The development of a simple and accurate quantitative method for the determination of 6-mercaptopurine (6-MP) is of great importance because of its serious side effects. Ratiometric fluorescence (RF) sensors are not subject to interference from environmental factors, and exhibit enhanced precision and accuracy. Therefore, a novel RF sensor for the selective detection of 6-MP was developed. The present work reports a sensitive and selective RF sensor for the detection of 6-mercaptopurine, by hybridizing carbon nanodots (CDots) and gold nanoclusters (AuNCs) capped with bovine serum albumin (BSA). The CDots serve as the reference signal and the AuNCs as the reporter. On addition of the 6-MP, AuNCs formed aggregates, because the existing cross-links within the AuNCs and BSA structure were broken in favour of the Au-S bonds, which can enhance the fluorescence of AuNCs, while the fluorescence of CDots is stable against 6-MP, leading to distinct ratiometric fluorescence changes when exposed to 6-MP. 6-MP could be detected in the range of 0 - 30.22 μM with a detection limit of 54 nM. The developed sensor was applied for the determination of 6-MP in human serum samples and satisfactory results were obtained.
References
[1]
Sahasranaman, S., Howard, D. and Roy, S. (2008) Clinical Pharmacology and Pharmacogenetics of Thiopurines. European Journal of Clinical Pharmacology, 64, 753-767. https://doi.org/10.1007/s00228-008-0478-6
[2]
Nielsen, O.H., Vainer, B. and Rask-Madsen, J. (2001) Review Article: The Treatment of Inflammatory Bowel Disease with 6-Mercaptopurine or Azathioprine. Alimentary Pharmacology & Therapeutics, 15, 1699-1708. https://doi.org/10.1046/j.1365-2036.2001.01102.x
[3]
Kanemitsu, H., Yamauchi, H., Komatsu, M., Yamamoto, S., Okazaki, S., Uchida, K. and Nakayama, H. (2009) 6-Mercaptopurine (6-MP) Induces Cell Cycle Arrest and Apoptosis of Neural Progenitor Cells in the Developing Fetal Rat Brain. Neurotoxicology and Teratology, 31, 104-109. https://doi.org/10.1016/j.ntt.2008.10.001
[4]
Su, Y., Hen, Y.Y., Chu, Y.Q., Van de Poll, M.E.C. and Relling, M.V. (1999) Assay of 6-Mercaptopurine and Its Metabolites in Patient Plasma by High-Performance Liquid Chromatography with Diode-Array Detection. Journal of Chromatography B: Biomedical Sciences and Applications, 732, 459-468. https://doi.org/10.1016/S0378-4347(99)00311-4
[5]
Zimm, S., Collins, J.M., Riccardi, R., O’Neill, D., Narang, P.K., Chabner, B. and Poplack, D.G. (1983) Variable Bioavailability of Oral Mercaptopurine Is Maintenance Chemotherapy in Acute Lymphoblastic Leukemia Being Optimally Delivered. The New England Journal of Medicine, 308, 1005-1009. https://doi.org/10.1056/NEJM198304283081705
[6]
Jacqz-Aigrain, E., Nafa, S., Médard, Y., Bessa, E., Lescoeur, B. and Vilmer, E. (1997) Pharmacokinetics and Distribution of 6-Mercaptopurine Administered Intravenously in Children with Lymphoblastic Leukaemia. European Journal of Clinical Pharmacology, 53, 71-74. https://doi.org/10.1007/s002280050339
[7]
Vinita, T.M., Agnihotri, N., Singh, M., Singh, A.K. and Prakash, R. (2019) Nanonetwork of Coordination Polymer AHMT-Ag for the Effective and Broad Spectrum Detection of 6-Mercaptopurine in Urine and Blood Serum. ACS Omega, 4, 16733-16742. https://doi.org/10.1021/acsomega.9b01122
[8]
Kumar, A., Pathak, P.K. and Prasad, B.B. (2019) Electrocatalytic Imprinted Polymer of N-Doped Hollow Carbon Nanosphere-Palladium Nanocomposite for Ultratrace Detection of Anticancer Drug 6-Mercaptopurine. ACS Applied Materials & Interfaces, 11, 16065-16074. https://doi.org/10.1021/acsami.9b02947
[9]
Hanko, M., Svorc, L., Plankova, A. and Mikus, P. (2019) Novel Electrochemical Strategy for Determination of 6-Mercaptopurine Using Anodically Pretreated Boron-Doped Diamond Electrode. Journal of Electroanalytical Chemistry, 840, 295-304. https://doi.org/10.1016/j.jelechem.2019.03.067
[10]
Hatamluyi, B. and Es’haghi, Z. (2018) Electrochemical Biosensing Platform Based on Molecularly Imprinted Polymer Reinforced by ZnO-Graphene Capped Quantum Dots for 6-Mercaptopurine Detection. Electrochimica Acta, 283, 1170-1177. https://doi.org/10.1016/j.electacta.2018.07.068
[11]
Cao, X.N., Lin, L., Zhou, Y.Y., Shi, G.Y., Zhang, W., Yamamoto, K. and Jin, L.T. (2003) Amperometric Determination of 6-Mercaptopurine on Functionalized Multi-Wall Carbon Nanotubes Modified Electrode by Liquid Chromatography Coupled with Microdialysis and Its Application to Pharmacokinetics in Rabbit. Talanta, 60, 1063-1070. https://doi.org/10.1016/S0039-9140(03)00187-5
[12]
Sun, H.W., Wang, T., Liu, X.Y. and Chen, P.Y. (2013) A Sensitive Inhibition Chemiluminescence Method for the Determination of 6-Mercaptopurine in Tablet and Biological Fluid Using the Reaction of Luminol-Ag(III) Complex in Alkaline Medium. Journal of Luminescence, 134, 154-159. https://doi.org/10.1016/j.jlumin.2012.08.056
[13]
Biparva, P., Abedirad, S.M. and Kazemi, S.Y. (2015) Silver Nanoparticles Enhanced a Novel TCPO-H2O2-Safranin O Chemiluminescence System for Determination of 6-Mercaptopurine. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 145, 454-460. https://doi.org/10.1016/j.saa.2015.03.019
[14]
Somasekhar, V. (2014) Optimization and Validation of an RP-HPLC Method for the Estimation of 6-Mercaptopurine in Bulk and Pharmaceutical Formulations. Brazilian Journal of Pharmaceutical Sciences, 50, 793-797. https://doi.org/10.1590/S1984-82502014000400015
[15]
Zakrzewski, R., Borowczyk, K., Luczak, A., Mlynarski, W. and Trelinska, J. (2013) Determination of Urinary 6-Mercaptopurine and Three of Its Metabolites by HPLC-UV Coupled with the Iodine-Azide Reaction. Bioanalysis, 5, 869-877. https://doi.org/10.4155/bio.13.46
[16]
Diamai, S., Warjri, W., Saha, D. and Negi, D.P.S. (2018) Sensitive Determination of 6-Mercaptopurine Based on the Aggregation of Phenylalanine-Capped Gold Nanoparticles. Colloid Surface A, 538, 593-599. https://doi.org/10.1016/j.colsurfa.2017.11.052
[17]
Zhang, L.X., Li, H.L., Chu, G., Luo, L., Jin, J., Zhao, B. and Tian, Y. (2016) Detection of 6-Mercaptopurine by Silver Nanowires-Coated Silicon Wafer Based on Surface-Enhanced Raman Scattering Spectroscopy. Colloid Surface A, 508, 309-315. https://doi.org/10.1016/j.colsurfa.2016.08.069
[18]
Yang, L., Chen, Y.H., Li, H.L., Luo, L., Zhao, Y., Zhang, H.Q. and Tian, Y. (2015) Application of Silver Nanoparticles Decorated with Beta-Cyclodextrin in Determination of 6-Mercaptopurine by Surface-Enhanced Raman Spectroscopy. Analytical Methods, 7, 6520-6527. https://doi.org/10.1039/C5AY01212K
[19]
Zhang, F., Liu, H., Liu, Q. and Su, X.G. (2018) An Enzymatic Ratiometric Fluorescence Assay for 6-Mercaptopurine by Using MoS2 Quantum Dots. Microchimica Acta, 185, 540-547. https://doi.org/10.1007/s00604-018-3039-4
[20]
Jin, M., Mou, Z.L., Zhang, R.L., Liang, S.S. and Zhang, Z.Q. (2017) An Efficient Ratiometric Fluorescence Sensor Based on Metal-Organic Frameworks and Quantum Dots for Highly Selective Detection of 6-Mercaptopurine. Biosensors and Bioelectronics, 91, 162-168. https://doi.org/10.1016/j.bios.2016.12.022
[21]
Shen, X.C., Jiang, L.F., Liang, H., Lu, X., Zhang, L.J. and Liu, X.Y. (2006) Determination of 6-Mercaptopurine Based on the Fluorescence Enhancement of Au Nanoparticles. Talanta, 69, 456-462. https://doi.org/10.1016/j.talanta.2005.10.017
[22]
Yuan, Y., Wang, Y., Liu, S., Li, Y., Duan, R., Zhang, H. and Hu, X. (2016) Fluorescence Quenching and Spectrophotometric Methods for the Determination of 6-Mercaptopurine Based on Carbon dots. RSC Advances, 6, 52255-52263. https://doi.org/10.1039/C6RA07675K
[23]
Li, Z., Wang, Y., Ni, Y.N. and Kokot, S. (2015) Fluorescence Analysis of 6-Mercaptopurine with the Use of a Nano-Composite Consisting of BSA-Capped Au Nano-Clusters and Core-Shell Fe3O4-SiO2 Nanoparticles. Biosensors and Bioelectronics, 70, 246-253. https://doi.org/10.1016/j.bios.2015.03.035
[24]
Chen, Z., Zhang, G., Chen, X., Chen, J., Liu, J. and Yuan, H. (2013) A Fluorescence Switch Sensor for 6-Mercaptopurine Detection Based on Gold Nanoparticles Stabilized by Biomacromolecule. Biosensors and Bioelectronics, 41, 844-847. https://doi.org/10.1016/j.bios.2012.07.079
[25]
Gao, M.X., Xu, J.L., Li, Y.F. and Huang, C.Z. (2013) A Rapid and Sensitive Spectrofluorometric Method for 6-Mercaptopurine Using CdTe Quantum Dots. Analytical Methods, 5, 673-677. https://doi.org/10.1039/C2AY25971K
[26]
Li, Z., Ni, Y. and Kokot, S. (2015) A New Fluorescent Nitrogen-Doped Carbon Dot System Modified by the Fluorophore-Labeled ssDNA for the Analysis of 6-Mercaptopurine and Hg(II). Biosensors and Bioelectronics, 74, 91-97. https://doi.org/10.1016/j.bios.2015.06.014
[27]
Wang, L. and Zhang, Z.J. (2008) The Study of Oxidization Fluorescence Sensor with Molecular Imprinting Polymer and Its Application for 6-Mercaptopurine (6-MP) Determination. Talanta, 76, 768-771. https://doi.org/10.1016/j.talanta.2008.04.024
[28]
Choi, J.Y., Kim, G.H., Guo, Z.Q., Lee, H.Y., Swamy, K.M.K., Pai, J., Shin, S., Shin, I. and Yoon, J. (2013) Highly Selective Ratiometric Fluorescent Probe for Au3+ and Its Application to Bioimaging. Biosensors and Bioelectronics, 49, 438-441. https://doi.org/10.1016/j.bios.2013.05.033
[29]
Lei, Y.J., Xue, C., Zhang, S.C. and Sha, Y.W. (2016) A Ratiometric Fluorescent Probe for Sensing Hydrogen Peroxide Based on a Hemicyanine-Naphthol Fluorophore. Luminescence, 31, 660-664. https://doi.org/10.1002/bio.3008
[30]
Zhao, A.D., Chen, Z.W., Zhao, C.Q., Gao, N., Ren, J.S. and Qu, X.G. (2015) Recent Advances in Bioapplications of C-Dots. Carbon, 85, 309-327. https://doi.org/10.1016/j.carbon.2014.12.045
[31]
Zheng, Y.K., Lai, L.M., Liu, W.W., Jiang, H. and Wang, X.M. (2017) Recent Advances in Biomedical Applications of Fluorescent Gold Nanoclusters. Advances in Colloid and Interface Science, 242, 1-16. https://doi.org/10.1016/j.cis.2017.02.005
[32]
Ren, X.L., Ge, J.J., Li, S., Shao, H.B., Qiu, X.Z., Tang, F.Q. and Meng, X.W. (2017) A Dual-Emission Nanohybrid of Gold Nanoclusters and Carbon Dots for Ratiometric Fluorescence Detection of Reactive Oxygen Species and Glucose. Journal of Biomedical Nanotechnology, 13, 1425-1434. https://doi.org/10.1166/jbn.2017.2432
[33]
Ju, E.G., Liu, Z., Du, Y.D., Tao, Y., Ren, J.S. and Qu, X.G. (2014) Heterogeneous Assembled Nanocomplexes for Ratiometric Detection of Highly Reactive Oxygen Species in Vitro and in Vivo. Acs Nano, 8, 6014-6023. https://doi.org/10.1021/nn501135m
[34]
Niu, W.J., Shan, D., Zhu, R.H., Deng, S.Y., Cosnier, S. and Zhang, X.J. (2016) Dumbbell-Shaped Carbon Quantum dots/AuNCs Nanohybrid as an Efficient Ratiometric Fluorescent Probe for Sensing Cadmium(II) Ions and L-Ascorbic Acid. Carbon, 96, 1034-1042. https://doi.org/10.1016/j.carbon.2015.10.051
[35]
Li, Z.H., Guo, S., Yuan, Z.Q. and Lu, C. (2017) Carbon Quantum Dot-Gold Nanocluster nanoSatellite for Ratiometric Fluorescence Probe and Imaging for Hydrogen Peroxide in Living Cells. Sensors and Actuators B: Chemical, 241, 821-827. https://doi.org/10.1016/j.snb.2016.10.134
[36]
Xie, H.Z., Dong, J., Duan, J.L., Waterhouse, G.I.N., Hou, J.Y. and Ai, S.Y. (2018) Visual and Ratiometric Fluorescence Detection of Hg2+ Based on a Dual-Emission Carbon Dots-Gold Nanoclusters Nanohybrid. Sensors and Actuators B: Chemical, 259, 1082-1089. https://doi.org/10.1016/j.snb.2017.12.149
[37]
Liu, W., Wang, X.Y., Wang, Y.Q., Li, J.H., Shen, D.Z., Kang, Q. and Chen, L.X. (2018) Ratiometric Fluorescence Sensor Based on Dithiothreitol Modified Carbon Dots-Gold Nanoclusters for the Sensitive Detection of Mercury Ions in Water Samples. Sensors and Actuators B: Chemical, 262, 810-817. https://doi.org/10.1016/j.snb.2018.01.222
[38]
Yan, Y.H., Yu, H., Zhang, K., Sun, M.T., Zhang, Y.J., Wang, X.K. and Wang, S.H. (2016) Dual-Emissive Nanohybrid of Carbon Dots and Gold Nanoclusters for Sensitive Determination of Mercuric Ions. Nano Research, 9, 2088-2096. https://doi.org/10.1007/s12274-016-1099-5
[39]
He, Y.S., Pan, C.G., Cao, H.X., Yue, M.Z., Wang, L. and Liang, G.X. (2018) Highly Sensitive and Selective Dual-Emission Ratiometric Fluorescence Detection of Dopamine Based on Carbon Dots-Gold Nanoclusters Hybrid. Sensors and Actuators B: Chemical, 265, 371-377. https://doi.org/10.1016/j.snb.2018.03.080
[40]
Yu, X., Zhang, C.X., Zhang, L.N., Xue, Y.R., Li, H.W. and Wu, Y.Q. (2018) The Construction of a FRET Assembly by Using Gold Nanoclusters and Carbon Dots and Their Application as a Ratiometric Probe for Cysteine Detection. Sensors and Actuators B: Chemical, 263, 327-335. https://doi.org/10.1016/j.snb.2018.02.072
[41]
Gui, R.J., He, W.J., Jin, H., Sun, J. and Wang, Y.F. (2018) DNA Assembly of Carbon Dots and 5-Fluorouracil Used for Room-Temperature Phosphorescence Turn-On Sensing of AFP and AFP-Triggered Simultaneous Release of Dual-Drug. Sensors and Actuators B: Chemical, 255, 1623-1630. https://doi.org/10.1016/j.snb.2017.08.178
[42]
Xie, J.P., Zheng, Y.G. and Ying, J.Y. (2009) Protein-Directed Synthesis of Highly Fluorescent Gold Nanoclusters. Journal of the American Chemical Society, 131, 888-889. https://doi.org/10.1021/ja806804u
[43]
Zhao, Q., Chen, S.N., Zhang, L.Y., Huang, H.W., Zeng, Y.L. and Liu, F.P. (2014) Multiplex Sensor for Detection of Different Metal Ions Based on On-Off of Fluorescent Gold Nanoclusters. Analytica Chimica Acta, 852, 236-243. https://doi.org/10.1016/j.aca.2014.09.029
[44]
Ding, H., Liang, C., Sun, K.B., Wang, H., Hiltunen, J.K., Chen, Z.J. and Shen, J.C. (2014) Dithiothreitol-Capped Fluorescent Gold Nanoclusters: An Efficient Probe for Detection of Copper(II) Ions in Aqueous Solution. Biosensors and Bioelectronics, 59, 216-220. https://doi.org/10.1016/j.bios.2014.03.045
[45]
Bain, D., Maity, S., Paramanik, B. and Patra, A. (2018) Core-Size Dependent Fluorescent Gold Nanoclusters and Ultrasensitive Detection of Pb2+ Ion. ACS Sustainable Chemistry & Engineering, 6, 2334-2343. https://doi.org/10.1021/acssuschemeng.7b03794
[46]
Zhang, H.Y., Liu, Q., Wang, T., Yun, Z.J., Li, G.L., Liu, J.Y. and Jiang, G.B. (2013) Facile Preparation of Glutathione-Stabilized Gold Nanoclusters for Selective Determination of Chromium(III) and Chromium(VI) in Environmental Water Samples. Analytica Chimica Acta, 770, 140-146. https://doi.org/10.1016/j.aca.2013.01.042