适配体在受体和分子传感器中的应用研究进展
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摘要
适配体是从随机寡核苷酸文库中筛选得到的一类可以结合特异靶分子的寡核苷酸序列,在生物医学中具有极其诱人的应用前景.与传统抗体相比,由于具有制备简便、易于修饰、稳定性好,以及结合目标物范围广等特点,适配体已广泛应用于生物传感器的开发,一方面可以用作敏感元件,用于实现对靶分子的识别和检测;另一方面,可以作为敏感元件与传感器件耦合的桥梁,提高耦合的效率.此外,近年来在基于适配体的生物传感器中引入各种纳米材料例如金属纳米颗粒、碳材料和功能性纳米球等也促进了基于适配体的生物传感器在分析性能和商业应用等方面的提升和改进.本文首先简要介绍了基于SELEX技术筛选适配体的方法,总结了适配体的基本特性;其次,详细概括和总结了适配体生物传感器的基本原理及其分类;随后,结合近年来基于适配体的生物传感器领域的最新研究成果,重点介绍了适配体在生物传感器开发中的应用,主要包括在仿生嗅觉与味觉受体传感器方面的应用以及在检测小分子物质和蛋白质的应用;最后,对适配体在生物传感器中的应用面临的问题及其发展趋势进行了分析和展望.
Aptamer is an oligonucleotide sequence that can bind to a specific target molecule,which is screened from a random oligonucleotide library.It has shown promising prospects in biomedical applications.Due to its decisive advantages such as simple preparation,easy modification,good stability and wide range of targets compared with traditional antibodies,aptamer has been widely applied in the development of biosensors,which can not only be used to realize the identification and detection of target molecules,but also be utilized as the bridge between sensitive elements and transducers to improve the coupling efficiency.In addition,in recent years,the introduction of various nanomaterials such as metal nanoparticles,carbon materials and functional nanospheres to aptamer-based biosensors has contributed to their improvement in analytical performances and commercial applications.First,this review briefly introduces the methods for aptamer screening based on the SELEX technique and summarizes basic properties of aptamers.Second,the basic principle and classification of aptamer-based biosensors are introduced in detail.Third,based on the most recent progress in the field of aptamer-based biosensors,we focus on the applications of aptamers in biosensor development,including the applications in the field of biomimetic olfactory and taste receptor biosensors as well as applications in the detection of small molecules and proteins.Finally,we analyze and discuss the problems and development trends of applications of aptamers in biosensors.
Aptamer is an oligonucleotide sequence that can bind to a specific target molecule,which is screened from a random oligonucleotide library.It has shown promising prospects in biomedical applications.Due to its decisive advantages such as simple preparation,easy modification,good stability and wide range of targets compared with traditional antibodies,aptamer has been widely applied in the development of biosensors,which can not only be used to realize the identification and detection of target molecules,but also be utilized as the bridge between sensitive elements and transducers to improve the coupling efficiency.In addition,in recent years,the introduction of various nanomaterials such as metal nanoparticles,carbon materials and functional nanospheres to aptamer-based biosensors has contributed to their improvement in analytical performances and commercial applications.First,this review briefly introduces the methods for aptamer screening based on the SELEX technique and summarizes basic properties of aptamers.Second,the basic principle and classification of aptamer-based biosensors are introduced in detail.Third,based on the most recent progress in the field of aptamer-based biosensors,we focus on the applications of aptamers in biosensor development,including the applications in the field of biomimetic olfactory and taste receptor biosensors as well as applications in the detection of small molecules and proteins.Finally,we analyze and discuss the problems and development trends of applications of aptamers in biosensors.
引文
1祝文琪,高磊,王晶,等.适配体传感器的研究进展.中国兽药杂志,2011,45:35-40
2左明艳.基于SELEX技术筛选前白蛋白的核酸适配体及磁珠适配体传感器检测细菌内毒素的应用.硕士学位论文.合肥:中国科学技术大学,2014
3 Song S,Wang L,Li J,et al.Aptamer-based biosensors.Tr AC Trends Anal Chem,2008,27:108-117
4王一娴,叶尊忠,斯城燕,等.适配体生物传感器在病原微生物检测中的应用.分析化学,2012,40:634-642
5周玲,王明华,王剑平,等.传感器表面的适配体固定方法及其在生物传感器中的研究进展.分析化学,2011,39:432-438
6 Seok K Y,Ahmad Raston N H,Bock G M.Aptamer-based nanobiosensors.Biosens Bioelectron,2016,76:2-19
7 Radi A E,Acero Sánchez J L,Baldrich E,et al.Reusable impedimetric aptasensor.Anal Chem,2005,77:6320-6323
8 Xu Y,Yang L,Ye X,et al.An aptamer-based protein biosensor by detecting the amplified impedance signal.Electroanalysis,2006,18:1449-1456
9 Kawde A N,Rodriguez M C,Lee T M H,et al.Label-free bioelectronic detection of aptamer-protein interactions.Electrochem Commun,2005,7:537-540
10 Matsuo T,Wise K D.An integrated field-effect electrode for biopotential recording.IEEE Trans,1974,21:485-487
11 Zong X L,Wu C S,Wu X L,et al.A non-labeled DNA biosensor based on light addressable potentiometric sensor modified with Ti O2,thin film.J Zhejiang Univ Sci B,2009,10:860
12 Hianik T,OstatnáV,ZajacováZ,et al.Detection of aptamer-protein interactions using QCM and electrochemical indicator methods.Bioorgan Med Chem Lett,2005,15:291-295
13 Mir M,Vreeke M,Katakis I.Different strategies to develop an electrochemical thrombin aptasensor.Electrochem Commun,2006,8:505-511
14李婷.纳米Cd S及其量子点的制备和性能研究.硕士学位论文.天津:天津大学,2007
15 Hansen J A,Wang J,Kawde A N,et al.Quantum-dot/aptamer-based ultrasensitive multi-analyte electrochemical biosensor.J Am Chem Soc,2006,128:2228-2229
16刘晓静,刘韧,顾长国,等.核酸适体的研究进展.生理科学进展,2004,35:374-378
17 Xiao Y,Lubin A A,Heeger A J,et al.Label-free electronic detection of thrombin in blood serum by using an aptamer-based sensor.Angew Chem Int Ed,2005,44:5456-5459
18 Wei F,Wang J,Liao W,et al.Electrochemical detection of low-copy number salivary RNA based on specific signal amplification with a hairpin probe.Nucleic Acids Res,2008,36:e65
19 Du L,Wu C,Peng H,et al.Piezoelectric olfactory receptor biosensor prepared by aptamer-assisted immobilization.Sensors Actuat B Chem,2013,187:481-487
20吴春生,杜立萍,邹玲,等.基于适配体分子传感器的味蕾细胞间通信ATP检测的研究.全国敏感元件与传感器学术会议,2014
21 Wu C,Du L,Zou L,et al.An ATP sensitive light addressable biosensor for extracellular monitoring of single taste receptor cell.Biomed Microdev,2012,14:1047-1053
22 Wu C,Du L,Zou L,et al.A biomimetic bitter receptor-based biosensor with high efficiency immobilization and purification using self-assembled aptamers.Analyst,2013,138:5989-5994
23于寒松,隋佳辰,代佳宇,等.核酸适配体技术在食品重金属检测中的应用研究进展.食品科学,2015,36:228-233
24詹深山,吴远根,邱树毅,等.基于纳米金和核酸适配体的重金属离子传感器研究进展.上海交通大学学报(农业科学版),2012,30:1-7
25 Mckeague M,Derosa M C.Challenges and opportunities for small molecule aptamer development.J Nucleic Acids,2012,2012:748913
26 Pfeiffer F,Mayer G.Selection and biosensor application of aptamers for small molecules.Front Chem,2016,4:25
27梁顺超,魏小平,黄文刚,等.适配体电化学传感器检测汞离子进展.分析测试学报,2016,35:618-626
28赵秋伶,张尤华,于晓艳.基于核酸外切酶Ⅰ的适配体荧光传感器检测人尿液中的Hg2+.分析化学,2016,44:1099-1105
29李慧,王鸣刚,刘巍.适配体技术及其在肿瘤标志物检测中的应用.甘肃科技,2009,25:156-158
30徐雯,薛婷,余娟,等.一种基于适配体的快速检测宫颈癌标志物P16INK4A的方法.华中科技大学学报(医学版),2015,(6):667-673
31 Cheng A K H,Su H,Wang YA,et al.Aptamer-based detection of epithelial tumor marker mucin 1 with quantum dot-based fluorescence readout.Anal Chem,2009,81:6130-6139
32 Li H,Bai X,Wang N,et al.Aptamer-based microcantilever biosensor for ultrasensitive detection of tumor marker nucleolin.Talanta,2015,146:727-731
33 Lin M Y,Lu Y P,Grumezescu A,et al.Tumor marker detection by aptamer-functionalized graphene oxide.Curr Organic Chemist,2013,17:132-136
34 Li T,Yang J,Ali Z,et al.Synthesis of aptamer-functionalized Ag nanoclusters for MCF-7 breast cancer cells imaging.Sci China Chem,2017,60:370-376
35 Yan L,Shi H,He D,et al.A p H-responsive activatable aptamer probe for targeted cancer imaging based on i-motif-driven conformation alteration.Sci China Chem,2016,59:802-808
36徒永华,程圭芳,林莉,等.基于核酸适配体的新型荧光纳米生物传感器用于凝血酶的测定.高等学校化学学报,2006,27:2266-2270
37 Degefa T H,Hwang S,Kwon D,et al.Aptamer-based electrochemical detection of protein using enzymatic silver deposition.Electrochim Acta,2009,54:6788-6791
38 Wang W,Xu D D,Pang D W,et al.Fluorescent sensing of thrombin using a magnetic nano-platform with aptamer-target-aptamer sandwich and fluorescent silica nanoprobe.J Lumin,2017,187:9-13
39贵莉莉.基于无标记的核酸适配体荧光生物传感器检测凝血酶.分析测试学报,2016,35:1054-1057
40赵瑞芳,冯锋,双少敏,等.基于金纳米和适配体的表面等离子体共振技术检测溶菌酶.山西大同大学学报(自然科学版),2013,29:34-36
41 Oca?a C,Hayat A,Mishra R,et al.A novel electrochemical aptamer-antibody sandwich assay for lysozyme detection.Analyst,2015,140:4148-4153
42 Erdem A,Eksin E,Muti M.Chitosan-graphene oxide based aptasensor for the impedimetric detection of lysozyme.Colloids Surfaces BBiointerfaces,2014,115:205-211
43 Lu L,Wang W,Wang M,et al.A luminescent G-quadruplex-selective iridium(iii)complex for the label-free detection of lysozyme.J Mater Chem B,2016,4:2407-2411
44 Mihai I,Vezeanu A,Polonschii C,et al.Label-free detection of lysozyme in wines using an aptamer based biosensor and SPR detection.Sensors Actuat B Chemical,2015,206:198-204
45 Rodríguez M C,Rivas G A.Label-free electrochemical aptasensor for the detection of lysozyme.Talanta,2009,78:212-216
46 Tran D T,Janssen K P F,Pollet J,et al.Selection and characterization of DNA aptamers for egg white lysozyme.Molecules,2010,15:1127-1140
47 Mishra R K,Hayat A,Mishra G K,et al.A novel colorimetric competitive aptamer assay for lysozyme detection based on superparamagnetic nanobeads.Talanta,2016,165:436-441
48 Yao X,Ma X,Ding C,et al.Colorimetric determination of lysozyme based on the aggregation of gold nanoparticles controlled by a cationic polymer and an aptamer.Microchim Acta,2016,183:2353-2359
2左明艳.基于SELEX技术筛选前白蛋白的核酸适配体及磁珠适配体传感器检测细菌内毒素的应用.硕士学位论文.合肥:中国科学技术大学,2014
3 Song S,Wang L,Li J,et al.Aptamer-based biosensors.Tr AC Trends Anal Chem,2008,27:108-117
4王一娴,叶尊忠,斯城燕,等.适配体生物传感器在病原微生物检测中的应用.分析化学,2012,40:634-642
5周玲,王明华,王剑平,等.传感器表面的适配体固定方法及其在生物传感器中的研究进展.分析化学,2011,39:432-438
6 Seok K Y,Ahmad Raston N H,Bock G M.Aptamer-based nanobiosensors.Biosens Bioelectron,2016,76:2-19
7 Radi A E,Acero Sánchez J L,Baldrich E,et al.Reusable impedimetric aptasensor.Anal Chem,2005,77:6320-6323
8 Xu Y,Yang L,Ye X,et al.An aptamer-based protein biosensor by detecting the amplified impedance signal.Electroanalysis,2006,18:1449-1456
9 Kawde A N,Rodriguez M C,Lee T M H,et al.Label-free bioelectronic detection of aptamer-protein interactions.Electrochem Commun,2005,7:537-540
10 Matsuo T,Wise K D.An integrated field-effect electrode for biopotential recording.IEEE Trans,1974,21:485-487
11 Zong X L,Wu C S,Wu X L,et al.A non-labeled DNA biosensor based on light addressable potentiometric sensor modified with Ti O2,thin film.J Zhejiang Univ Sci B,2009,10:860
12 Hianik T,OstatnáV,ZajacováZ,et al.Detection of aptamer-protein interactions using QCM and electrochemical indicator methods.Bioorgan Med Chem Lett,2005,15:291-295
13 Mir M,Vreeke M,Katakis I.Different strategies to develop an electrochemical thrombin aptasensor.Electrochem Commun,2006,8:505-511
14李婷.纳米Cd S及其量子点的制备和性能研究.硕士学位论文.天津:天津大学,2007
15 Hansen J A,Wang J,Kawde A N,et al.Quantum-dot/aptamer-based ultrasensitive multi-analyte electrochemical biosensor.J Am Chem Soc,2006,128:2228-2229
16刘晓静,刘韧,顾长国,等.核酸适体的研究进展.生理科学进展,2004,35:374-378
17 Xiao Y,Lubin A A,Heeger A J,et al.Label-free electronic detection of thrombin in blood serum by using an aptamer-based sensor.Angew Chem Int Ed,2005,44:5456-5459
18 Wei F,Wang J,Liao W,et al.Electrochemical detection of low-copy number salivary RNA based on specific signal amplification with a hairpin probe.Nucleic Acids Res,2008,36:e65
19 Du L,Wu C,Peng H,et al.Piezoelectric olfactory receptor biosensor prepared by aptamer-assisted immobilization.Sensors Actuat B Chem,2013,187:481-487
20吴春生,杜立萍,邹玲,等.基于适配体分子传感器的味蕾细胞间通信ATP检测的研究.全国敏感元件与传感器学术会议,2014
21 Wu C,Du L,Zou L,et al.An ATP sensitive light addressable biosensor for extracellular monitoring of single taste receptor cell.Biomed Microdev,2012,14:1047-1053
22 Wu C,Du L,Zou L,et al.A biomimetic bitter receptor-based biosensor with high efficiency immobilization and purification using self-assembled aptamers.Analyst,2013,138:5989-5994
23于寒松,隋佳辰,代佳宇,等.核酸适配体技术在食品重金属检测中的应用研究进展.食品科学,2015,36:228-233
24詹深山,吴远根,邱树毅,等.基于纳米金和核酸适配体的重金属离子传感器研究进展.上海交通大学学报(农业科学版),2012,30:1-7
25 Mckeague M,Derosa M C.Challenges and opportunities for small molecule aptamer development.J Nucleic Acids,2012,2012:748913
26 Pfeiffer F,Mayer G.Selection and biosensor application of aptamers for small molecules.Front Chem,2016,4:25
27梁顺超,魏小平,黄文刚,等.适配体电化学传感器检测汞离子进展.分析测试学报,2016,35:618-626
28赵秋伶,张尤华,于晓艳.基于核酸外切酶Ⅰ的适配体荧光传感器检测人尿液中的Hg2+.分析化学,2016,44:1099-1105
29李慧,王鸣刚,刘巍.适配体技术及其在肿瘤标志物检测中的应用.甘肃科技,2009,25:156-158
30徐雯,薛婷,余娟,等.一种基于适配体的快速检测宫颈癌标志物P16INK4A的方法.华中科技大学学报(医学版),2015,(6):667-673
31 Cheng A K H,Su H,Wang YA,et al.Aptamer-based detection of epithelial tumor marker mucin 1 with quantum dot-based fluorescence readout.Anal Chem,2009,81:6130-6139
32 Li H,Bai X,Wang N,et al.Aptamer-based microcantilever biosensor for ultrasensitive detection of tumor marker nucleolin.Talanta,2015,146:727-731
33 Lin M Y,Lu Y P,Grumezescu A,et al.Tumor marker detection by aptamer-functionalized graphene oxide.Curr Organic Chemist,2013,17:132-136
34 Li T,Yang J,Ali Z,et al.Synthesis of aptamer-functionalized Ag nanoclusters for MCF-7 breast cancer cells imaging.Sci China Chem,2017,60:370-376
35 Yan L,Shi H,He D,et al.A p H-responsive activatable aptamer probe for targeted cancer imaging based on i-motif-driven conformation alteration.Sci China Chem,2016,59:802-808
36徒永华,程圭芳,林莉,等.基于核酸适配体的新型荧光纳米生物传感器用于凝血酶的测定.高等学校化学学报,2006,27:2266-2270
37 Degefa T H,Hwang S,Kwon D,et al.Aptamer-based electrochemical detection of protein using enzymatic silver deposition.Electrochim Acta,2009,54:6788-6791
38 Wang W,Xu D D,Pang D W,et al.Fluorescent sensing of thrombin using a magnetic nano-platform with aptamer-target-aptamer sandwich and fluorescent silica nanoprobe.J Lumin,2017,187:9-13
39贵莉莉.基于无标记的核酸适配体荧光生物传感器检测凝血酶.分析测试学报,2016,35:1054-1057
40赵瑞芳,冯锋,双少敏,等.基于金纳米和适配体的表面等离子体共振技术检测溶菌酶.山西大同大学学报(自然科学版),2013,29:34-36
41 Oca?a C,Hayat A,Mishra R,et al.A novel electrochemical aptamer-antibody sandwich assay for lysozyme detection.Analyst,2015,140:4148-4153
42 Erdem A,Eksin E,Muti M.Chitosan-graphene oxide based aptasensor for the impedimetric detection of lysozyme.Colloids Surfaces BBiointerfaces,2014,115:205-211
43 Lu L,Wang W,Wang M,et al.A luminescent G-quadruplex-selective iridium(iii)complex for the label-free detection of lysozyme.J Mater Chem B,2016,4:2407-2411
44 Mihai I,Vezeanu A,Polonschii C,et al.Label-free detection of lysozyme in wines using an aptamer based biosensor and SPR detection.Sensors Actuat B Chemical,2015,206:198-204
45 Rodríguez M C,Rivas G A.Label-free electrochemical aptasensor for the detection of lysozyme.Talanta,2009,78:212-216
46 Tran D T,Janssen K P F,Pollet J,et al.Selection and characterization of DNA aptamers for egg white lysozyme.Molecules,2010,15:1127-1140
47 Mishra R K,Hayat A,Mishra G K,et al.A novel colorimetric competitive aptamer assay for lysozyme detection based on superparamagnetic nanobeads.Talanta,2016,165:436-441
48 Yao X,Ma X,Ding C,et al.Colorimetric determination of lysozyme based on the aggregation of gold nanoparticles controlled by a cationic polymer and an aptamer.Microchim Acta,2016,183:2353-2359