Abstract
Strategies for electrochemical sensing of DNA can be classified into label-free and label-based approaches, categories of which include enzyme-, nanomaterial- and redox labels that are attached to DNA either by covalent or non-covalent means. Metallointercalators represent one group of small molecule redox labels that non-covalently enter the groove of a DNA. The metallointercalator plays a dual-role in acting as a structure indicator (for hybridization) and a signal generator. Labeling is not needed, and electrochemical measurements can be carried out in a label-free solution of an electrolyte. However, such metallointercalators lack the option of catalytic signal generation as in the case of enzyme- and nanomaterial-based labels. Therefore, signal amplification becomes crucial. We first survey here recent progress in this area. A signal-amplifying system is presented that relies on the electroatalytic oxidation of a metallointercalator ruthenium(II)bipyridine/phenoxazine complex in the presence of electron donor species such as oxalate, DNA bases, or tripropylamine. Recent work on such DNA sensors is discussed. Results suggest that such metallointercalator-based DNA sensors represent a viable platform for developing high-throughput and automated PCR/lab-on-a-chip devices as well as visualized multifunctional DNA sensors.
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References
IUPAC (1996) Electrochemical biosensors: definitions and classification proposed. Biosens Bioelectron 11(4):R1
Teles FRR, Fonseca LR (2008) Trends in DNA biosensors. Talanta 77(2):606
Scarano S, Mascini M, Turner APF, Minunni M (2010) Surface plasmon resonance imaging for affinity-based biosensors. Biosens Bioelectron 25(5):957
Epstein JR, Biran I, Walt DR (2002) Fluorescence-based nucleic acid detection and microarrays. Anal Chim Acta 469(1):3
O’Sullivan CK, Guilbault GG (1999) Commercial quartz crystal microbalances - theory and applications. Biosens Bioelectron 14(8–9):663
Marx KA (2003) Quartz crystal microbalance: a useful tool for studying thin polymer films and complex biomolecular systems at the solution-surface interface. Biomacromolecules 4(5):1099
Fritz J (2008) Cantilever biosensors. Analyst 133(7):855
Hu PA, Zhang J, Li L, Wang ZL, O’Neill W, Estrela P (2010) Carbon nanostructure-based field-effect transistors for label-free chemical/biological sensors. Sensors-Basel 10(5):5133
Katz E, Willner I (2003) Probing biomolecular interactions at conductive and semiconductive surfaces by impedance spectroscopy: routes to impedimetric immunosensors, DNA-sensors, and enzyme biosensors. Electroanal 15(11):913
Palecek E (2002) Past, present and future of nucleic acids electrochemistry. Talanta 56(5):809
Wang J (2002) Electrochemical nucleic acid biosensors. Anal Chim Acta 469(1):63
Drummond TG, Hill MG, Barton JK (2003) Electrochemical DNA sensors. Nat Biotechnol 21(10):1192
de-los-Santos-Alvarez P, Lobo-Castanon MJ, Miranda-Ordieres AJ, Tunon-Blanco P (2004) Current strategies for electrochemical detection of DNA with solid electrodes. Anal Bioanal Chem 378(1):104
Lucarelli F, Marrazza G, Turner APF, Mascini M (2004) Carbon and gold electrodes as electrochemical transducers for DNA hybridisation sensors. Biosens Bioelectron 19(6):515
Mir M, Homs A, Samitier J (2009) Integrated electrochemical DNA biosensors for lab-on-a-chip devices. Electrophoresis 30(19):3386
Ricci F, Plaxco KW (2008) E-DNA sensors for convenient, label-free electrochemical detection of hybridization. Microchim Acta 163(3–4):149
Ronkainen NJ, Halsall HB, Heineman WR (2010) Electrochemical biosensors. Chem Soc Rev 39(5):1747
Wang J, Bollo S, Paz JLL, Sahlin E, Mukherjee B (1999) Ultratrace measurements of nucleic acids by baseline-corrected adsorptive stripping square-wave voltammetry. Anal Chem 71(9):1910
Singhal P, Kuhr WG (1997) Ultrasensitive voltammetric detection of underivatized oligonucleotides and DNA. Anal Chem 69(23):4828
Umek RM, Lin SW, Vielmetter J, Terbrueggen RH, Irvine B, Yu CJ, Kayyem JF, Yowanto H, Blackburn GF, Farkas DH, Chen YP (2001) Electronic detection of nucleic acids - a versatile platform for molecular diagnostics. J Mol Diagn 3(2):74
Nakayama M, Ihara T, Nakano K, Maeda M (2002) DNA sensors using a ferrocene-oligonucleotide conjugate. Talanta 56(5):857
Fan CH, Plaxco KW, Heeger AJ (2003) Electrochemical interrogation of conformational changes as a reagentless method for the sequence-specific detection of DNA. P Natl Acad Sci USA 100(16):9134
Xie H, Zhang CY, Gao ZQ (2004) Amperometric detection of nucleic acid at femtomolar levels with a nucleic acid/electrochemical activator bilayer on gold electrode. Anal Chem 76(6):1611
Zhang YC, Pothukuchy A, Shin W, Kim Y, Heller A (2004) Detection of similar to 10(3) copies of DNA by an electrochemical enzyme-amplified sandwich assay with ambient o-2 as the substrate. Anal Chem 76(14):4093
Patolsky F, Katz E, Willner I (2002) Amplified DNA detection by electrogenerated biochemiluminescence and by the catalyzed precipitation of an insoluble product on electrodes in the presence of the doxorubicin intercalator. Angew Chem Int Edit 41(18):3398
Katz E, Willner I, Wang J (2004) Electroanalytical and bioelectroanalytical systems based on metal and semiconductor nanoparticles. Electroanal 16(1–2):19
Abu Salah K, Alrokyan SA, Khan MN, Ansari AA (2010) Nanomaterials as analytical tools for genosensors. Sensors-Basel 10(1):963
Millan KM, Mikkelsen SR (1993) Sequence-selective biosensor for DNA-based on electroactive hybridization indicators. Anal Chem 65(17):2317
Steel AB, Herne TM, Tarlov MJ (1998) Electrochemical quantitation of DNA immobilized on gold. Anal Chem 70(22):4670
Armistead PM, Thorp HH (2000) Modification of indium tin oxide electrodes with nucleic acids: detection of attomole quantities of immobilized DNA by electrocatalysis. Anal Chem 72(16):3764
Zeglis BM, Pierre VC, Barton JK (2007) Metallo-intercalators and metallo-insertors. Chem Commun (44):4565
Erkkila KE, Odom DT, Barton JK (1999) Recognition and reaction of metallointercalators with DNA. Chem Rev 99(9):2777
Delaney S, Pascaly M, Bhattacharya PK, Han K, Barton JK (2002) Oxidative damage by ruthenium complexes containing the dipyridophenazine ligand or its derivatives: a focus on intercalation. Inorg Chem 41(7):1966
Jenkins Y, Friedman AE, Turro NJ, Barton JK (1992) Characterization of dipyridophenazine complexes of ruthenium(ii) - the light switch effect as a function of nucleic-acid sequence and conformation. Biochemistry-US 31(44):10809
Hartshorn RM, Barton JK (1992) Novel dipyridophenazine complexes of ruthenium(ii) - exploring luminescent reporters of DNA. J Am Chem Soc 114(15):5919
Friedman AE, Chambron JC, Sauvage JP, Turro NJ, Barton JK (1990) Molecular light switch for DNA - Ru(bpy)2(dppz)2+. J Am Chem Soc 112(12):4960
Lincoln P, Broo A, Norden B (1996) Diastereomeric DNA-binding geometries of intercalated ruthenium(ii) trischelates probed by linear dichroism: [Ru(phen)(2)dppz](2+) and [ru(phen)(2)bdppz](2+). J Am Chem Soc 118(11):2644
Haq I, Lincoln P, Suh DC, Norden B, Chowdhry BZ, Chaires JB (1995) Interaction of delta-[ru(phen)(2)dppz](2+) and lambda-[ru(phen)(2)dppz](2+) with DNA - a calorimetric and equilibrium binding study. J Am Chem Soc 117(17):4788
Takenaka S, Yamashita K, Takagi M, Uto Y, Kondo H (2000) DNA sensing on a DNA probe-modified electrode using ferrocenylnaphthalene diimide as the electrochemically active ligand. Anal Chem 72(6):1334
Maruyama K, Mishima Y, Minagawa K, Motonaka J (2002) DNA sensor with a dipyridophenazine complex of osmium(ii) as an electrochemical probe. Anal Chem 74(15):3698
Yang IV, Thorp HH (2001) Modification of indium tin oxide electrodes with repeat polynucleotides: electrochemical detection of trinucleotide repeat expansion. Anal Chem 73(21):5316
Wang BQ, Rusling JF (2003) Voltammetric sensor for chemical toxicity using [ru(bpy)(2)poly(4-vinylpyridine)(10)cl)](+) as catalyst in ultrathin films. DNA damage from methylating agents and an enzyme-generated epoxide. Anal Chem 75(16):4229
Dennany L, Forster RJ, Rusling JF (2003) Simultaneous direct electrochemiluminescence and catalytic voltammetry detection of DNA in ultrathin films. J Am Chem Soc 125(17):5213
Rusling JF (2004) Sensors for toxicity of chemicals and oxidative stress based on electrochemical catalytic DNA oxidation. Biosens Bioelectron 20(5):1022
Boon EM, Ceres DM, Drummond TG, Hill MG, Barton JK (2000) Mutation detection by electrocatalysis at DNA-modified electrodes. Nat Biotechnol 18(10):1096
de-los-Santos-Alvarez P, Lobo-Castanon MJ, Miranda-Ordieres AJ, Tunon-Blanco P (2005) Electrocatalytic oxidation of nadh by brilliant cresyl blue-DNA intercalation adduct. Electrochim Acta 50(5):1107
Wain AJ, Zhou FM (2008) Scanning electrochemical microscopy imaging of DNA microarrays using methylene blue as a redox-active intercalator. Langmuir 24(9):5155
Zheng D, Wang N, Wang FQ, Dong DA, Li YG, Yang XQ, Guo LH, Cheng J (2004) Sensitive chemically amplified electrochemical detection of ruthenium tris-(2, 2′-bipyridine) on tin-doped indium oxide electrode. Anal Chim Acta 508(2):225
Wei MY, Wen SD, Yang XQ, Guo LH (2009) Development of redox-labeled electrochemical immunoassay for polycyclic aromatic hydrocarbons with controlled surface modification and catalytic voltammetric detection. Biosens Bioelectron 24(9):2909
Li C, Liu SL, Guo LH, Chen DP (2005) A new chemically amplified electrochemical system for DNA detection in solution. Electrochem Commun 7(1):23
Liu SL, Li C, Cheng J, Zhou YX (2006) Selective photoelectrochemical detection of DNA with high-affinity metallointercalator and tin oxide nanoparticle electrode. Anal Chem 78(13):4722
Wei MY, Guo LH, Chen H (2006) Determination of surface-immobilized double-stranded DNA using a metallointercalator and catalytic voltammetry. Microchim Acta 155(3–4):409
Dong D, Zheng D, Wang FQ, Yang XQ, Wang N, Li YG, Guo LH, Cheng J (2004) Quantitative photoelectrochemical detection of biological affinity reaction: biotin-avidin interaction. Anal Chem 76(2):499
Liang MM, Liu SL, Wei MY, Guo LH (2006) Photoelectrochemical oxidation of DNA by ruthenium tris(bipyridine) on a tin oxide nanoparticle electrode. Anal Chem 78(2):621
Liang MM, Guo LH (2007) Photoelectrochemical DNA sensor for the rapid detection of DNA damage induced by styrene oxide and the fenton reaction. Environ Sci Technol 41(2):658
Liang MM, Jia SP, Zhu SC, Guo LH (2008) Photoelectrochemical sensor for the rapid detection of in situ DNA damage induced by enzyme-catalyzed fenton reaction. Environ Sci Technol 42(2):635
Jia SP, Liang MM, Guo LH (2008) Photoelectrochemical detection of oxidative DNA damage induced by fenton reaction with low concentration and DNA-associated fe2+. J Phys Chem B 112(14):4461
Jia SP, Zhu BZ, Guo LH (2010) Detection and mechanistic investigation of halogenated benzoquinone induced DNA damage by photoelectrochemical DNA sensor. Anal Bioanal Chem 397(6):2395
Xu XH, Yang HC, Mallouk TE, Bard AJ (1994) Immobilization of DNA on an aluminum(iii) alkanebisphosphonate thin-film with electrogenerated chemiluminescent detection. J Am Chem Soc 116(18):8386
So MJ, Hvastkovs EG, Schenkman JB, Rusling JF (2007) Electrochemiluminescent/voltammetric toxicity screening sensor using enzyme-generated DNA damage. Biosens Bioelectron 23(4):492
Hu LZ, Xu GB (2010) Applications and trends in electrochemiluminescence. Chem Soc Rev 39(8):3275
Hu LZ, Bian Z, Li HJ, Han S, Yuan YL, Gao LX, Xu GB (2009) [ru(bpy)(2)dppz](2+) electrochemiluminescence switch and its applications for DNA interaction study and label-free atp aptasensor. Anal Chem 81(23):9807
Maruyama K, Mishima Y, Minagawa K, Motonaka J (2001) Electrochemical and DNA-binding properties of dipyridophenazine complexes of osmium(ii). J Electroanal Chem 510(1–2):96
Welch TW, Corbett AH, Thorp HH (1995) Electrochemical determination of nucleic-acid diffusion-coefficients through noncovalent association of a redox-active probe. J Phys Chem-Us 99(30):11757
Carter MT, Bard AJ (1987) Voltammetric studies of the interaction of tris(1, 10-phenanthroline)cobalt(iii) with DNA. J Am Chem Soc 109(24):7528
Carter MT, Rodriguez M, Bard AJ (1989) Voltammetric studies of the interaction of metal-chelates with DNA.2. Tris-chelated complexes of cobalt(iii) and iron(ii) with 1, 10-phenanthroline and 2, 2′-bipyridine. J Am Chem Soc 111(24):8901
Ling LS, He ZK, Song GW, Han HY, Zhang HS, Zeng YE (2000) Determination of DNA by use of the molecular “light switch” complex of ru(bipy)(2)(dppz)(2+). Microchim Acta 134(1–2):57
Ling LS, He ZK, Song GW, Zeng YE, Wang C, Bai CL, Chen XD, Shen P (2001) High sensitive determination of DNA by use of molecular “light switch” complex of ru(phen)(2)(dppx)(2+). Anal Chim Acta 436(2):207
Wang LR, Qu N, Guo LH (2008) Electrochemical displacement method for the investigation of the binding interaction of polycyclic organic compounds with DNA. Anal Chem 80(10):3910
Wang LR, Wang Y, Chen JW, Guo LH (2009) A structure-based investigation on the binding interaction of hydroxylated polycyclic aromatic hydrocarbons with DNA. Toxicology 262(3):250
Guo LH, Yang XQ (2005) A new chemically amplified electrochemical system for the detection of biological affinity reactions: direct and competitive biotin assay. Analyst 130(7):1027
Huang RF, Wang LR, Guo LH (2010) Highly sensitive electrochemiluminescence displacement method for the study of DNA/small molecule binding interactions. Anal Chim Acta 676(1–2):41
Guo LH, Wei MY, Chen H (2006) Multiple DNA binding modes of a metallointercalator revealed by DNA film voltammetry. J Phys Chem B 110(41):20568
Armstrong FA, Heering HA, Hirst J (1997) Reactions of complex metalloproteins studied by protein-film voltammetry. Chem Soc Rev 26(3):169
Pang DW, Abruna HD (1998) Micromethod for the investigation of the interactions between DNA and redox active molecules. Anal Chem 70(15):3162
Mahadevan S, Palaniandavar M (1996) Chiral discrimination in the binding of tris(phenanthroline)ruthenium(ii) to calf thymus DNA: an electrochemical study. Bioconjugate Chem 7(1):138
Matsumoto Y, Terui N, Tanaka S (2006) Electrochemical detection and control of interactions between DNA and electroactive intercalator using a DNA - alginate complex film modified electrode. Environ Sci Technol 40(13):4240
Arias P, Ferreyra NF, Rivas GA, Bollo S (2009) Glassy carbon electrodes modified with cnt dispersed in chitosan: analytical applications for sensing DNA-methylene blue interaction. J Electroanal Chem 634(2):123
Girousi ST, Gherghi IC, Karava MK (2004) DNA-modified carbon paste electrode applied to the study of interaction between rifampicin (rif) and DNA in solution and at the electrode surface. J Pharmaceut Biomed 36(4):851
Takenaka S, Uto Y, Saita H, Yokoyama M, Kondo H, Wilson WD (1998) Electrochemically active threading intercalator with high double stranded DNA selectivity. Chem Commun (10):1111
Karadeniz H, Gulmez B, Erdem A, Jelen F, Ozsoz M, Palecek E (2006) Echinomycin and cobalt-phenanthroline as redox indicators of DNA hybridization at gold electrodes. Front Biosci 11:1870
Aladag N, Ozkan-Ariksoysal D, Gezen-Ak D, Yilmazer S, Ozsoz M (2010) An electrochemical DNA biosensor for the detection of the apa i polymorphism in the vitamin d receptor gene using meldola’s blue as a hybridization indicator. Electroanal 22(5):590
Gao ZQ, Tansil NC (2005) An ultrasensitive photoelectrochemical nucleic acid biosensor. Nucleic Acids Res 33 (13)
Okamoto A, Kamei T, Saito I (2006) DNA hole transport on an electrode: application to effective photoelectrochemical snp typing. J Am Chem Soc 128(2):658
Yin XB, Xin YY, Zhao Y (2009) Label-free electrochemiluminescent aptasensor with attomolar mass detection limits based on a ru(phen)(3)(2+)-double-strand DNA composite film electrode. Anal Chem 81(22):9299
Zhang SB, Wu ZS, Shen GL, Yu RQ (2009) A label-free strategy for snp detection with high fidelity and sensitivity based on ligation-rolling circle amplification and intercalating of methylene blue. Biosens Bioelectron 24(11):3201
Wakai J, Takagi A, Nakayama M, Miya T, Miyahara T, Iwanaga T, Takenaka S, Ikeda Y, Amano M (2004) A novel method of identifying genetic mutations using an electrochemical DNA array. Nucleic Acids Res 32 (18)
Sato S, Hokazono K, Irie T, Ueki T, Waki M, Nojima T, Kondo H, Takenaka S (2006) Ferrocenylnaphthalene diimide-based electrochemical detection of methylated gene. Anal Chim Acta 578(1):82
Ting BP, Zhang J, Gao ZQ, Ying JY (2009) A DNA biosensor based on the detection of doxorubicin-conjugated ag nanoparticle labels using solid-state voltammetry. Biosens Bioelectron 25(2):282
Dharuman V, Hahn JH (2008) Label free electrochemical DNA hybridization discrimination effects at the binary and ternary mixed monolayers of single stranded DNA/diluent/s in presence of cationic intercalators. Biosens Bioelectron 23(8):1250
Won BY, Lee DW, Shin SC, Cho DY, Lee SS, Yoon HC, Park HG (2008) A DNA intercalation-based electrochemical method for detection of chlamydia trachomatis utilizing peroxidase-catalyzed signal amplification. Biosens Bioelectron 24(4):665
Gebala M, Stoica L, Guschin D, Stratmann L, Hartwich G, Schuhmann W (2010) A biotinylated intercalator for selective post-labeling of double-stranded DNA as a basis for high-sensitive DNA assays. Electrochem Commun 12(5):684
Gorodetsky AA, Hammond WJ, Hill MG, Slowinski K, Barton JK (2008) Scanning electrochemical microscopy of DNA monolayers modified with nile blue. Langmuir 24(24):14282
Tansil NC, Xie F, Xie H, Gao ZQ (2005) An ultrasensitive nucleic acid biosensor based on the catalytic oxidation of guanine by a novel redox threading intercalator. Chem Commun (8):1064
Tansil NC, Xie H, Xie F, Gao ZQ (2005) Direct detection of DNA with an electrocatalytic threading intercalator. Anal Chem 77(1):126
Gao ZQ, Tansil N (2009) A DNA biosensor based on the electrocatalytic oxidation of amine by a threading intercalator. Anal Chim Acta 636(1):77
Dervan PB (2001) Molecular recognition of DNA by small molecules. Bioorgan Med Chem 9(9):2215
Graves DE, Velea LM (2000) Intercalative binding of small molecules to nucleic acids. Curr Org Chem 4(9):915
Kelley SO, Barton JK, Jackson NM, Hill MG (1997) Electrochemistry of methylene blue bound to a DNA-modified electrode. Bioconjugate Chem 8(1):31
Kelley SO, Jackson NM, Hill MG, Barton JK (1999) Long-range electron transfer through DNA films. Angew Chem Int Edit 38(7):941
Steel AB, Herne TM, Tarlov MJ (1999) Electrostatic interactions of redox cations with surface-immobilized and solution DNA. Bioconjugate Chem 10(3):419
Erdem A, Ozsoz M (2002) Electrochemical DNA biosensors based on DNA-drug interactions. Electroanal 14(14):965
Fojta M (2002) Electrochemical sensors for DNA interactions and damage. Electroanal 14(21):1449
Wang J, Chicharro M, Rivas G, Cai XH, Dontha N, Farias PAM, Shiraishi H (1996) DNA biosensor for the detection of hydrazines. Anal Chem 68(13):2251
Wang J, Rivas G, Luo DB, Cai XH, Valera FS, Dontha N (1996) DNA-modified electrode for the detection of aromatic amines. Anal Chem 68(24):4365
Vyskocil V, Labuda J, Barek J (2010) Voltammetric detection of damage to DNA caused by nitro derivatives of fluorene using an electrochemical DNA biosensor. Anal Bioanal Chem 397(1):233
Ramanathan K, Rogers K (2003) A fluorescence based assay for DNA damage induced by styrene oxide. Sensor Actuat B-Chem 91(1–3):205
Thorp HH (2004) Electrocatalytic DNA oxidation. Top Curr Chem 237:159
Goetz ME, Luch A (2008) Reactive species: a cell damaging rout assisting to chemical carcinogens. Cancer Lett 266(1):73
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem-Biol Interact 160(1):1
Pierard F, Kirsch-De Mesmaeker A (2006) Bifunctional transition metal complexes as nucleic acid photoprobes and photoreagents. Inorg Chem Commun 9(1):111
Luo XT, Hsing IM (2009) Electrochemical techniques on sequence-specific pcr amplicon detection for point-of-care applications. Analyst 134(10):1957
Hou CSJ, Godin M, Payer K, Chakrabarti R, Manalis SR (2007) Integrated microelectronic device for label-free nucleic acid amplification and detection. Lab Chip 7(3):347
Defever T, Druet M, Rochelet-Dequaire M, Joannes M, Grossiord C, Limoges B, Marchal D (2009) Real-time electrochemical monitoring of the polymerase chain reaction by mediated redox catalysis. J Am Chem Soc 131(32):11433
Fang TH, Ramalingam N, Dong XD, Ngin TS, Zeng XT, Kuan ATL, Huat EYP, Gong HQ (2009) Real-time pcr microfluidic devices with concurrent electrochemical detection. Biosens Bioelectron 24(7):2131
Anne A, Cambril E, Chovin A, Demaille C (2010) Touching surface-attached molecules with a microelectrode: mapping the distribution of redox-labeled macromolecules by electrochemical-atomic force microscopy. Anal Chem 82(15):6353
Casero E, Vazquez L, Parra-Alfambra AM, Lorenzo E (2010) Afm, secm and qcm as useful analytical tools in the characterization of enzyme-based bioanalytical platforms. Analyst 135(8):1878
Acknowledgement
Financial support for this work was provided by the National Science Foundation grant (NSF-0901303) and by the WV EPSCoR. This work was also financially supported by the National Natural Science Foundation of China (20890112, 20825519, 20921063).
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Wei, MY., Guo, LH. & Famouri, P. DNA biosensors based on metallo-intercalator probes and electrocatalytic amplification. Microchim Acta 172, 247–260 (2011). https://doi.org/10.1007/s00604-010-0519-6
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DOI: https://doi.org/10.1007/s00604-010-0519-6