CN109724949B - 一种用于肿瘤标志物可视化检测的柔性杂化膜的制备方法 - Google Patents
一种用于肿瘤标志物可视化检测的柔性杂化膜的制备方法 Download PDFInfo
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Abstract
本发明属于柔性杂化膜材料和可视化检测探针的制备技术领域，具体涉及一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法。采用超声和溶剂热制备金属离子掺杂黑磷量子点M‑BPQDs，在其表面生长介孔SiO2和氨基化改性，连接羧基化单链DNA1，受体分子进入孔内，单链DNA2适体与DNA1因碱基互补结合封装受体于孔内，制得M‑BPQDs探针。DNA1终端‑SH与聚异丁烯酸甲酯‑聚酰亚胺‑金纳米粒层层组装复合薄膜以Au‑S键结合，连接薄膜与探针构筑柔性杂化膜。与现有技术相比，本发明柔性杂化膜的制备简单，成本低，灵敏度高，当含有肿瘤标志物的生物流体样品滴加到杂化膜上，在近红外光激发下构建上转换发光强度与标志物浓度之间的联系，实现标志物可视化检测。
Description
技术领域：
本发明属于柔性杂化膜材料和可视化检测探针的制备技术领域，具体涉及一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其制备的柔性杂化膜可用于生物流体样品中肿瘤标志物的上转换发光可视化检测。
背景技术：
近年来，量子点的上转换发光引起了广泛的研究兴趣。量子点具有较高的双光子吸收能力，表现出强烈的反斯托克斯发射，即上转换发光或双光子荧光。在生物和医学应用领域，量子点的上转换发光具有显著优于其常规下转换荧光的特点。上转换发光的激发波长(如近红外光，其能量低但穿透力强)大于其发射波长(如可见光，其能量高但穿透力弱)，故可避免生物自体荧光和背景荧光的干扰，提高了上转换发光检测和成像分析的敏感度与分辨率。量子点的上转换发光在细胞与活体的深组织成像、生化分析、光动力学治疗及能量转换等领域展现出广阔的应用前景。尤其在生物医学领域，量子点的上转换发光将会逐步取代常规下转换荧光，发展为更高效的光致发光分析方法。
当前，肿瘤标志物检测技术主要包括两大类：即免疫分析和生物传感器。免疫分析涉及酶联免疫催化反应，其存在检测成本高，操作复杂，特定染料标记等问题。近年来，科研人员发展了不同类型的光学和电化学生物传感器，但在临床实践中发展简单、快速和高效检测肿瘤标志物的方法仍然是一项重要的研究课题。本发明利用可见区上转换发光在纳米生物分析中独特的优势，采用近红外光激发量子点产生可见区上转换发光，基于上转换发光颜色渐变来实现对目标物的可视化检测，构建新型的上转换发光柔性杂化膜，实现对肿瘤标志物的简单、精准、快速、高灵敏、定量和可视化检测。本发明的肿瘤标志物检测方法在肿瘤早期精准诊断、生物成像、医疗器械开发等关键技术领域具备广阔的应用前景。
张群社等公开了一种含有上转换发光量子点的晶体硅的制备方法(发明专利公开号CN102832267A)；李佳苏等将稀土离子掺杂的上转换发光纳米粒嵌入聚苯乙烯纤维中制备复合纤维网毡薄膜(发明专利公开号CN105063889A)；邓胜松等设计了一种白色发光的上转换纳米颗粒及其同时多组分肿瘤标志物检测的试纸条(发明专利公开号CN107748147A)；Jin等报道了基于量子点的上转换发光探针用于生物流体中多巴胺的检测(Hui Jin,RijunGui,ZonghuaWang,et al.Two-photon excited quantum dots with compact surfacecoatings ofpolymer ligands used as an upconversion luminescent probe fordopamine detection in biological fluids.Analyst 2015,140,2037)；Jin等制备了基于双量子点的探针用于比率上转换发光检测一氧化氮(Hui Jin,Rijun Gui,Jie Sun,etal.Ratiometric two-photon excited photoluminescence of quantum dots triggeredby near-infrared-light for real-time detection ofnitric oxide release insitu.Anal.Chim.Acta 2016,922,48)。
尽管先前研究涉及了量子点和稀土离子掺杂纳米粒的上转换发光探针用于化学和生物检测，涉及基于稀土离子掺杂纳米粒构建上转换发光薄膜，截至目前，尚未有基于上转换发光量子点构建柔性杂化膜，用于肿瘤标志物可视化检测的国内外文献和专利的报道。本发明设计了新型金属离子掺杂黑磷量子点的上转换发光探针，将其与柔性基底结合以构筑柔性杂化膜，微量滴加生物流体样品于杂化膜表面，在近红外光激发下，样品中肿瘤标志物引发探针的可见区上转换发光强度有规律变化，实现对肿瘤标志物的可视化检测。
发明内容：
本发明的目的在于克服上述现有技术存在的缺陷，设计一种方法简单、成本低、灵敏度高的用于肿瘤标志物可视化检测的上转换发光柔性杂化膜。
为实现上述目的，本发明涉及的一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法包括以下步骤：
1.一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其特征在于，该方法具体包括以下步骤：
(1)将块状黑磷晶体研磨成粉末，加入溶解了金属盐的极性溶剂中，采用探头和浴池超声剥离出黑磷纳米片，加入硫醇配体，通过超声辅助溶剂热制备金属离子掺杂的黑磷量子点M-BPQDs。
(2)依据法在M-BPQDs表面生长介孔二氧化硅mSiO2，然后进行-NH2功能化改性制得M-BPQDs/mSiO2-NH2，再与单链DNA1(HS-DNA1-COOH)通过羧-胺偶联反应结合，制备M-BPQDs/mSiO2@DNA1。
(3)电子受体分子进入mSiO2孔道内完成受体分子负载，添加特异性适体单链DNA2与DNA1碱基互补配对形成双螺旋结构，封装受体分子，得到纳米杂化物载体探针M-BPQDs/mSiO2@DNA1-DNA2@受体。
(4)以聚异丁烯酸甲酯PMMA为层状基底，表面黏合一层聚酰亚胺PI，电极夹固定PMAA-PI薄膜浸没在电解液中。以KCl饱和甘汞电极为参比，铂丝电极为辅助，PMAA-PI薄膜为工作电极，在电解液中加入HAuCl4，循环伏安扫描，在薄膜表面电化学还原生成金纳米颗粒AuNPs制得PMMA-PI-AuNPs复合薄膜。
(5)探针上DNA1(HS-DNA1-COOH)末端-SH与薄膜上AuNPs通过Au-S键结合，将薄膜与探针连接在一起构筑成柔性杂化膜。当生物流体样品中含有肿瘤标志物时，将其滴加至该杂化膜上，在近红外光激发下观察浸润杂化膜的上转换发光颜色变化，实现对肿瘤标志物的可视化检测。
步骤(1)中所述的金属离子为Ag+,Mn2+,Co2+,Ni2+等，M-BPQDs为1～5nm；
步骤(2)中所述的表面mSiO2厚度为50～200nm；
步骤(3)中所述的受体为5-氟尿嘧啶、多巴胺、芦丁、槲皮素等，DNA2是癌胚抗原、甲胎蛋白、糖类抗原、前列腺特异性抗原等标志物的单链DNA适体；
步骤(4)中所述的PMMA厚度为50～100nm，PI厚度为1～2μm，AuNPs厚度为10～100nm；
步骤(5)中所述的上转换发光发射峰波长为500～600nm，肿瘤标志物浓度为1nM～1mM。
本发明以硫醇为稳定剂，超声和溶剂热法制备了新型金属离子掺杂黑磷量子点M-BPQDs，在其表面生长介孔SiO2和氨基化改性，链接一端羧基化的单链DNA1，受体分子进入孔道，单链DNA2与DNA1因碱基互补配对结合封装受体于孔道内，制得基于M-BPQDs的纳米载体探针。DNA1另一端-SH与聚异丁烯酸甲酯-聚酰亚胺-金纳米颗粒层层组装的PMMA-PI-AuNPs复合薄膜上AuNPs通过Au-S键结合，使薄膜与探针连接在一起构筑成柔性杂化膜。DNA2是特定肿瘤标志物的单链适体，当生物流体样品中含该标志物时，将样品微量滴加到杂化膜表面，标志物与DNA2特异性结合使DNA2竞争性地挣脱开DNA1，引起载体孔道内受体释放，受体远离M-BPQDs，其光诱导的电子转移受抑制。在近红外光激发下，M-BPQDs可见区上转换发光随着标志物浓度的增大而逐渐恢复，实现对该标志物的上转换发光可视化检测之目的。
附图说明：
图1.金属离子掺杂黑磷量子点M-BPQDs的制备过程及原理示意图；
图2.基于M-BPQDs的上转换发光柔性杂化膜的制备过程及其用于肿瘤标志物可视化检测的原理示意图。
具体实施方式：
下面结合附图并通过具体实施例对本发明进行详细说明。
实施例1：
本发明涉及的一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其制备过程与检测原理如图1和2所示，具体制备步骤如下：
将块状的黑磷晶体研磨成粉末，加入溶解了硝酸银的N-甲基吡咯烷酮NMP中，采用探头和浴池超声剥离出黑磷纳米片，加入巯基丙酸配体，通过超声辅助溶剂热制备平均尺寸为2nm的Ag-BPQDs。依据法在Ag-BPQDs表面生长50nm厚度的mSiO2，然后进行-NH2功能化改性制得Ag-BPQDs/mSiO2-NH2，再与单链DNA1(HS-DNA1-COOH)通过羧-胺偶联结合，制备Ag-BPQDs/mSiO2@DNA1。5-氟尿嘧啶5FU进入mSiO2孔道内，完成受体分子负载，添加特异性适体单链DNA2与DNA1因碱基互补配对形成双螺旋结构封装受体分子，制得纳米杂化物载体探针Ag-BPQDs/mSiO2@DNA1-DNA2@5FU。以聚异丁烯酸甲酯PMMA为层状基底～80nm，表面黏合一层～1.6μm聚酰亚胺PI，电极夹固定PMAA-PI薄膜浸没在电解液中。以KCl饱和甘汞电极为参比电极，铂丝电极为辅助电极，PMAA-PI薄膜为工作电极，在电解液中加入10mM的HAuCl4，循环伏安扫描50圈，在薄膜表面电化学还原沉积金纳米颗粒AuNPs其层厚度～50nm，最终制得PMMA-PI-AuNPs复合薄膜。探针上DNA1(HS-DNA1-COOH)尾端-SH与薄膜上AuNPs通过Au-S键结合，将薄膜与探针连接在一起构筑成柔性杂化膜。当人血清样品中含癌胚抗原时，将微量样品滴加至该杂化膜上，在800nm和5mW近红外光激发下，观察浸润杂化膜的可见区～550nm橘红色上转换发光的强弱变化，随着样品中癌胚抗原浓度从10nM增大至10μM，Ag-BPQDs橘红色上转换发光逐渐增强，实现对人血清样品肿瘤标志物癌胚抗原的上转换发光可视化检测。
实施例2：
将块状的黑磷晶体研磨成粉末，加入溶解了硝酸镍的N-甲基吡咯烷酮NMP中，采用探头和浴池超声剥离出黑磷纳米片，加入巯基丙酸配体，通过超声辅助溶剂热制备平均尺寸为3nm的Ni-BPQDs。依据法在Ni-BPQDs表面生长100nm厚度的mSiO2，然后进行-NH2功能化改性制得Ni-BPQDs/mSiO2-NH2，再与单链DNA1(HS-DNA1-COOH)通过羧-胺偶联结合，制备Ni-BPQDs/mSiO2@DNA1。多巴胺DA进入mSiO2孔道内，完成受体分子负载，添加特异性适体单链DNA2与DNA1因碱基互补配对形成双螺旋结构封装受体分子，制得纳米杂化物载体探针Ni-BPQDs/mSiO2@DNA1-DNA2@DA。以聚异丁烯酸甲酯PMMA为层状基底～50nm，表面黏合一层～1.5μm聚酰亚胺PI，电极夹固定PMAA-PI薄膜浸没在电解液中。以KCl饱和甘汞电极为参比电极，铂丝电极为辅助电极，PMAA-PI薄膜为工作电极，在电解液中加入10mM的HAuCl4，循环伏安扫描50圈，在薄膜表面电化学还原沉积金纳米颗粒AuNPs其层厚度～40nm，最终制得PMMA-PI-AuNPs复合薄膜。探针上DNA1(HS-DNA1-COOH)尾端-SH与薄膜上AuNPs通过Au-S键结合，将薄膜与探针连接在一起构筑成柔性杂化膜。当人尿液样品中含甲胎蛋白时，将微量样品滴加至该杂化膜上，在800nm和5mW近红外光激发下，观察浸润杂化膜的可见区～540nm橘红色上转换发光的强弱变化，随着样品中甲胎蛋白浓度从10nM增大至100μM，Ni-BPQDs橘红色上转换发光逐渐增强，实现对人尿液样品肿瘤标志物甲胎蛋白的上转换发光可视化检测。
实施例3：
将块状的黑磷晶体研磨成粉末，加入溶解了硝酸钴的N-甲基吡咯烷酮NMP中，采用探头和浴池超声剥离出黑磷纳米片，加入巯基丙酸配体，通过超声辅助溶剂热制备平均尺寸为5nm的Co-BPQDs。依据法在Co-BPQDs表面生长150nm厚度的mSiO2，然后进行-NH2功能化改性制得Co-BPQDs/mSiO2-NH2，再与单链DNA1(HS-DNA1-COOH)通过羧-胺偶联结合，制备Co-BPQDs/mSiO2@DNA1。芦丁LU进入mSiO2孔道内，完成受体分子负载，添加特异性适体单链DNA2与DNA1因碱基互补配对形成双螺旋结构，以执行受体分子封装，制得纳米杂化物载体探针Ni-BPQDs/mSiO2@DNA1-DNA2@LU。以聚异丁烯酸甲酯PMMA为层状基底～60nm，表面黏合一层～1.8μm聚酰亚胺PI，电极夹固定PMAA-PI薄膜浸没在电解液中。以KCl饱和甘汞电极为参比电极，铂丝电极为辅助电极，PMAA-PI薄膜为工作电极，在电解液中加入10mM的HAuCl4，循环伏安扫描50圈，在薄膜表面电化学还原沉积金纳米颗粒AuNPs其层厚度～20nm，最终制得PMMA-PI-AuNPs复合薄膜。探针上DNA1(HS-DNA1-COOH)尾端-SH与薄膜上AuNPs通过Au-S键结合，将薄膜与探针连接在一起构筑成柔性杂化膜。当人尿液样品中含前列腺特异性抗原时，将微量样品滴加至该杂化膜上，在800nm和5mW近红外光激发下，观察浸润杂化膜的可见区～575nm橘红色上转换发光的强弱变化，随着样品中前列腺特异性抗原浓度从10nM增大至1mM，Co-BPQDs橘红色上转换发光逐渐增强，实现对人尿液样品肿瘤标志物前列腺特异性抗原的上转换发光可视化检测。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其特征在于，该方法具体包括以下步骤：
（1）将块状黑磷晶体研磨成粉末，加入溶解了金属盐的极性溶剂中，采用探头和浴池超声剥离出黑磷纳米片，加入硫醇配体，通过超声辅助溶剂热制备金属离子掺杂的黑磷量子点M-BPQDs；
（2）依据Stöber法在M-BPQDs 表面生长介孔二氧化硅mSiO2，然后进行-NH2 功能化改性制得M-BPQDs/mSiO2-NH2，再与单链DNA1通过羧-胺偶联反应结合，制备M-BPQDs/mSiO2@DNA1；
（3）电子受体分子进入mSiO2孔道内完成受体分子负载，添加特异性适体单链DNA2与DNA1碱基互补配对形成双螺旋结构，封装受体分子，得到纳米杂化物载体探针M-BPQDs/mSiO2@DNA1-DNA2@受体；
（4）以聚异丁烯酸甲酯PMMA为层状基底，表面黏合一层聚酰亚胺PI，电极夹固定PMAA-PI 薄膜浸没在电解液中，以KCl 饱和甘汞电极为参比，铂丝电极为辅助，PMAA-PI 薄膜为工作电极，在电解液中加入HAuCl4，循环伏安扫描，在薄膜表面电化学还原生成金纳米颗粒AuNPs制得PMMA-PI-AuNPs复合薄膜；
（5）探针上DNA1末端-SH与薄膜上AuNPs通过Au-S键结合，将薄膜与探针连接在一起构筑成柔性杂化膜，当生物流体样品中含有肿瘤标志物时，将其滴加至该杂化膜上，在近红外光激发下观察浸润杂化膜的上转换发光颜色变化，实现对肿瘤标志物的可视化检测。
2.根据权利要求1所述的一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其特征在于，步骤（1）中所述的金属离子为Ag+, Mn2+, Co2+, Ni2+，M-BPQDs为1~5nm。
3.根据权利要求1所述的 一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其特征在于，步骤（2）中所述的表面mSiO2厚度为50~200 nm。
4.根据权利要求1所述的一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其特征在于，步骤（3）中所述的受体为5-氟尿嘧啶、多巴胺、芦丁、槲皮素，DNA2是癌胚抗原、甲胎蛋白、糖类抗原、前列腺特异性抗原标志物的单链DNA适体。
5.根据权利要求1所述的一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其特征在于，步骤（4）中所述的PMMA厚度为50~100 nm，PI厚度为1~2 μm，AuNPs厚度为10~100 nm。
6.根据权利要求1所述的一种用于肿瘤标志物可视化检测的上转换发光柔性杂化膜的制备方法，其特征在于， 步骤（5）中所述的上转换发光发射峰波长为500~600 nm，肿瘤标志物浓度为1 nM~1 mM。
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