向治疗和诊断以及生物成像及传感等领域具备极高的应用前景,例如其具备的极高的生物光敏性,在和生物分子或细胞作用后能够迅速地发生荧光的蓝移,在生物传感领域具有极大的应用潜力。
附图说明
图1为纳米粒子Ⅱ的透射电镜照片;
图2为纳米粒子Ⅲ的透射电镜照片;
图3为纳米粒子IV的透射电镜照片;
图4为纳米粒子I、Ⅱ、Ⅲ的红外光谱图;
图5为纳米粒子Ⅲ的荧光光谱;
图6为不同种氨基酸修饰的纳米粒子Ⅱ的红外光谱图;
图7为纳米粒子Ⅱ和不同种氨基酸修饰的纳米粒子Ⅱ的紫外-可见吸收光谱(a)、稳态荧光光谱(b)以及它们各自的荧光衰减寿命(c,d)结果图;
图8为纳米粒子Ⅱ加入至293T肾脏细胞和U2OS骨肉瘤细胞中孵育后的细胞成像图。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整的描述,以充分地理解本发明的目的、方案和效果。需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互组合。
实施例1:制备表面具有胺共价连接活性的纳米粒子
(1)制备表面具有醛基修饰的硅纳米粒子CHO-Si(纳米粒子Ⅱ):将三甲氧基硅烷(4mL)、甲醇(5mL)、水(5mL)和硝酸(50mmol)混匀搅拌2分钟,当体系出现凝胶乃至完全凝固后,停止搅拌。反应物陈化两天后,将反应物在真空环境下干燥24小时后取出。将干燥完全的富硅醇干凝胶置于管式炉内,在氢气和氩气混合气氛下,1100℃加热1小时。待冷却后用玛瑙研钵预磨,再加入球磨机进行球磨。所得淡黄色粉末分散于水、乙醇和氢氟酸的混合蚀刻溶液中。待蚀刻反应进行一小时后,用甲苯萃取出氢键表面修饰的纳米粒子I(其红外光谱图如图4中的I所示),将萃取液反复离心后去除甲苯上清液以及少量的水和乙醇,然后再重新分散在甲苯中,和偶氮二异丁腈(0.01g)、十一烯醛(100mmol)混匀加热50℃反应3天,将反应体系旋蒸干燥后,所得固体即为表面具有醛基修饰的纳米粒子Ⅱ,记为CHO-Si。
该纳米粒子Ⅱ具有胺反应活性的醛基功能团修饰,形貌为球形,尺寸为3nm~5nm,分子量为1200-3000之间(由图1的针对纳米粒子Ⅱ的TEM图估测出,左下角黑色部分即为图中方框部位的选区电子衍射能够实现所选区域的形貌观察和电子衍射的微观对应,得到了所选区域为硅纳米晶体的特征电子衍射),具有600-1000nm的红光-近红外荧光发射范围(由图7中的b,即A-SiNCs(Aldehyde silicon nanocrystals,也就是CHO-Si)的荧光光谱可以看出),其红外光谱图如图4的II所示,红外光谱图充分地反映了该硅纳米颗粒表面官能团的发展和变化过程,展示了该种纳米颗粒从氢键钝化经氢化反应通过硅-碳共价键的形成得到第一层醛基封端的表面配体层,再通过“席夫碱”的合成策略通过配体的醛基和不同种类的氨基化合物醛胺缩合得到C=N双键结合的第二层表面配体层,通过这种方法可以比较容易地利用某些生物分子例如氨基酸,多肽以及抗体上的氨基活性位点与纳米颗粒进行直接的有效连接,不仅可以有效提高纳米颗粒的生物相容性,同时也能改变纳米颗粒的发光特性。
(2)制备表面具有羧基修饰的硅纳米粒子COOH-Si(纳米粒子Ⅲ):将三甲氧基硅烷(10mL)、甲醇(10mL)、水(10mL)和硝酸(90mmol,10mL)混匀搅拌5分钟,当体系出现凝胶乃至完全凝固后,停止搅拌。反应物陈化两天后,将反应物在真空环境下干燥24小时后取出。将干燥完全的富硅醇干凝胶置于管式炉内,在氢气和氩气混合气氛下,1100℃加热1小时。待冷却后用玛瑙研钵预磨,再加入球磨机进行球磨。所得淡黄色粉末分散于水、乙醇和氢氟酸的混合蚀刻溶液中。待蚀刻反应进行一小时后,用甲苯萃取出氢键表面修饰的纳米粒子,将萃取液反复离心后去除甲苯上清液以及少量的水和乙醇,然后再重新分散在甲苯中,和偶氮二异丁腈(0.01g)、十一烯酸(100mmol)混匀加热50℃反应3天,将反应体系旋蒸干燥后,所得固体即为表面具有羧基修饰的纳米粒子Ⅲ,记为COOH-Si。
该纳米粒子表面修饰有胺反应活性的羧基功能团,形貌为球形,尺寸为3nm~5nm,分子量为1500-4000之间(由图2的针对纳米粒子Ⅲ的TEM图估测出,左下角黑色部分即为大图方框部位的选区电子衍射能够实现所选区域的形貌观察和电子衍射的微观对应,得到了所选区域为硅纳米晶体的特征电子衍射),具有600-1200nm的红光-近红外区域荧光发射范围(由图5的荧光光谱可以看出)。
实施例2:制备表面具有亚胺键共价连接的纳米粒子IV
将实施例1中制得的醛基功能团修饰的硅纳米粒子CHO-Si(纳米粒子Ⅱ)超声良好分散于溶剂氯仿中,并移入配有聚四氟乙烯塞子的耐压管中,加入具有活性伯胺基团的丁胺0.2mol,在85~120℃之间加热反应24~36h。体系的红色荧光逐渐变淡,显示呈现紫红色的荧光,最后反应结束时呈现出蓝色的荧光。将整个体系进行离心处理,取上清液旋蒸干燥去除溶剂后重新将纳米粒子分散于超纯水中,即得到表面具有亚胺键共价连接的纳米粒子IV,其透射电镜图如图3所示(左下角黑色部分即为大图方框部位的选区电子衍射能够实现所选区域的形貌观察和电子衍射的微观对应,得到了所选区域为硅纳米晶体的特征电子衍射),形貌为球形,尺寸为3nm~5nm,其红外光谱图如图4中的Ⅲ所示。
实施例3:制备表面具有酰胺键共价连接活性的纳米粒子V
将实施例1制得的羧基功能团修饰的硅纳米粒子COOH-Si(纳米粒子Ⅲ)超声良好分散于溶剂乙腈中,并移入配有聚四氟乙烯塞子的耐压管中,加入苯乙胺0.2mol,在25~120℃之间加热反应24~48h。体系的红色荧光逐渐变淡,显示呈现紫红色的荧光,最后反应结束时呈现出蓝色的荧光。将整个体系进行离心处理,取上清液旋蒸干燥去除溶剂后重新将纳米粒子分散于超纯水中,即得到表面具有酰胺键共价连接的纳米粒子V。
实施例4:醛基修饰的硅纳米粒子(纳米粒子Ⅱ)的性质表征
将不同种(Gly甘氨酸、L-thr苏氨酸、L-cys半胱氨酸和L-his组氨酸)氨基酸与醛基修饰的硅纳米粒子(纳米粒子Ⅱ)直接进行连接(纳米粒子IV),对产物进行红外光谱分析,结果如图6所示,图6中从上至下分别为Gly甘氨酸、L-thr苏氨酸、L-cys半胱氨酸和L-his组氨酸修饰的硅纳米粒子,从图6中可以看出氨基酸成功连接在纳米粒子Ⅱ上了。
对实施例1制得的醛基修饰硅纳米粒子(纳米粒子Ⅱ)A-SiNCs和上述氨基酸修饰的纳米粒子Ⅱ产物进行紫外可见光谱分析、荧光光谱分析和荧光寿命分析,结果如图7所示,图7中a为醛基修饰的硅纳米粒子A-SiNCs和四种不同的氨基酸修饰的纳米粒子Ⅱ产物的紫外可见光吸收光谱,体现出硅半导体的特征吸收带,说明他们的吸收都是硅的本征吸收,荧光的表现也同样来源于硅自身,不是配体或氨基化合物的吸收和荧光。图7中b为醛基修饰的硅纳米粒子A-SiNCs和四种不同的氨基酸修饰的纳米粒子Ⅱ产物的稳态荧光光谱,表现为在通过在硅纳米粒子表面进行亚胺键的构筑以及功能化后其荧光发射出现了显著的蓝移。图7中的c和d为醛基修饰的硅纳米粒子A-SiNCs的荧光寿命,从微秒级到纳秒级的转变,说明载流子和电子空穴的复合变快了,提高了发光效率,说明在亚胺功能化之后其电子的传输和复合的速度都得到了提高。
实施例5:醛基修饰的硅纳米粒子(纳米粒子Ⅱ)在生物成像中的应用
取293T肾脏细胞和U2OS骨肉瘤细胞置于细胞培养基中,将实施例1制得的醛基修饰硅纳米粒子(纳米粒子Ⅱ)分散到水中(现有的纳米粒子在水中的分散都很差,但是本发明制得的纳米粒子在水中的分散性很好),然后滴加至细胞培养基中,孵育12h,使用荧光显微镜进行拍摄,然后再孵育12h,然后通过荧光显微镜再次进行拍摄得到细胞成像图,如图8所示(a为孵育12h时293T肾脏细胞的细胞成像图,b为孵育24h时293T肾脏细胞的细胞成像图;c为孵育12h时U2OS骨肉瘤细胞的细胞成像图,b为孵育24h时U2OS骨肉瘤细胞的细胞成像图),可以观察到纳米颗粒在进入细胞前(孵育12h时)仍然是呈现出红色荧光,在进入细胞之后(孵化24h时)显现蓝色荧光,这对于纳米颗粒进行药物运输、诊断成像都具有十分有潜力的应用前景。
以上结果表明,本发明能制备得到具有不同表面功能团构筑的纳米粒子,通过在纳米尺度下的结构设计来调控纳米粒子的光物理特性以及生物活性,使得该纳米粒子材料在生物医药,临床及成像治疗等领域具有良好的应用前景。
Claims (10)
1.一种纳米材料的制备方法,其特征在于,包括以下步骤:
1)将烷基化合物水解,制得纳米粒子前驱体;
2)将纳米粒子前驱体还原,制得包裹纳米粒子的基底复合物;
3)通过蚀刻反应去除基底复合物中的基底,制得表面具有活性端基修饰的纳米粒子I;
4)将表面具有活性端基修饰的纳米粒子I与不饱和醛或不饱和羧酸混合反应,并通过调控外界刺激响应,制得表面具有醛基修饰的纳米粒子II或羧基修饰的纳米粒子III,即所述纳米材料。
2.根据权利要求1所述的制备方法,其特征在于,步骤4)后还包括步骤5),步骤5)的过程为以下任一种:
过程1:将纳米粒子II与一级胺混合反应,并通过调控外界刺激响应,制得纳米粒子IV;
过程2:在酸存在的条件下,将纳米粒子III与一级胺混合反应,并通过调控外界刺激响应,制得纳米粒子V。
3.根据权利要求2所述的制备方法,其特征在于,所述烷基化合物为硅烷化合物、锗烷化合物、硅-锗烷化合物中的至少一种;所述不饱和羧酸为丙烯酸、戊烯酸、庚烯酸、十一烯酸中的至少一种;所述不饱和醛为丙烯醛、戊烯醛、庚烯醛、十一烯醛中的至少一种;
优选地,所述硅烷化合物为三甲氧基硅烷、四甲氧基硅烷、三乙氧基硅烷、四乙氧基硅烷、甲基三甲氧基硅烷、乙基三甲氧基硅烷中的至少一种。
4.根据权利要求3所述的制备方法,其特征在于,所述一级胺为丙胺、丁胺、苯乙胺、苄胺、烯丙基胺、甘氨酸、苏氨酸、精氨酸、半胱氨酸、组氨酸中的至少一种。
5.根据权利要求2所述的制备方法,其特征在于,步骤4)和步骤5)的过程1中所述的外界刺激响应分别独立为光刺激、温度刺激、酸碱刺激、化学引发、催化刺激、电场刺激、磁场刺激、超声刺激、生物功能分子刺激中的至少一种;步骤5)的过程2中所述的外界刺激响应为光刺激、温度刺激、化学引发、催化刺激、电场刺激、磁场刺激、超声刺激、生物功能分子刺激中的至少一种。
6.根据权利要求5所述的制备方法,其特征在于,所述外界刺激响应为光刺激时,光刺激所采用的光源的波长为350~650nm,功率为1~100W;所述外界刺激响应为温度刺激时,温度刺激的温度为25~200℃;所述外界刺激为酸碱刺激时,所述酸碱刺激的pH为0.1~4或10~13;所述外界刺激为化学引发或催化刺激时,引发剂或催化剂为偶氮二异庚腈、偶氮二异丁腈、过氧化苯甲酰、过氧化环己酮、叔丁基过氧化氢、钯、铑中的至少一种。
7.根据权利要求6所述的制备方法,其特征在于,步骤1)中,将烷基化合物与醇类化合物、水和无机酸混合,在惰性气体的保护下进行水解;
步骤2)中,将纳米粒子前驱体置于氢气和惰性气体的混合气体中进行还原;
步骤3)中,所述蚀刻反应中的蚀刻液为乙醇、水和氢氟酸的混合液;
步骤4)在惰性气体的保护下进行。
8.根据权利要求7所述的制备方法,其特征在于,蚀刻液中的乙醇、水和氢氟酸的体积比为1:(1~3):1。
9.一种纳米材料,其特征在于,由权利要求1至8任一项所述的制备方法制得,其形貌为球状、棒状、板状、碟状或锥状,其粒径为1nm~1μm。
10.权利要求9所述的纳米材料在药物研发、靶向治疗、生物传感及活体成像领域中的应用。
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