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Chromo-fluorogenic probes for β-galactosidase detection

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Abstract

β-Galactosidase (β-Gal) is a widely used enzyme as a reporter gene in the field of molecular biology which hydrolyzes the β-galactosides into monosaccharides. β-Gal is an essential enzyme in humans and its deficiency or its overexpression results in several rare diseases. Cellular senescence is probably one of the most relevant physiological disorders that involve β-Gal enzyme. In this review, we assess the progress made to date in the design of molecular-based probes for the detection of β-Gal both in vitro and in vivo. Most of the reported molecular probes for the detection of β-Gal consist of a galactopyranoside residue attached to a signalling unit through glycosidic bonds. The β-Gal-induced hydrolysis of the glycosidic bonds released the signalling unit with remarkable changes in color and/or emission. Additional examples based on other approaches are also described. The wide applicability of these probes for the rapid and in situ detection of de-regulation β-Gal–related diseases has boosted the research in this fertile field.

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References

  1. Fernandes P. Enzymes in food processing: a condensed overview on strategies for better biocatalysts. Enzyme Res. 2010;2010:86253–73.

    Article  Google Scholar 

  2. Likidlilid A, Patchanans N, Peerapatdit T, Sriratanasathavorn C. Lipid peroxidation and antioxidant enzyme activities in erythrocytes of type 2 diabetic patients. J Med Assoc Thail. 2010;93(6):682–93.

    Google Scholar 

  3. Pinto N, Dolan ME. Clinically relevant genetic variations in drug metabolizing enzymes. Curr Drug Metab. 2011;12(5):487–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Giannini EG, Testa R, Savarinom V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005;172(3):367–79.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Peters C, Shapiro EG, Krivit W. Hurler syndrome: past, present, and future. J Pediatr. 1998;133(1):7–9.

    Article  CAS  PubMed  Google Scholar 

  6. Rodriguez M, O'Brien JS, Garrett RS, Powell HC. Canine GM1 gangliosidosis: an ultrastructural and biochemical study. J Neuropathol Exp Neurol. 1982;41(6):618–29.

    Article  CAS  PubMed  Google Scholar 

  7. Cozma C, Eichler S, Wittmann G, Flores Bonet A, Kramp G, Giese AK, et al. Diagnosis of Morquio syndrome in dried blood spots based on a new MRM-MS assay. PLoS One. 2015;10(7):e0131228.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Suzuki K, Suzuki Y. Globoid cell leucodystrophy (Krabbe's disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci U S A. 1970;66(2):302–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Holtzman D, Ulrich J. Senescent glia spell trouble in Alzheimer’s disease. Nat Neurosci. 2019;22(5):683–4.

    Article  CAS  PubMed  Google Scholar 

  10. Robert L, Fulop T. Aging: facts and theories. Indian J Med Res. 2016;143(3):385–6.

    Article  Google Scholar 

  11. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995;92(20):9363–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Biran A, Zada L, Karam PA, Vadai E, Roitman L, et al. Quantitative identification of senescent cells in aging and disease. Aging Cell. 2017;16(4):661–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Grynkiewicz G, Poenie M, Tsien RY, Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly fluorescence properties. J Biol Chem. 1985;260(6):3440–50.

    Article  CAS  PubMed  Google Scholar 

  14. de Silva AP, Gunaratne HQN, Gunnlaugsson T, Huxley AJ, McCoy CP, Rademacher JT, et al. Signaling recognition events with fluorescent sensors and switches. Chem Rev. 1997;97(5):1515–66.

    Article  PubMed  Google Scholar 

  15. Que EL, Domaille DW, Chang CJ. Metals in neurobiology: probing their chemistry and biology with molecular imaging. Chem Rev. 2008;108(5):1517–49.

    Article  CAS  PubMed  Google Scholar 

  16. Ueno T, Nagano T. Fluorescent probes for sensing and imaging. Nat Methods. 2011;8(8):642–5.

    Article  CAS  PubMed  Google Scholar 

  17. Kobayashi H, Ogawa M, Alford R, Choyke PL, Urano Y. New strategies for fluorescent probe design in medical diagnostic imaging. Chem Rev. 2010;110(5):2620–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Valeur B, Leray I. Design principles of fluorescent molecular sensors for cation recognition. Coord Chem Rev. 2000;205(1):3–40.

    Article  CAS  Google Scholar 

  19. Kim HM, Cho BR. Small-molecule two-photon probes for bioimaging applications. Chem Rev. 2015;115(11):5014–55.

    Article  CAS  PubMed  Google Scholar 

  20. Huang J, Pu K. Activatable molecular probes for second near-infrared fluorescence, chemiluminescence, and photoacoustic imaging. Angew Chem Int Ed. 2020;59(29):11717–31.

    Article  CAS  Google Scholar 

  21. Miao Q, Pu K. Organic semiconducting agents for deep-tissue molecular imaging: second near-infrared fluorescence, self-luminescence, and photoacoustics. Adv Mater. 2018;30(49):e1801778.

    Article  PubMed  Google Scholar 

  22. Cheng P, Miao Q, Li J, Huang J, Xie C, Pu K. Unimolecular chemo-fluoro-luminescent reporter for crosstalk-free duplex imaging of hepatotoxicity. J Am Chem Soc. 2019;141(27):10581–4.

    Article  CAS  PubMed  Google Scholar 

  23. Wei H, Wu G, Tian X, Liu Z. Smart fluorescent probes for in situ imaging of enzyme activity: design strategies and applications. Future Med Chem. 2018;10(23):2729–44.

    Article  CAS  Google Scholar 

  24. Liu HW, Chen L, Xu C, Li Z, Zhang H, Zhang XB, et al. Recent progresses in small-molecule enzymatic fluorescent probes for cancer imaging. Chem Soc Rev. 2018;47(18):7140–80.

    Article  CAS  PubMed  Google Scholar 

  25. Huang J, Li J, Lyu Y, Miao Q, Pu K. Molecular optical imaging probes for early diagnosis of drug-induced acute kidney injury. Nat Mater. 2019;18:1133–43.

    Article  CAS  PubMed  Google Scholar 

  26. Roth ME, Green O, Gnaim S, Shabat D. Dendritic, oligomeric, and polymeric self-immolative molecular amplification. Chem Rev. 2016;116(3):1309–52.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang J, Cheng P, Pu K. Recent advances of molecular optical probes in imaging of β-galactosidase. Bioconjug Chem. 2019;30(8):2089–101.

    Article  CAS  PubMed  Google Scholar 

  28. Rotman B. Measurement of activity of single molecules of β-D-galactosidase. Proc Natl Acad Sci U S A. 1961;47(12):1981–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rotman B, Zderic JA, Edelstein M. Fluorogenic substrates for beta-D-galactosidases and phosphatases derived from flurescein (3,6-dihydroxyfluoran) and its monomethylether. Proc Natl Acad Sci U S A. 1963;50(1):1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mandal PK, Cattiaux L, Bensimon D, Mallet JM. Monogalactopyranosides of fluorescein and fluorescein methyl ester: synthesis, enzymatic hydrolysis by biotnylated β-galactosidase, and determination of translational diffusion coefficient. Carbohydr Res. 2012;358(40):40–6.

    Article  CAS  PubMed  Google Scholar 

  31. Stracean R, Wooda J, Irschmann R. Synthesis and properties of 4-Methyl-2-oxo-1,2-benzopyran-7-yl β-D-galactoside (galactoside of 4-methylumbelliferone). J Org Chem. 1962;27(3):1074–5.

    Article  Google Scholar 

  32. Gee KR, Sun WC, Bhalgat KM, Upson RH, Klaubert DH, Latham KA, et al. Fluorogenic substrates based on fluorinated umbelliferones for continuous assays of phosphatases and beta-galactosidases. Anal Biochem. 1999;273(1):41–8.

    Article  CAS  PubMed  Google Scholar 

  33. Chilvers KF, Perry JD, James AL, Reed RH. Synthesis and evaluation of novel fluorogenic substrates for the detection of bacterial beta-galactosidase. J Appl Microbiol. 2001;91(6):1118–30.

    Article  CAS  PubMed  Google Scholar 

  34. Aizawa K. Studien über Carbohydrasen, I. I. Die fermentative Hydrolyse des p-nitrophenol-β-galactoside. Enzymologia. 1939;6:321–4.

    CAS  Google Scholar 

  35. Na SY, Kim HJ. Fused oxazolidine-based dual optical probe for galactosidase with a dramatic chromogenic and fluorescence turn-on effect. Dyes Pigments. 2016;134:526–30.

    Article  CAS  Google Scholar 

  36. Corey PE, Trimmer RW, Biddlecom WG. A new chromogenic β-Galactosidase substrate: 7-β-D-galactopyranosyloxy-9,9-dimethyl-9H-acridin-2-one. Angew Chem Int Ed. 1991;30(12):1646–8.

    Article  Google Scholar 

  37. Wang P, Du J, Liu H, Bi G, Zhang G. Small quinolinium-based enzymatic probes via blue-to-red ratiometric fluorescence. Analyst. 2016;141:1483–7.

    Article  CAS  PubMed  Google Scholar 

  38. Otsubo T, Minami A, Fujii H, Taguchi R, Takahashi T, Suzuki T, et al. 2-(Benzothiazol-2-yl)-phenyl-β-d-galactopyranoside derivatives as fluorescent pigment dyeing substrates and their application for the assay of β-d-galactosidase activities. Bioorg Med Chem Lett. 2013;23(7):2245–9.

    Article  CAS  PubMed  Google Scholar 

  39. Sun C, Zhang X, Tanga M, Liu L, Shi L, Gao C, et al. New optical method for the determination of β-galactosidase and α-fetoprotein based on oxidase-like activity of fluorescein. Talanta. 194:164–70.

  40. Hirabayashi K, Hanaoka K, Takayanagi T, Toki Y, Egawa T, Kamiya M, et al. Analysis of chemical equilibrium of silicon-substituted fluorescein and its application to develop a scaffold for red fluorescent probes. Anal Chem. 2015;87(17):9061–9.

    Article  CAS  PubMed  Google Scholar 

  41. Horwitz JP, Chua J, Curby RJ, Tomson AJ, Da Rooge MA, Fisher BE, et al. Substrates for cytochemical demonstration of enzyme activity. i. some substituted 3-Indolyl-β-D-glycopyranosides. Med Chem. 1964;7(4):574–5.

    Article  CAS  Google Scholar 

  42. Ho NH, Weissleder R, Tung CH. A self-immolative reporter for beta-galactosidase sensing. ChemBioChem. 2007;8(5):560–6.

    Article  CAS  PubMed  Google Scholar 

  43. Huang Y, Feng H, Liu W, Zhang S, Tang C, Chen J, et al. Cation-driven luminescent self-assembled dots of copper nanoclusters with aggregation-induced emission for β-galactosidase activity monitoring. J Mater Chem B. 2017;5(26):5120–7.

    Article  CAS  PubMed  Google Scholar 

  44. Xie X, Liana Y, Xiao L, Weia L. Facile and label-free fluorescence sensing of β-galactosidase activity by graphene quantum dots. Spectrochim Acta A Mol Biomol Spectrosc. 2020;240:118594.

    Article  CAS  PubMed  Google Scholar 

  45. Hu Q, Ma K, Mei Y, He M, Kong J, Zhang X. Metal-to-ligand charge-transfer: applications to visual detection of β-galactosidase activity and sandwich immunoassay. Talanta. 2017;167:253–9.

    Article  CAS  PubMed  Google Scholar 

  46. Urano Y, Kamiya M, Kanda K, Ueno T, Hirose K, Nagano T. Evolution of fluorescein as a platform for finely tunable fluorescence probes. J Am Chem Soc. 2005;127(13):4888–94.

    Article  CAS  PubMed  Google Scholar 

  47. Komatsu T, Kikuchi K, Takakusa H, Hanaoka K, Ueno T, Kamiya M, et al. Design and synthesis of an enzyme activity-based labeling molecule with fluorescence spectral change. J Am Chem Soc. 2006;128(50):15946–7.

    Article  CAS  PubMed  Google Scholar 

  48. Koide Y, Urano Y, Yatsushige A, Hanaoka K, Terai T, Nagano T. Design and development of enzymatically activatable photosensitizer based on unique characteristics of thiazole orange. J Am Chem Soc. 2009;131(17):6058–9.

    Article  CAS  PubMed  Google Scholar 

  49. Egawa T, Koide Y, Hanaoka K, Komatsu T, Teraiab T, Nagano T. Development of a fluorescein analogue, TokyoMagenta, as a novel scaffold for fluorescence probes in red region. Chem Commun. 2011;47(14):4162–4.

    Article  CAS  Google Scholar 

  50. Kamiya M, Asanuma D, Kuranaga E, Takeishi A, Sakabe M, Miura M, et al. β-Galactosidase fluorescence probe with improved cellular accumulation based on a spirocyclized rhodol scaffold. J Am Chem Soc. 2011;133(33):12960–3.

    Article  CAS  PubMed  Google Scholar 

  51. Han J, Han MS, Tung CH. A fluorogenic probe for β-galactosidase activity imaging in living cells. Mol BioSyst. 2013;9(12):3001–8.

    Article  CAS  PubMed  Google Scholar 

  52. Peng L, Gao M, Cai X, Zhang R, Li K, Feng G, et al. A fluorescent light-up probe based on AIE and ESIPT processes for β-galactosidase activity detection and visualization in living cells. J Mater Chem B. 2015;3(47):9168–72.

    Article  CAS  PubMed  Google Scholar 

  53. Tseng JC, Kung AL. In vivo imaging of endogenous enzyme activities using luminescent 1,2-dioxetane compounds. J Biomed Sci. 2015;22(1):45.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Grimm JB, Gruber TD, Ortiz G, Brown TA, Lavis LD. Virginia Orange: a versatile, red-shifted fluorescein scaffold for single- and dual-input fluorogenic probes. Bioconjug Chem. 2016;27(2):474–80.

    Article  CAS  PubMed  Google Scholar 

  55. Wei X, Hu XX, Zhang LL, Li J, Wang J. et al. Highly selective and sensitive FRET based ratiometric two-photon fluorescent probe for endogenous β-galactosidase detection in living cells and tissues Microchem. J. 2020;157:105046.

  56. Calatrava-Pérez E, Bright SA, Achermann S, Moylan C, Senge MO, Veale EB, et al. Glycosidase activated release of fluorescent 1,8-naphthalimide probes for tumor cell imaging from glycosylated pro-probes. Chem Commun. 2016;52(89):13086–9.

    Article  Google Scholar 

  57. Jiang G, Zeng G, Zhu W, Li Y, Dong X, Zhang G, et al. A selective and light-up fluorescent probe for β-galactosidase activity detection and imaging in living cells based on an AIE tetraphenylethylene derivative. Chem Commun. 2017;53(32):4505–8.

    Article  CAS  Google Scholar 

  58. Yang W, Zhao X, Zhang Y, Zhou Y, Fan S, Sheng H, et al. Hydroxyphenylquinazolinone-based turn-on fluorescent probe for β-galactosidase activity detection and application in living cells. Dyes Pigments. 2018;156:100–7.

  59. Li Y, Ning L, Yuan F, Zhang F, Zhang J, Xu Z, et al. Activatable formation of emissive excimers for highly selective detection of β-galactosidase. Anal Chem. 2020;92(8):5733–40.

    Article  CAS  PubMed  Google Scholar 

  60. Huang J, Li N, Wang Q, Gu Y, Wang P. A lysosome-targetable and two-photon fluorescent probe for imaging endogenous β-galactosidase in living ovarian cancer cells. Sensor Actuat B-Chem. 2017;246:833–9.

    Article  CAS  Google Scholar 

  61. Chen X, Zhang X, Ma X, Zhang Y, Gao G, Liu J, et al. Novel fluorescent probe for rapid and ratiometric detection of β-galactosidase and live cell imaging. Talanta. 2019;192:308–13.

    Article  CAS  PubMed  Google Scholar 

  62. Fu W, Yan C, Zhang Y, Ma Y, Guo Z, Zhu WH. Near-infrared aggregation-induced emission-active probe enables in situ and long-term tracking of endogenous β-galactosidase activity. Front Chem. 2019;7:291–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang X, Chen X, Zhang Y, Liu K, Shen H, et al. A near-infrared fluorescent probe for the ratiometric detection and living cell imaging of β-galactosidase. Anal Bioanal Chem. 2019;411:7957–66.

    Article  CAS  PubMed  Google Scholar 

  64. Chen M, Mu L, Cao X, She G, Shi W. A novel ratiometric fluorescent probe for highly sensitive and selective detection of β-galactosidase in living cells. Chin J Chem. 2019;37(4):330–6.

    Article  CAS  Google Scholar 

  65. Kong X, Li M, Dong B, Yin Y, Song W, Lin W. An ultrasensitivity fluorescent probe based on the ict-fret dual mechanisms for imaging β-galactosidase in vitro and ex vivo. Anal Chem. 2019;91(24):15591–8.

    Article  CAS  PubMed  Google Scholar 

  66. Lee HW, Lim CS, Choi H, Cho MK, Noh CH, Lee K, et al. Discrimination between human colorectal neoplasms with a dual-recognitive two-photon probe. Anal Chem. 2019;91(22):14705–11.

    Article  CAS  PubMed  Google Scholar 

  67. Zhao X, Yang W, Fan S, Zhou Y, Sheng H, Cao Y, et al. A hemicyanine-based colorimetric turn-on fluorescent probe for β-galactosidase activity detection and application in living cells. J Lumin. 2019;205:310–7.

  68. Li X, Pan Y, Chen H, Duan Y, Zhou S, Wu W, et al. Specific near-infrared probe for ultrafast imaging of lysosomal β-galactosidase in ovarian cancer cells. Anal Chem. 2020;92(8):5772–9.

    Article  CAS  PubMed  Google Scholar 

  69. Long R, Tang C, Yang Z, Fu Q, Xu J, Tong C, et al. A natural hyperoside based novel light-up fluorescent probe with AIE and ESIPT characteristics for on-site and long-term imaging of β-galactosidase in living cells. J Mater Chem C. 2020;8(34):11860–5.

    Article  CAS  Google Scholar 

  70. Tang C, Zhou J, Qian Z, Ma Y, Huang Y, Feng H. A universal fluorometric assay strategy for glycosidases based on functional carbon quantum dots: β-galactosidase activity detection in vitro and in living cells. J Mater Chem B. 2017;5(10):1971–9.

    Article  CAS  PubMed  Google Scholar 

  71. Wang W, Vellaisamy K, Li W, Wu C, Ko CN, Leung CL, et al. Development of a long-lived luminescence probe for visualizing β-galactosidase in ovarian carcinoma cells. Anal Chem. 2017;89(21):11679–84.

    Article  CAS  PubMed  Google Scholar 

  72. James AL, Perry JD, Ford M, Armstrong L, Gould FK. Evaluation of cyclohexenoesculetin-beta-D-galactoside and 8-hydroxyquinoline-beta-D-galactoside as substrates for the detection of beta-galactosidase. Appl Environ Microbiol. 1996;62(10):3868–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. James AL, Perry JD, Chilvers K, Robson IS, Armstrong L, Orr KE. Alizarin-beta-D-galactoside: a new substrate for the detection of bacterial beta-galactosidase. Lett Appl Microbiol. 2000;30(4):336–40.

    Article  CAS  PubMed  Google Scholar 

  74. Wei X, Wu Q, Zhang J, Zhang Y, Guo W, Chen M, et al. Synthesis of precipitating chromogenic/fluorogenic β-glucosidase/β-galactosidase substrates by a new method and their application in the visual detection of foodborne pathogenic bacteria. Chem Commun. 2017;53(1):103–6.

    Article  CAS  Google Scholar 

  75. Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15(7):482–96.

    Article  PubMed  Google Scholar 

  76. Filho MS, Dao P, Gesson M, Martin AR, Benhida R. Development of highly sensitive fluorescent probes for the detection of β-galactosidase activity- application to the real-time monitoring of senescence in live cells. Analyst. 2018;143(11):2680–8.

    Article  Google Scholar 

  77. Kim EJ, Podder A, Maiti M, Lee JM, Chung BG, Bhuniya S. Selective monitoring of vascular cell senescence via β-Galactosidase detection with a fluorescent chemosensor. Sensor Actuat B-Chem. 2018;274:194–200.

    Article  CAS  Google Scholar 

  78. Jiang J, Tan Q, Zhao S, Song H, Hua L, Xie H. Late-stage difluoromethylation leading to a self-immobilizing fluorogenic probe for the visualization of enzyme activities in live cells. Chem Commun. 2019;55(99):15000–3.

    Article  CAS  Google Scholar 

  79. Qiu W, Li X, Shi D, Li X, Gao Y, Li J, et al. A rapid-response near-infrared fluorescent probe with large Stokes shift for senescence-associated β-galactosidase activity detection and imaging of senescent cells. Dyes Pigments. 2020;182(99):108657.

    Article  CAS  Google Scholar 

  80. Makau JN, Kitagawa A, Kitamura K, Yamaguchi T, Mizuta S. Design and development of an HBT-based ratiometric fluorescent probe to monitor stress-induced premature senescence. ACS Omega. 2020;5:11299–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Senter PD, Saulnier MG, Schreiber GJ, Hirschberg DL, Brown JP, Hellström I, et al. Antitumor effect of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate. Proc Natl Acad Sci U S A. 1988;85(13):4842–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Senter PD, Springer CJ. Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates. Adv Drug Deliv Rev. 2001;53(3):247–64.

    Article  CAS  PubMed  Google Scholar 

  83. Gu K, Xu Y, Li H, Guo Z, Zhu S, Shi P, et al. Real-time tracking and in vivo visualization of β-galactosidase activity in colorectal tumor with a ratiometric near-infrared fluorescent probe. J Am Chem Soc. 2016;138(16):5334–40.

    Article  CAS  PubMed  Google Scholar 

  84. Tung CH, Zeng Q, Shah K, Kim DE, Schellingerhout D, Weissleder R. In vivo imaging of beta-galactosidase activity using far red fluorescent switch. Cancer Res. 2004;64(5):1579–83.

    Article  CAS  PubMed  Google Scholar 

  85. Wehrman TS, von Degenfeld G, Krutzik PO, Nolan GP, Blau HM. Luminescent imaging of beta-galactosidase activity in living subjects using sequential reporter-enzyme luminescence. Nat Methods. 2006;3(4):295–301.

    Article  CAS  PubMed  Google Scholar 

  86. Oushiki D, Kojima H, Takahashi Y, Komatsu T, Terai T, Hanaoka K, et al. Near-infrared fluorescence probes for enzymes based on binding affinity modulation of squarylium dye scaffold. Anal Chem. 2012;84(10):4404–10.

    Article  CAS  PubMed  Google Scholar 

  87. Zhang XX, Wu H, Li P, Qu ZJ, Tan MQ, Han KL. A versatile two-photon fluorescent probe for ratiometric imaging E. coliβ-galactosidase in live cells and in vivo. Chem Commun. 2016;52(53):8283–6.

    Article  CAS  Google Scholar 

  88. Kim EJ, Kumar R, Sharma A, Yoon B, Kim HM, Lee H, et al. In vivo imaging of β-galactosidase stimulated activity in hepatocellular carcinoma using ligand-targeted fluorescent probe. Biomaterials. 2017;122:83–90.

    Article  CAS  PubMed  Google Scholar 

  89. Shi L, Yan C, Ma Y, Wang T, Guo Z, Zhu WH. In vivo ratiometric tracking of endogenous β-galactosidase activity using an activatable near-infrared fluorescent probe. Chem Commun. 2019;55(82):12308–11.

    Article  CAS  Google Scholar 

  90. Zhen X, Zhang J, Huang J, Xie C, Miao Q, Pu K. Macrotheranostic probe with disease-activated near-infrared fluorescence, photoacoustic, and photothermal signals for imaging-guided therapy. Angew Chem Int Ed. 2018;57(26):7804–8.

    Article  CAS  Google Scholar 

  91. Li Z, Ren M, Wang L, Dai L, Lin W. Development of a red-emissive two-photon fluorescent probe for sensitive detection of beta-galactosidase in vitro and in vivo. Sensor Actuat B-Chem. 2020;307:127643.

    Article  Google Scholar 

  92. González-Gualda E, Pàez-Ribes M, Lozano-Torres B, Macias D, Wilson JR 3rd, González-López C, et al. Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell. 2020;19(4):e13142.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Lozano-Torres B, Galiana I, Rovira M, Garrido E, Chaib S, Bernardos A, et al. An OFF–ON two-photon fluorescent probe for tracking cell senescence in vivo. J Am Chem Soc. 2017;139(26):8808–11.

    Article  CAS  PubMed  Google Scholar 

  94. Lozano-Torres B, Blandez JF, Galiana I, García-Fernández A, Alfonso M, Marcos MD, et al. Real-time in vivo detection of cellular senescence through the controlled release of the NIR fluorescent dye Nile blue. Angew Chem Int Ed. 2020;59(35):5152–6.

    Article  Google Scholar 

  95. Wang Y, Liu J, Ma X, Cui C, Deenik PR, Henderson KP, et al. Real-time imaging of senescence in tumors with DNA damage. Sci Rep. 2019;9:2102.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Chen JA, Guo W, Wang Z, Sun N, Pan H, Tan J, et al. In vivo imaging of senescent vascular cells in atherosclerotic mice using a β-galactosidase-activatable nanoprobe. Anal Chem. 2020;92(18):12613–21.

    Article  CAS  PubMed  Google Scholar 

  97. Liu J, Ma X, Cui C, Wang Y, Deenik PR, Cui L. A self-immobilizing NIR probe for non-invasive imaging of senescence. bioRxiv. 2020. https://doi.org/10.1101/2020.03.27.010827.

  98. Aznar E, Oroval M, Pascual L, Murguía JR, Martínez-Máñez R, Sancenón F. Gated materials for on-command release of guest molecules. Chem Rev. 2016;116(2):561–718.

    Article  CAS  PubMed  Google Scholar 

  99. García-Fernández A, Aznar E, Martínez-Máñez R, Sancenón F. New advances in in vivo applications of gated mesoporous silica as drug delivery nanocarriers. Small. 2020;16(3):1902242–304.

    Article  Google Scholar 

  100. Coll C, Bernardos A, Martínez-Máñez R, Sancenón F. Gated silica mesoporous supports for controlled release and signaling applications. Acc Chem Res. 2013;46(2):339–49.

    Article  CAS  PubMed  Google Scholar 

  101. Muñoz-Espín D, Rovira M, Galiana I, Giménez C, Lozano-Torres B, Paez-Ribes M. A versatile drug delivery system targeting senescent cells. EMBO Mol Med. 2018;10(9):e9355.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Lozano-Torres B, Estepa-Fernández A, Rovira M, Orzáez M, Serrano M, Martínez-Máñez R, et al. The chemistry of senescence. Nat Rev Chem. 2019;3:426–41.

    Article  CAS  Google Scholar 

  103. Mazur A, Kro’l JE, Marczak M, Skorupska A. Membrane topology of PssT, the transmembrane protein component of the type I exopolysaccharide transport system in rhizobium leguminosarum bv trifolii strain TA1. J Bacteriol. 2003;85(8):2503–11.

    Article  Google Scholar 

  104. Agostini A, Mondragón L, Bernardos A, Martínez-Máñez R, Marcos MD, Sancenón F, et al. Targeted cargo delivery in senescent cells using capped mesoporous silica nanoparticles. Angew Chem Int Ed. 2012;51(42):10556–60.

    Article  CAS  Google Scholar 

  105. Asanuma D, Sakabe M, Kamiya M, Yamamoto K, Hiratake J, Ogawa M, et al. Sensitive β-galactosidase-targeting fluorescence probe for visualizing small peritoneal metastatic tumours in vivo. Nat Commun. 2015;6:6463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sakabe M, Asanuma D, Kamiya M, Iwatate RI, Hanaoka K, Terai T, et al. Rational design of highly sensitive fluorescence probes for protease and glycosidase based on precisely controlled spirocyclization. J Am Chem Soc. 2013;135(1):409–14.

    Article  CAS  PubMed  Google Scholar 

  107. Doura T, Kamiya M, Obata F, Yamaguchi Y, Hiyama TY, Matsuda T, et al. Detection of LacZ-positive cells in living tissue with single-cell resolution. Angew Chem Int Ed. 2016;55(33):9620–4.

    Article  CAS  Google Scholar 

  108. Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009;361:2353–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chatterjee SK, Bhattacharya M, Barlow JJ. Glycosyltransferase and glycosidase activities in ovarian cancer patients. Cancer Res. 1979;39:1943–51.

    CAS  PubMed  Google Scholar 

  110. Wu C, Ni Z, Li P, Li Y, Pang X, Xie R, et al. A near-infrared fluorescent probe for monitoring and imaging of β-galactosidase in living cells. Talanta. 2020;219:121307.

    Article  CAS  PubMed  Google Scholar 

  111. Pang X, Li Y, Zhou Z, Lu Q, Xie R, Wu C, et al. Visualization of endogenous β-galactosidase activity in living cells and zebrafish with a turn-on near-infrared fluorescent probe. Talanta. 2020;217:121098.

    Article  CAS  PubMed  Google Scholar 

  112. Lee HW, Heo CH, Sen D, Byun HO, Kwak IH, Yoon G, et al. Ratiometric two-photon fluorescent probe for quantitative detection of β-galactosidase activity in senescent cells. Anal Chem. 2014;86(20):10001–5.

    Article  CAS  PubMed  Google Scholar 

  113. Zhang J, Li C, Dutta C, Fang M, Zhang S, Tiwari A, et al. A novel near-infrared fluorescent probe for sensitive detection of β-galactosidase in living cells. Anal Chim Acta. 2017;968:97–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kamiya M, Kobayashi H, Hama Y, Koyama Y, Bernardo M, Nagano T, et al. An enzymatically activated fluorescence probe for targeted tumor imaging. J Am Chem Soc. 2007;129(13):3918–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gnaim S, Green O, Shabat D. The emergence of aqueous chemiluminescence: new promising class of phenoxy 1,2-dioxetane luminophores. Chem Commun. 2018;54(17):2073–85.

    Article  CAS  Google Scholar 

  116. Galiana I, Lozano-Torres B, Sancho M, Alfonso M, Bernardos A, Bisbal V, et al. Preclinical antitumor efficacy of senescence-inducing chemotherapy combined with a nanoSenolytic. J Control Release. 2020;323:624–34.

    Article  CAS  PubMed  Google Scholar 

  117. Eilon-Shaffer T, Roth-Konforti M, Eldar-Boock A, Satchi-Fainarob R, Shabat D. ortho-Chlorination of phenoxy 1,2-dioxetane yields superior chemiluminescent probes for in vitro and in vivo imaging. Org. Biomol Chem. 2018;16(10):1708–12.

    Article  CAS  PubMed  Google Scholar 

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Funding

R.M laboratory members received the financial support from the Spanish Government (project RTI2018-100910-B-C41) and the Generalitat Valenciana (project PROMETEO 2018/024). B.L-T. received support from the Spanish Ministry of Economy for their PhD grants (FPU15/02707). J. F.-B received fellowship (CD19/00038).

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  1. Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Camino de Vera s/n, 46022, Valencia, Spain

    Beatriz Lozano-Torres, Juan F. Blandez, Félix Sancenón & Ramón Martínez-Máñez

  2. Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, 46022, Valencia, Spain

    Beatriz Lozano-Torres, Juan F. Blandez, Félix Sancenón & Ramón Martínez-Máñez

  3. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain

    Beatriz Lozano-Torres, Juan F. Blandez, Félix Sancenón & Ramón Martínez-Máñez

  4. Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, IIS La Fe, 46026, Valencia, Spain

    Beatriz Lozano-Torres, Juan F. Blandez, Félix Sancenón & Ramón Martínez-Máñez

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  1. Beatriz Lozano-Torres
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  2. Juan F. Blandez
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  3. Félix Sancenón
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  4. Ramón Martínez-Máñez
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Correspondence to Félix Sancenón or Ramón Martínez-Máñez.

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Lozano-Torres, B., Blandez, J.F., Sancenón, F. et al. Chromo-fluorogenic probes for β-galactosidase detection. Anal Bioanal Chem 413, 2361–2388 (2021). https://doi.org/10.1007/s00216-020-03111-8

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  • DOI: https://doi.org/10.1007/s00216-020-03111-8

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