Fluorescent-based nanosensors for selective detection of a wide range of biological macromolecules: A comprehensive review

Thanks to their unique attributes, such as good sensitivity, selectivity, high surface-to-volume ratio, and versatile optical and electronic properties, fluorescent-based bioprobes have been used to create highly sensitive nano -biosensors to detect various biological and chemical agents. These sensors are superior to other analytical instrumentation techniques like gas chromatography, high-performance liquid chromatography, and capillary electrophoresis for being biodegradable, eco-friendly, and more economical, operational, and cost-effective. Moreover, several reports have also highlighted their application in the early detection of biomarkers associ-ated with drug-induced organ damage such as liver, kidney, or lungs. In the present work, we comprehensively overviewed the electrochemical sensors that employ nanomaterials (nanoparticles/colloids or quantum dots, carbon dots, or nanoscaled metal-organic frameworks, etc.) to detect a variety of biological macromolecules based on fluorescent emission spectra. In addition, the most important mechanisms and methods to sense amino acids, protein, peptides, enzymes, carbohydrates, neurotransmitters, nucleic acids, vitamins, ions, metals, and electrolytes, blood gases, drugs (i.e., anti-inflammatory agents and antibiotics), toxins, alkaloids, antioxidants, cancer biomarkers, urinary metabolites (i.e., urea, uric acid, and creatinine), and pathogenic microorganisms were outlined and compared in terms of their selectivity and sensitivity. Altogether, the small dimensions and capability of these nanosensors for sensitive, label-free, real-time sensing of chemical, biological, and pharma-ceutical agents could be used in array-based screening and in-vitro or in-vivo diagnostics. Although fluorescent nanoprobes are widely applied in determining biological macromolecules, unfortunately, they present many challenges and limitations. Efforts must be made to minimize such limitations in utilizing such nanobiosensors with an emphasis on their commercial developments. We believe that the current review can foster the wider incorporation of nanomedicine and will be of particular interest to researchers working on fluorescence tech-nology, material chemistry, coordination polymers, and related research areas

RATIOMETRIC NEAR-INFRARED FLUORESCENT PROBES FOR THE SENSITIVE DETECTION OF INTRACELLULAR pH AND BIO-THIOLS IN LIVE CELLS

In the past twenty years, fluorescence sensing and imaging based on fluorescent probes has been developed as an imperative technique due to the merits including excellent sensitivity, operational simplicity, instant time effectiveness and outstanding selectivity in the research areas such as mineralogy, gemology, biological medicine, materials and environmental engineering. Protons act as a significant role in a variety of pathological and physiological processes, and there are obvious differences in the pH among organelles: the pH in lysosomes is acid within the range of 4.5–5.5, whereas mitochondrial pH is basic that can be as high as 8.0. Abnormal intracellular pH is always an indication of a disrupted pH homeostasis in the whole cell. Furthermore, intracellular bio-thiols are vital to cell metabolism, which by either elevated or deficiency levels of bio-thiols will lead to some diseases. Possessing the advantages of avoiding systematic errors and undesirable photophysical properties of certain fluorophores, novel near-infrared ratiometric fluorescent sensors for the accurately monitoring intracellular pH and biothiols have become the spotlight in research topics. Throughout this dissertation, we firstly have designed and synthesized two novel rhodamine-based dyes with high fluorescence quantum yield, good pH stability large Stokes shifts and excellent photostability by introducing an additional amino residue with fused rings into a classic rhodamine skeleton. We also have constructed a fluorescent sensor by incorporating a receptor to one of these dyes and applied it as an effective sensor for the quick and sensitive monitoring of lysosomal pH fluctuations. Then, we have prepared two sets of ratiometric fluorescent probes for the sensitive detection of lysosomal pH values. The former series were based on π-conjugation modulation strategy, which was accomplished by conjugating a visible coumarin motif to a classic near-infrared hemicyanine skeleton via a vinyl linker. The lysosome-targeting goal was reached by introducing a morpholine ligand or a o-phenylenediamine group to the hemicyanine acceptor. For the latter series, we have obtained three near-infrared ratiometric fluorescent sensors containing a TPE as a donor and a rhodamine as an acceptor for the quantitative, sensitive and comparative analysis of lysosomal pH alterations through FRET and TBET approaches. Furthermore, we have prepared two near-infrared hybrid rhodol dyes for the ratiometric and sensitive visualization of pH value alterations in mitochondria taking advantage of conjugating typical hemicyanine fluorophores into a classic rhodol motif. Upon pH changes, a rhodol hydroxyl group in the probe acts as a spiropyran switch, resulting in the change of π-conjugation and the appearance of a new fluorescent peak. Due to the positive charge, these two novel rhodol dyes possessed the mitochondria-targeting property. In the end, besides the ratiometric fluorescent pH probes, we have reported a FRET-based fluorescent sensor for the ratiometric, selective and accurate detection of cysteine (Cys), which was achieved by linking a visible coumarin skeleton and a near-infrared rhodamine motif through a piperazine spacer. This probe could be used to monitor the intracellular cysteine concentration ratiometrically and be further applied for imaging of Drosophila melanogaster larvae to detect cysteine concentration alterations in vivo

Chromogenic and fluorogenic chemosensors and reagents for anions. A comprehensive review of the years 2010-2011

This review focuses on examples reported in the years 2010¿2011 dealing with the design of chromogenic and fluorogenic chemosensors or reagents for anions.Santos Figueroa, LE.; Moragues Pons, ME.; Climent Terol, E.; Agostini, A.; Martínez Mañez, R.; Sancenón Galarza, F. (2013). Chromogenic and fluorogenic chemosensors and reagents for anions. A comprehensive review of the years 2010-2011. Chemical Society Reviews. 42(8):3489-3613. doi:10.1039/C3CS35429FS34893613428Martínez-Máñez, R., & Sancenón, F. (2003). Fluorogenic and Chromogenic Chemosensors and Reagents for Anions. Chemical Reviews, 103(11), 4419-4476. doi:10.1021/cr010421eKatayev, E. A., Ustynyuk, Y. A., & Sessler, J. L. (2006). Receptors for tetrahedral oxyanions. Coordination Chemistry Reviews, 250(23-24), 3004-3037. doi:10.1016/j.ccr.2006.04.013Suksai, C., & Tuntulani, T. (2003). Chromogenic anion sensors. Chemical Society Reviews, 32(4), 192. doi:10.1039/b209598jKim, S. K., Lee, D. H., Hong, J.-I., & Yoon, J. (2009). Chemosensors for Pyrophosphate. Accounts of Chemical Research, 42(1), 23-31. doi:10.1021/ar800003fBeer, P. (2000). Electrochemical and optical sensing of anions by transition metal based receptors. Coordination Chemistry Reviews, 205(1), 131-155. doi:10.1016/s0010-8545(00)00237-xZhou, Y., Xu, Z., & Yoon, J. (2011). Fluorescent and colorimetric chemosensors for detection of nucleotides, FAD and NADH: highlighted research during 2004–2010. Chemical Society Reviews, 40(5), 2222. doi:10.1039/c0cs00169dGunnlaugsson, T., Glynn, M., Tocci (née Hussey), G. M., Kruger, P. E., & Pfeffer, F. M. (2006). Anion recognition and sensing in organic and aqueous media using luminescent and colorimetric sensors. Coordination Chemistry Reviews, 250(23-24), 3094-3117. doi:10.1016/j.ccr.2006.08.017Amendola, V., Esteban-Gómez, D., Fabbrizzi, L., & Licchelli, M. (2006). What Anions Do to N−H-Containing Receptors. Accounts of Chemical Research, 39(5), 343-353. doi:10.1021/ar050195lGunnlaugsson, T., Ali, H. D. P., Glynn, M., Kruger, P. E., Hussey, G. M., Pfeffer, F. M., … Tierney, J. (2005). Fluorescent Photoinduced Electron Transfer (PET) Sensors for Anions; From Design to Potential Application. Journal of Fluorescence, 15(3), 287-299. doi:10.1007/s10895-005-2627-yWiskur, S. L., Ait-Haddou, H., Lavigne, J. J., & Anslyn, E. V. (2001). Teaching Old Indicators New Tricks. Accounts of Chemical Research, 34(12), 963-972. doi:10.1021/ar9600796Nguyen, B. T., & Anslyn, E. V. (2006). Indicator–displacement assays. Coordination Chemistry Reviews, 250(23-24), 3118-3127. doi:10.1016/j.ccr.2006.04.009Xu, Z., Chen, X., Kim, H. N., & Yoon, J. (2010). Sensors for the optical detection ofcyanide ion. Chem. Soc. Rev., 39(1), 127-137. doi:10.1039/b907368jKaur, K., Saini, R., Kumar, A., Luxami, V., Kaur, N., Singh, P., & Kumar, S. (2012). Chemodosimeters: An approach for detection and estimation of biologically and medically relevant metal ions, anions and thiols. Coordination Chemistry Reviews, 256(17-18), 1992-2028. doi:10.1016/j.ccr.2012.04.013Zhou, Y., & Yoon, J. (2012). Recent progress in fluorescent and colorimetric chemosensors for detection ofamino acids. Chem. Soc. Rev., 41(1), 52-67. doi:10.1039/c1cs15159bMoragues, M. E., Martínez-Máñez, R., & Sancenón, F. (2011). Chromogenic and fluorogenic chemosensors and reagents for anions. A comprehensive review of the year 2009. Chemical Society Reviews, 40(5), 2593. doi:10.1039/c0cs00015aAldrey, A., Núñez, C., García, V., Bastida, R., Lodeiro, C., & Macías, A. (2010). Anion sensing properties of new colorimetric chemosensors based on macrocyclic ligands bearing three nitrophenylurea groups. Tetrahedron, 66(47), 9223-9230. doi:10.1016/j.tet.2010.09.054Odago, M. O., Colabello, D. M., & Lees, A. J. (2010). A simple thiourea based colorimetric sensor for cyanide anion. Tetrahedron, 66(38), 7465-7471. doi:10.1016/j.tet.2010.07.006Piątek, P. (2011). A selective chromogenic chemosensor for carboxylate salt recognition. Chemical Communications, 47(16), 4745. doi:10.1039/c0cc05537aHe, X., Herranz, F., Cheng, E. C.-C., Vilar, R., & Yam, V. W.-W. (2010). Design, Synthesis, Photophysics, and Anion-Binding Studies of Bis(dicyclohexylphosphino)methane-Containing Dinuclear Gold(I) Thiolate Complexes with Urea Receptors. Chemistry - A European Journal, 16(30), 9123-9131. doi:10.1002/chem.201000647Lin, W.-C., Tseng, Y.-P., Lin, C.-Y., & Yen, Y.-P. (2011). Synthesis of alanine-based colorimetric sensors and enantioselective recognition of aspartate and malate anions. Organic & Biomolecular Chemistry, 9(15), 5547. doi:10.1039/c1ob05135kRegueiro-Figueroa, M., Djanashvili, K., Esteban-Gómez, D., de Blas, A., Platas-Iglesias, C., & Rodríguez-Blas, T. (2010). Towards Selective Recognition of Sialic Acid Through Simultaneous Binding to Its cis-Diol and Carboxylate Functions. European Journal of Organic Chemistry, 2010(17), 3237-3248. doi:10.1002/ejoc.201000186Carasel, I. A., Yamnitz, C. R., Winter, R. K., & Gokel, G. W. (2010). Halide Ions Complex and Deprotonate Dipicolinamides and Isophthalamides: Assessment by Mass Spectrometry and UV−Visible Spectroscopy. The Journal of Organic Chemistry, 75(23), 8112-8116. doi:10.1021/jo101749aRostami, A., Colin, A., Li, X. Y., Chudzinski, M. G., Lough, A. J., & Taylor, M. S. (2010). N,N′-Diarylsquaramides: General, High-Yielding Synthesis and Applications in Colorimetric Anion Sensing. The Journal of Organic Chemistry, 75(12), 3983-3992. doi:10.1021/jo100104gAmendola, V., Bergamaschi, G., Boiocchi, M., Fabbrizzi, L., & Milani, M. (2010). The Squaramide versus Urea Contest for Anion Recognition. Chemistry - A European Journal, 16(14), 4368-4380. doi:10.1002/chem.200903190Sola, A., Orenes, R. A., García, M. A., Claramunt, R. M., Alkorta, I., Elguero, J., … Molina, P. (2011). Unprecedented 1,3-Diaza[3]ferrocenophane Scaffold as Molecular Probe for Anions. Inorganic Chemistry, 50(9), 4212-4220. doi:10.1021/ic102314rLee, D. Y., Singh, N., Satyender, A., & Jang, D. O. (2011). An azo dye-coupled tripodal chromogenic sensor for cyanide. Tetrahedron Letters, 52(51), 6919-6922. doi:10.1016/j.tetlet.2011.10.061Haridas, V., Sahu, S., & Praveen Kumar, P. P. (2011). Triazole-based chromogenic and non-chromogenic receptors for halides. Tetrahedron Letters, 52(51), 6930-6934. doi:10.1016/j.tetlet.2011.10.066Park, J. J., Kim, Y.-H., Rhim, S., & Kang, J. (2012). Anion receptors with viologen molecular scaffold. Tetrahedron Letters, 53(2), 247-252. doi:10.1016/j.tetlet.2011.11.040Amendola, V., Fabbrizzi, L., Mosca, L., & Schmidtchen, F.-P. (2011). Urea-, Squaramide-, and Sulfonamide-Based Anion Receptors: A Thermodynamic Study. Chemistry - A European Journal, 17(21), 5972-5981. doi:10.1002/chem.201003411You, J.-M., Jeong, H., Seo, H., & Jeon, S. (2010). A new fluoride ion colorimetric sensor based on dipyrrolemethanes. Sensors and Actuators B: Chemical, 146(1), 160-164. doi:10.1016/j.snb.2010.02.042Farinha, A. S. F., Tomé, A. C., & Cavaleiro, J. A. S. (2010). (E)-3-(meso-Octamethylcalix[4]pyrrol-2-yl)propenal: a versatile precursor for calix[4]pyrrole-based chromogenic anion sensors. Tetrahedron Letters, 51(16), 2184-2187. doi:10.1016/j.tetlet.2010.02.091Lee, G. W., Kim, N.-K., & Jeong, K.-S. (2010). Synthesis of Biindole−Diazo Conjugates as a Colorimetric Anion Receptor. Organic Letters, 12(11), 2634-2637. doi:10.1021/ol100830bBose, P., & Ghosh, P. (2010). Visible and near-infrared sensing of fluoride by indole conjugated urea/thiourea ligands. Chemical Communications, 46(17), 2962. doi:10.1039/b919128cWang, L., He, X., Guo, Y., Xu, J., & Shao, S. (2011). Tris(indolyl)methene molecule as an anion receptor and colorimetric chemosensor: tunable selectivity and sensitivity for anions. Org. Biomol. Chem., 9(3), 752-757. doi:10.1039/c0ob00472cTetilla, M. A., Aragoni, M. C., Arca, M., Caltagirone, C., Bazzicalupi, C., Bencini, A., … Meli, V. (2011). Colorimetric response to anions by a «robust» copper(ii) complex of a [9]aneN3 pendant arm derivative: CN− and I− selective sensing. Chemical Communications, 47(13), 3805. doi:10.1039/c0cc04500dKundu, T., Mobin, S. M., & Lahiri, G. K. (2010). Paramagnetic ruthenium-biimidazole derivatives [(acac)2RuIII(LHn)]m, n/m = 2/+, 1/0, 0/−. Synthesis, structures, solution properties and anion receptor features in solution state. Dalton Transactions, 39(17), 4232. doi:10.1039/b919036hLee, C.-H., Lee, S., Yoon, H., & Jang, W.-D. (2011). Strong Binding Affinity of a Zinc-Porphyrin-Based Receptor for Halides through the Cooperative Effects of Quadruple CH Hydrogen Bonds and Axial Ligation. Chemistry - A European Journal, 17(49), 13898-13903. doi:10.1002/chem.201101884Swinburne, A. N., Paterson, M. J., Fischer, K. H., Dickson, S. J., Wallace, E. V. B., Belcher, W. J., … Steed, J. W. (2010). Colourimetric Carboxylate Anion Sensors Derived from Viologen-Based Receptors. Chemistry - A European Journal, 16(5), 1480-1492. doi:10.1002/chem.200902609Kannappan, R., Bucher, C., Saint-Aman, E., Moutet, J.-C., Milet, A., Oltean, M., … Chaix, C. (2010). Viologen-based redox-switchable anion-binding receptors. New Journal of Chemistry, 34(7), 1373. doi:10.1039/b9nj00757aKumari, N., Jha, S., & Bhattacharya, S. (2011). Colorimetric Probes Based on Anthraimidazolediones for Selective Sensing of Fluoride and Cyanide Ion via Intramolecular Charge Transfer. The Journal of Organic Chemistry, 76(20), 8215-8222. doi:10.1021/jo201290aAmendola, V., Boiocchi, M., Fabbrizzi, L., & Fusco, N. (2011). Putting the Anion into the Cage - Fluoride Inclusion in the Smallest Trisimidazolium Macrotricycle. European Journal of Organic Chemistry, 2011(32), 6434-6444. doi:10.1002/ejoc.201100902Kumar, A., Kumar, V., & Upadhyay, K. K. (2011). A ninhydrin based colorimetric molecular switch for Hg2+ and CH3COO−/F−. Tetrahedron Letters, 52(50), 6809-6813. doi:10.1016/j.tetlet.2011.10.046Bao, X., & Zhou, Y. (2010). Synthesis and recognition properties of a class of simple colorimetric anion chemosensors containing OH and CONH groups. Sensors and Actuators B: Chemical, 147(2), 434-441. doi:10.1016/j.snb.2010.03.068Lou, X., Zhang, Y., Li, Q., Qin, J., & Li, Z. (2011). A highly specific rhodamine-based colorimetric probe for hypochlorites: a new sensing strategy and real application in tap water. Chemical Communications, 47(11), 3189. doi:10.1039/c0cc04911eShang, X.-F., Su, H., Lin, H., & Lin, H.-K. (2010). A supramolecular optic sensor for selective recognition AMP. Inorganic Chemistry Communications, 13(8), 999-1003. doi:10.1016/j.inoche.2010.04.006Mendy, J. S., Saeed, M. A., Fronczek, F. R., Powell, D. R., & Hossain, M. A. (2010). Anion Recognition and Sensing by a New Macrocyclic Dinuclear Copper(II) Complex: A Selective Receptor for Iodide. Inorganic Chemistry, 49(16), 7223-7225. doi:10.1021/ic100686mMahato, P., Ghosh, A., Mishra, S. K., Shrivastav, A., Mishra, S., & Das, A. (2011). Zn(II)−Cyclam Based Chromogenic Sensors for Recognition of ATP in Aqueous Solution Under Physiological Conditions and Their Application as Viable Staining Agents for Microorganism. Inorganic Chemistry, 50(9), 4162-4170. doi:10.1021/ic200223gMahato, P., Ghosh, A., Mishra, S. K., Shrivastav, A., Mishra, S., & Das, A. (2010). Zn(II) based colorimetric sensor for ATP and its use as a viable staining agent in pure aqueous media of pH 7.2. Chemical Communications, 46(48), 9134. doi:10.1039/c0cc01996hDalla Cort, A., Forte, G., & Schiaffino, L. (2011). Anion Recognition in Water with Use of a Neutral Uranyl-salophen Receptor. The Journal of Organic Chemistry, 76(18), 7569-7572. doi:10.1021/jo201213eDas, P., Mandal, A. K., Kesharwani, M. K., Suresh, E., Ganguly, B., & Das, A. (2011). Receptor design and extraction of inorganic fluoride ion from aqueous medium. Chemical Communications, 47(26), 7398. doi:10.1039/c1cc11458aBaumes, L. A., Buaki, M., Jolly, J., Corma, A., & Garcia, H. (2011). Fluorimetric detection and discrimination of α-amino acids based on tricyclic basic dyes and cucurbiturils supramolecular assembly. Tetrahedron Letters, 52(13), 1418-1421. doi:10.1016/j.tetlet.2011.01.071Baumes, L. A., Buaki Sogo, M., Montes-Navajas, P., Corma, A., & Garcia, H. (2010). A Colorimetric Sensor Array for the Detection of the Date-Rape Drug γ-Hydroxybutyric Acid (GHB): A Supramolecular Approach. Chemistry - A European Journal, 16(15), 4489-4495. doi:10.1002/chem.200903127Chifotides, H. T., Schottel, B. L., & Dunbar, K. R. (2010). The π-Accepting Arene HAT(CN)6 as a Halide Receptor through Charge Transfer: Multisite Anion Interactions and Self-Assembly in Solution and the Solid State. Angewandte Chemie International Edition, 49(40), 7202-7207. doi:10.1002/anie.201001755Gu, X., Liu, C., Zhu, Y.-C., & Zhu, Y.-Z. (2011). Development of a boron-dipyrromethene-Cu2+ ensemble based colorimetric probe toward hydrogen sulfide in aqueous media. Tetrahedron Letters, 52(39), 5000-5003. doi:10.1016/j.tetlet.2011.07.004Männel-Croisé, C., Meister, C., & Zelder, F. (2010). «Naked-Eye» Screening of Metal-Based Chemosensors for Biologically Important Anions. Inorganic Chemistry, 49(22), 10220-10222. doi:10.1021/ic1015115Watchasit, S., Kaowliew, A., Suksai, C., Tuntulani, T., Ngeontae, W., & Pakawatchai, C. (2010). Selective detection of pyrophosphate by new tripodal amine calix[4]arene-based Cu(II) complexes using indicator displacement strategy. Tetrahedron Letters, 51(26), 3398-3402. doi:10.1016/j.tetlet.2010.04.095Mateus, P., Delgado, R., Brandão, P., & Félix, V. (2011). Recognition of Oxalate by a Copper(II) Polyaza Macrobicyclic Complex. Chemistry - A European Journal, 17(25), 7020-7031. doi:10.1002/chem.201100428Chen, Z., Lu, Y., He, Y., & Huang, X. (2010). Recognition of pyrophosphate anion in aqueous solution using the competition displacement method. Sensors and Actuators B: Chemical, 149(2), 407-412. doi:10.1016/j.snb.2010.06.038Müller-Graff, P.-K., Szelke, H., Severin, K., & Krämer, R. (2010). Pattern-based sensing of sulfated glycosaminoglycans with a dynamic mixture of iron complexes. Organic & Biomolecular Chemistry, 8(10), 2327. doi:10.1039/c000420kHu, Z.-Q., Wang, X.-M., Feng, Y.-C., Ding, L., Li, M., & Lin, C.-S. (2011). A novel colorimetric and fluorescent chemosensor for acetate ions in aqueous media based on a rhodamine 6G–phenylurea conjugate in the presence of Fe(iii) ions. Chem. Commun., 47(5), 1622-1624. doi:10.1039/c0cc04136jSingh, N., & Jang, D. O. (2011). A selective ATP chromogenic sensor for use in an indicator displacement assay. Tetrahedron Letters, 52(39), 5094-5097. doi:10.1016/j.tetlet.2011.07.096Ghosh, K., & Ranjan Sarkar, A. (2011). Pyridinium-based symmetrical diamides as chemosensors in visual sensing of citrate through indicator displacement assay (IDA) and gel formation. Organic & Biomolecular Chemistry, 9(19), 6551. doi:10.1039/c1ob05707cAtta, A. K., Ahn, I.-H., Hong, A.-Y., Heo, J., Kim, C. K., & Cho, D.-G. (2012). Fluoride indicator that functions in mixed aqueous media: hydrogen bonding effects. Tetrahedron Letters, 53(5), 575-578. doi:10.1016/j.tetlet.2011.11.099Perry-Feigenbaum, R., Sella, E., & Shabat, D. (2011). Autoinductive Exponential Signal Amplification: A Diagnostic Probe for Direct Detection of Fluoride. Chemistry - A European Journal, 17(43), 12123-12128. doi:10.1002/chem.201101796Rajamalli, P., & Prasad, E. (2011). Low Molecular Weight Fluorescent Organogel for Fluoride Ion Detection. Organic Letters, 13(14), 3714-3717. doi:10.1021/ol201325jBhaumik, C., Das, S., Maity, D., & Baitalik, S. (2011). A terpyridyl-imidazole (tpy-HImzPh3) based bifunctional receptor for multichannel detection of Fe2+ and F− ions. Dalton Transactions, 40(44), 11795. doi:10.1039/c1dt10965kIsaad, J., & Perwuelz, A. (2010). New color chemosensors for cyanide based on water soluble azo dyes. Tetrahedron Letters, 51(44), 5810-5814. doi:10.1016/j.tetlet.2010.08.098Wade, C. R., & Gabbaï, F. P. (2010). Cyanide Anion Binding by a Triarylborane at the Outer Rim of a Cyclometalated Ruthenium(II) Cationic Complex. Inorganic Chemistry, 49(2), 714-720. doi:10.1021/ic9020349Ábalos, T., Jiménez, D., Moragues, M., Royo, S., Martínez-Máñez, R., Sancenón, F., … Gil, S. (2010). Multi-channel receptors based on thiopyrylium functionalised with macrocyclic receptors for the recognition of transition metal cations and anions. Dalton Transactions, 39(14), 3449. doi:10.1039/b921486kÁbalos, T., Royo, S., Martínez-Máñez, R., Sancenón, F., Soto, J., Costero, A. M., … Parra, M. (2009). Surfactant-assisted chromogenic sensing of cyanide in water. New Journal of Chemistry, 33(8), 1641. doi:10.1039/b909705hSumiya, S., Doi, T., Shiraishi, Y., & Hirai, T. (2012). Colorimetric sensing of cyanide anion in aqueous media with a fluorescein–spiropyran conjugate. Tetrahedron, 68(2), 690-696. doi:10.1016/j.tet.2011.10.097Shiraishi, Y., Itoh, M., & Hirai, T. (2011). Rapid colorimetric sensing of cyanide anion in aqueous media with a spiropyran derivative containing a dinitrophenolate moiety. Tetrahedron Letters, 52(13), 1515-1519. doi:10.1016/j.tetlet.2011.01.110Shiraishi, Y., Itoh, M., & Hirai, T. (2011). Colorimetric response of spiropyran derivative for anions in aqueous or organic media. Tetrahedron, 67(5), 891-897. doi:10.1016/j.tet.2010.12.021Isaad, J., & Achari, A. E. (2011). Biosourced 3-formyl chromenyl-azo dye as Michael acceptor type of chemodosimeter for cyanide in aqueous environment. Tetrahedron, 67(31), 5678-5685. doi:10.1016/j.tet.2011.05.083Isaad, J., & El Achari, A. (2011). A novel cyanide chemodosimeter based on trifluoroacetamide benzhydrol-2 as binding motif: importance of substituent positioning on intra-molecular charge transfer. Tetrahedron, 67(23), 4196-4201. doi:10.1016/j.tet.2011.04.059Park, I. S., Heo, E.-J., & Kim, J.-M. (2011). A photochromic phenoxyquinone based cyanide ion sensor. Tetrahedron Letters, 52(19), 2454-2457. doi:10.1016/j.tetlet.2011.02.105Tang, X., Liu, W., Wu, J., Zhao, W., Zhang, H., & Wang, P. (2011). A colorimetric chemosensor for fast detection of thiols based on intramolecular charge transfer. Tetrahedron Letters, 52(40), 5136-5139. doi:10.1016/j.tetlet.2011.07.111Wei, W., Liang, X., Hu, G., Guo, Y., & Shao, S. (2011). 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Synthesis, Characterization, and Evaluation of Small Molecule-based Fluorogenic Probes for the Detection of Cellular Thiols

Fluorescence methods for disease diagnosis and detection of important analytes are becoming popular route as a technique, as they offer a simple non-invasive approach. Recently, many novel fluorophores and probes have been reported for selectively and sensitively detecting low abundance biological species in disease pathways. Biological thiols, such as glutathione, cysteine, and homocysteine, along with the smallest member hydrogen sulfide, are key thiol analytes in biological environments, and they play a vital role in living systems by maintaining the redox homeostasis of cells. Alteration of their ratios can cause cellular dysfunction and cell death. Furthermore, thiol levels in cells and biological fluids act as biomarkers of several diseases, including neurodegenerative disorders, liver disease, cystic fibrosis, pulmonary and cardiovascular diseases, and Alzheimer’s disease. Thus, the development of efficacious methods for detection and quantification of biological thiols has received significant attention in recent years. Although many traditional thiol detection methods are available, fluorescent methods hold more promise for simple, non-invasive detection with simple instrumentation. The work presented in this dissertation discusses the successful fluorescent detection of biologically important thiols with two probes HMBQ-Nap 1 and DCM-Cys. The HMBQ-Nap 1 probe consists of a hydroxymethyl benzoquinone trigger group (HMBQ) and 4-amino-9-(n-butyl)-1,8-naphthalimide (Nap 2) as the reporter dye. This probe led to excellent class selective detection of the free thiols glutathione, cysteine, and homocysteine versus other analytes found in the body. The second probe, DCM-Cys, is composed of a cysteine-selective acrylate moiety attached to dicyanomethylene-4H-pyran (DCM) reporter dye via a benzyl alcohol linker. DCM-Cys exhibited a remarkable ability to detect free cysteine in media versus other thiols and various potent analytes found in biological environments. Both HMBQ-Nap 1 and DCM-Cys offer nM in vitro detection, and successful in cyto imaging of thiols. Selectivity, a relative low limit of detection (nM), the ability to function under physiological conditions and a high signal-to-background ratio of these methods as well as low thiol-to-probe ratios for the qualitative and quantitative detection, and relatively short response time make these probes excellent systems for thiol analysis

Covalent organic frameworks as multifunctional materials for chemical detection

Sensitive and selective detection of chemical and biological analytes is critical in various scientific and technological fields. As an emerging class of multifunctional materials, covalent organic frameworks (COFs) with their unique properties of chemical modularity, large surface area, high stability, low density, and tunable pore sizes and functionalities, which together define their programmable properties, show promise in advancing chemical detection. This review demonstrates the recent progress in chemical detection where COFs constitute an integral component of the achieved function. This review highlights how the unique properties of COFs can be harnessed to develop different types of chemical detection systems based on the principles of chromism, luminescence, electrical transduction, chromatography, spectrometry, and others to achieve highly sensitive and selective detection of various analytes, ranging from gases, volatiles, ions, to biomolecules. The key parameters of detection performance for target analytes are summarized, compared, and analyzed from the perspective of the detection mechanism and structure–property–performance correlations of COFs. Conclusions summarize the current accomplishments and analyze the challenges and limitations that exist for chemical detection under different mechanisms. Perspectives on how future directions of research can advance the COF-based chemical detection through innovation in novel COF design and synthesis, progress in device fabrication, and exploration of novel modes of detection are also discussed

Visualization and Quantification of Cancer-associated Enzymes with Fluorescent Small-molecule Substrate Probes

Fluorescence imaging can be used both as a tool to diagnose diseases and guide treatment in clinical settings, and as a technique to monitor dynamic events or biological species in basic research. Therefore, there is a great need for the development of a multitude of fluorescent probes that can be incorporated with fluorescence imaging techniques to track and report endogenous enzymes with high specificity and selectivity. In contrast to always-on and targeted always-on fluorescent probes that continually emit light, activity-based substrate probes either emit low numbers of photons or are completely quenched. They can be converted to highly fluorescent reporters by specific upregulated enzymes, thus offering a high target-to-background ratios contrast. Fluorescent probes have a promising impact in fluorescence-guided cytoreductive surgery, but complete resection in every patient is highly unlikely. Probes that emit near-infrared (NIR) light are more suitable for in vivo imaging. Therefore, in this work, hNQO1-activatable NIR imaging probes (Q3STCy and Q3NTCy) with different eliminating linker and different affinities for hNQO1 were developed. These probes were successful in imaging clinically relevant multicellular tumor spheroids (MCTSs) possessing spatially heterogeneous NQO1 activities and in identifying sub-millimeter dimension metastases in a preclinical mouse model of human ovarian serous adenocarcinoma. To further diversify the research, ratiometric probes (GalNap and CysTy) with the capability to quantify the enzyme beta-Galactosidase and cysteine were developed. GalNap was used in the real-time detection of beta-Galactosidase in human ovarian cancer cells and CysTy was used to detect cysteine in human plasma. As an initiative to contribute to effective cytoreductive surgery, a chemical agent (Q3Pyro) was designed and synthesized that can not only light up, but can also be toxic toward hNQO1-expressing tumor tissues. With various imaging and cell assays, the probe was validated to perform as both a profluorogenic probe and a prodrug

Molecular Probes, Chemosensors, and Nanosensors for Optical Detection of Biorelevant Molecules and Ions in Aqueous Media and Biofluids

Synthetic molecular probes, chemosensors, and nanosensors used in combination with innovative assay protocols hold great potential for the development of robust, low-cost, and fast-responding sensors that are applicable in biofluids (urine, blood, and saliva). Particularly, the development of sensors for metabolites, neurotransmitters, drugs, and inorganic ions is highly desirable due to a lack of suitable biosensors. In addition, the monitoring and analysis of metabolic and signaling networks in cells and organisms by optical probes and chemosensors is becoming increasingly important in molecular biology and medicine. Thus, new perspectives for personalized diagnostics, theranostics, and biochemical/medical research will be unlocked when standing limitations of artificial binders and receptors are overcome. In this review, we survey synthetic sensing systems that have promising (future) application potential for the detection of small molecules, cations, and anions in aqueous media and biofluids. Special attention was given to sensing systems that provide a readily measurable optical signal through dynamic covalent chemistry, supramolecular host–guest interactions, or nanoparticles featuring plasmonic effects. This review shall also enable the reader to evaluate the current performance of molecular probes, chemosensors, and nanosensors in terms of sensitivity and selectivity with respect to practical requirement, and thereby inspiring new ideas for the development of further advanced systems

Design and Analysis of Cloaked Fluorophores for Rapid Detection and Visualization of Cancer Cells Containing NAD(P)H:Quinone Oxidoreductase-1

The development of fluorogenic substrates for real-time tumor cell detection has led to a vastly expanding field for personal oncology. Fluorophores have been studied as appendages to larger scaffolds leading to accumulation of these dyes in tumor cells or their surrounding environment, taking advantage of tumor anatomy. A new class of fluorophores has been developed in which the dye is an active participant in the mechanism of cancer cell detection. These dyes have been conjugated such that their fluorescence has been eliminated or altered and will undergo a change to reveal their fluorescent signal upon activation by a mechanism that is unique to tumor cells. The research presented in this dissertation encompasses the design, synthesis, properties, and utilization of latent fluorophores that are specifically activated by an enzyme that is highly upregulated in tumor cells, NAD(P)H:quinone oxidoreductase-1 (NQO1). These dyes utilize the 2-electron reduction of quinones to hydroquinones, which NQO1 specifically catalyzes. A dye’s fluorescence can be quenched by conjugating a quinone directly to the fluorophore, only to have its signal uncloaked after activation by NQO1. The objectives in this research will be achieved by: (1) the characterization of properties (stability in biological environments, quantum yields) of the quinone, dyes, and their conjugated counterparts; (2) determination of kinetic parameters (Michaelis constant (Km), theoretical maximum velocity (Vmax), catalytic constant (kcat), enzyme efficiency (kcat/Km) of the substrates towards NQO1 and the way solvent affects such parameters during assay conditions; and (3) utilization of a latent fluorophore for in vivo NQO1 analysis (widefield imaging, confocal single-/two-photon microscopy, flow cytometry) and determining the fate of the released fluorophore. Integration of these studies led to the development of two different latent fluorophores that are readily activated by NQO1. Of these two fluorogenic cancer sensors, one was found to possess a highly novel quenching mechanism between the quinone and the dye

Supramolecular Luminescent Sensors

There is great need for stand-alone luminescence-based chemosensors that exemplify selectivity, sensitivity, and applicability and that overcome the challenges that arise from complex, real-world media. Discussed herein are recent developments toward these goals in the field of supramolecular luminescent chemosensors, including macrocycles, polymers, and nanomaterials. Specific focus is placed on the development of new macrocycle hosts since 2010, coupled with considerations of the underlying principles of supramolecular chemistry as well as analytes of interest and common luminophores. State-of-the-art developments in the fields of polymer and nanomaterial sensors are also examined, and some remaining unsolved challenges in the area of chemosensors are discussed

Near infrared fluorescent sensors for selective glucose recognition

With diabetes becoming a major health concern worldwide, it is growing clear that novel technologies are needed to monitor blood glucose in a manner that is continuous, real-time, and long-term --all while alleviating the burden of pain on the patient. Current meters commonly used for glucose are invasive in nature and require blood samples to offer intermittent readings on blood glucose levels. Despite extensive research on developing minimally invasive or non-invasive ways to monitor blood glucose levels, this objective has remained elusive. Previous attempts in providing a minimally invasive sensor for in vivo blood glucose detection via fluorescence spectroscopy have offered excellent information on how to design and develop a glucose recognition motif while at the same time suffer from a number of limitations such as poor water solubility, stability, and impractical spectroscopic features for in vivo sensing. To realize a viable sensor for long term in vivo monitoring of blood glucose, near IR pH probes based on cyanine fluorophores were designed and synthesized. These probes provided insight into practicality of cyaninebased near IR sensors for use in vivo and served as a starting point to achieve the ultimate goal of glucose recognition. By uniting the methodology for near IR pH sensing and the required architecture for glucose recognition, several NIR glucose sensors based on cyanine platforms were designed, synthesized, and tested