Skip to main content
Log in

Novel lysosome-targeted anticancer fluorescent agents used in zebrafish and nude mouse tumour imaging

  • Research Article
  • Published:
Frontiers of Chemical Science and Engineering Aims and scope Submit manuscript

Abstract

The design of three novel fatty nitrogen mustard-based anticancer agents with fluorophores incorporated into the alkene structure (CXL 118, CXL121, and CXL122) is described in this report. The results indicated that these compounds are selectively located in lysosomes and exhibit effective antitumour activity. Notably, these compounds can directly serve as both reporting and imaging agents in vitro and in vivo without the need to add other fluorescent tagging agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Liu Y, Zhou J, Wang L, Hu X, Liu X, Liu M, Cao Z, Shangguan D, Tan W. A cyanine dye to probe mitophagy: simultaneous detection of mitochondria and autolysosomes in live cells. Journal of the American Chemical Society, 2016, 138(38): 12368–12374

    Article  CAS  PubMed  Google Scholar 

  2. Luzio J P, Pryor P R, Bright N A. Lysosomes: fusion and function. Nature Reviews. Molecular Cell Biology, 2007, 8(8): 622–632

    Article  CAS  PubMed  Google Scholar 

  3. Zhang H, Liu J, Liu C, Yu P, Sun M, Yan X, Guo J P, Guo W. Imaging lysosomal highly reactive oxygen species and lighting up cancer cells and tumors enabled by a Si-rhodamine-based near-infrared fluorescent probe. Biomaterials, 2017, 133: 60–69

    Article  CAS  PubMed  Google Scholar 

  4. Li M, Fan J, Li H, Du J, Long S, Peng X. A ratiometric fluorescence probe for lysosomal polarity. Biomaterials, 2018, 164: 98–105

    Article  CAS  PubMed  Google Scholar 

  5. Maiuri M, Tasdemir E, Criollo A, Morselli E, Vicencio J, Carnuccio R, Kroemer G. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death and Differentiation, 2009, 16(1): 87–93

    Article  CAS  PubMed  Google Scholar 

  6. Mohamed M M, Sloane B F. Cysteine cathepsins: multifunctional enzymes in cancer. Nature Reviews. Cancer, 2006, 6(10): 764–775

    Article  CAS  PubMed  Google Scholar 

  7. Soreghan B, Thomas S N, Yang A J. Aberrant sphingomyelin/ceramide metabolic-induced neuronal endosomal/lysosomal dysfunction: potential pathological consequences in age-related neurodegeneration. Advanced Drug Delivery Reviews, 2003, 55(11): 1515–1524

    Article  CAS  PubMed  Google Scholar 

  8. Mizukami H, Mi Y, Wada R, Kono M, Yamashita T, Liu Y, Werth N, Sandhoff R, Sandhoff K, Proia R L. Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage. Journal of Clinical Investigation, 2002, 109(9): 1215–1221

    Article  CAS  Google Scholar 

  9. Reiser J, Adair B, Reinheckel T. Specialized roles for cysteine cathepsins in health and disease. Journal of Clinical Investigation, 2010, 120(10): 3421–3431

    Article  CAS  Google Scholar 

  10. Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B. Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Current Pharmaceutical Design, 2007, 13(4): 387–403

    Article  CAS  PubMed  Google Scholar 

  11. Miao R, Li M, Zhang Q, Yang C, Wang X. An ECM-to-nucleus signalling pathway activates lysosomes for C. elegans larval development. Developmental Cell, 2020, 52(1): 21–37

    Article  CAS  PubMed  Google Scholar 

  12. Fujimaki K, Li R, Chen H, Croce K D, Zhang H H, Xing J, Bai F, Yao G. Graded regulation of cellular quiescence depth between proliferation and senescence by a lysosomal dimmer switch. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116(45): 22624–22634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu R, Chen B, Wang Z, Qin A, Zhao Z, Lou X, Tang B Z. Intriguing “chameleon” fluorescent bioprobes for the visualization of lipid droplet-lysosome interplay. Biomaterials, 2019, 203: 43–51

    Article  CAS  PubMed  Google Scholar 

  14. Fan J, Dong H, Hu M, Wang J, Zhang H, Zhu H, Sun W, Peng X. Fluorescence imaging lysosomal changes during cell division and apoptosis observed using Nile blue based near-infrared emission. Chemical Communications, 2013, 50(7): 882–884

    Article  Google Scholar 

  15. Kroemer G, Jäättelä M. Lysosomes and autophagy in cell death control. Nature Reviews. Cancer, 2005, 5(11): 886–897

    Article  CAS  PubMed  Google Scholar 

  16. Chen J W, Pan W, D’souza M P, August J T. Lysosome-associated membrane proteins: characterization of LAMP-1 of macrophage P388 and mouse embryo 3T3 cultured cells. Archives of Biochemistry and Biophysics, 1985, 239(2): 574–586

    Article  CAS  PubMed  Google Scholar 

  17. Werneburg N W, Guicciardi M E, Bronk S F, Kaufmann S H, Gores G J. Tumor necrosis factor-related apoptosis-inducing ligand activates a lysosomal pathway of apoptosis that is regulated by bcl-2 proteins. Journal of Biological Chemistry, 2007, 282(39): 28960–28970

    Article  CAS  Google Scholar 

  18. Hu Q, Bally M B, Madden T D. Subcellular trafficking of antisense oligonucleotides and down-regulation of bcl-2 gene expression in human melanoma cells using a fusogenic liposome delivery system. Nucleic Acids Research, 2002, 30(16): 3632–3641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hanaki K, Momo A, Oku T, Komoto A, Maenosono S, Yamaguchi Y, Yamamoto K. Semiconductor quantum dot/albumin complex is a long-life and highly photostable endosome marker. Biochemical and Biophysical Research Communications, 2003, 302(3): 496–501

    Article  CAS  PubMed  Google Scholar 

  20. Hotchkiss R S, Strasser A, McDunn J E, Swanson P E. Cell death. New England Journal of Medicine, 2009, 361(16): 1570–1583

    Article  CAS  Google Scholar 

  21. Kroemer G, El-Deiry W S, Golstein P, Peter M E, Vaux D, Vandenabeele P, Zhivotovsky B, Blagosklonny M V, Malorni W, Knight R A, et al. Classification of cell death: recommendations of the nomenclature committee on cell death. Cell Death and Differentiation, 2005, 12(S2): 1463–1467

    Article  CAS  PubMed  Google Scholar 

  22. Galluzzi L, Maiuri M, Vitale I, Zischka H, Castedo M, Zitvogel L, Kroemer G. Cell death modalities: classification and pathophysiological implications. Cell Death and Differentiation, 2007, 14(7): 1237–1243

    Article  CAS  PubMed  Google Scholar 

  23. Walls K C, Ghosh A P, Franklin A V, Klocke B J, Ballestas M, Shacka J J, Zhang J, Roth K A. Lysosome dysfunction triggers Atg7-dependent neural apoptosis. Journal of Biological Chemistry, 2010, 285(14): 10497–10507

    Article  CAS  Google Scholar 

  24. Codogno P, Meijer A J. Atg5: more than an autophagy factor. Nature Cell Biology, 2006, 8(10): 1045–1047

    Article  CAS  PubMed  Google Scholar 

  25. Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, Qian Y, Kryczek I, Sun D, Nagarsheth N, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell, 2017, 170(3): 548–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Amaravadi R K, Thompson C B. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clinical Cancer Research, 2007, 13(24): 7271–7279

    Article  CAS  PubMed  Google Scholar 

  27. Marx J. Autophagy: is it cancer’s friend or foe? Science, 2006, 312 (5777): 1160–1161

    Article  CAS  PubMed  Google Scholar 

  28. Giralt S, Thall P F, Khouri I, Wang X, Braunschweig I, Ippolitti C, Claxton D, Donato M, Bruton J, Cohen A, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood, 2001, 97(3): 631–637

    Article  CAS  PubMed  Google Scholar 

  29. Pedersen P J, Christensen M S, Ruysschaert T, Linderoth L, Andresen T L, Melander F, Mouritsen O G, Madsen R, Clausen M H. Synthesis and biophysical characterization of chlorambucil anticancer ether lipid prodrugs. Journal of Medicinal Chemistry, 2009, 52(10): 3408–3415

    Article  CAS  PubMed  Google Scholar 

  30. Li W, Nie S, Chen Y, Wang Y, Li C, Xie M. Enhancement of cyclophosphamide-induced antitumor effect by a novel polysaccharide from Ganoderma atrum in sarcoma 180-bearing mice. Journal of Agricultural and Food Chemistry, 2011, 59(8): 3707–3716

    Article  CAS  PubMed  Google Scholar 

  31. Chen W, Balakrishnan K, Kuang Y, Han Y, Fu M, Gandhi V, Peng X. Reactive oxygen species (ROS) inducible DNA cross-linking agents and their effect on cancer cells and normal lymphocytes. Journal of Medicinal Chemistry, 2014, 57(11): 4498–4510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Verwilst P, Han J, Lee J, Mun S, Kang H G, Kim J S. Reconsidering azobenzene as a component of small-molecule hypoxia-mediated cancer drugs: a theranostic case study. Biomaterials, 2017, 115: 104–114

    Article  CAS  PubMed  Google Scholar 

  33. Detroja D, Chen T L, Lin Y W, Yen T Y, Wu M H, Tsai T H, Mehariya K, Kakadiya R, Lee T C, Shah A. Novel N-mustardbenzimidazoles/benzothiazoles, synthesis and anticancer evaluation. Anti-cancer Agents in Medicinal Chemistry, 2017, 17: 1741–1755

    CAS  PubMed  Google Scholar 

  34. Diethelm-Varela B, Ai Y, Liang D, Xue F. Nitrogen mustards as anticancer chemotherapies: historic perspective, current developments and future trends. Current Topics in Medicinal Chemistry, 2019, 19(9): 691–712

    Article  CAS  PubMed  Google Scholar 

  35. Singh R K, Prasad D N, Bhardwaj T R. Hybrid pharmacophore-based drug design, synthesis, and antiproliferative activity of 1,4-dihydropyridines-linked alkylating anticancer agents. Medicinal Chemistry Research, 2015, 24(4): 1534–1545

    Article  CAS  Google Scholar 

  36. Chen X, Chen H, Lu C, Yang C, Yu X, Li K, Xie Y. Novel mitochondria-targeted, nitrogen mustard-based DNA alkylation agents with near infrared fluorescence emission. Talanta, 2016, 161: 888–893

    Article  CAS  PubMed  Google Scholar 

  37. Chen X, Peng W, Huang S, Yang C, Hu M, Yang S, Yang S, Xie Y, Chen H, Lei N, Luo Y, Li K. Novel mitochondria-targeted and fluorescent DNA alkylation agents with highly selective activity against cancer cells. Dyes and Pigments, 2019, 170: 107610

    Article  CAS  Google Scholar 

  38. Tang L, He P, Yan X, Sun J, Zhong K, Hou S, Bian Y. A mitochondria-targetable fluorescent probe for ratiometric detection of SO2 derivatives and its application in live cell imaging. Sensors and Actuators. B, Chemical, 2017, 247: 421–427

    Article  CAS  Google Scholar 

  39. Zhou Q, Li K, Liu Y H, Li L L, Yu K K, Zhang H, Yu X Q. Fluorescent Wittig reagent as a novel ratiometric probe for the quantification of 5-formyluracil and its application in cell imaging. Chemical Communications, 2018, 54(97): 13722–13725

    Article  CAS  PubMed  Google Scholar 

  40. Wu M Y, Li K, Li C Y, Hou J T, Yu X Q. A water-soluble near-infrared probe for colorimetric and ratiometric sensing of SO2 derivatives in living cells. Chemical Communications, 2014, 50(2): 183–185

    Article  CAS  PubMed  Google Scholar 

  41. Liu Y, Li K, Wu M Y, Liu Y H, Xie Y M, Yu X Q. A mitochondria-targeted colorimetric and ratiometric fluorescent probe for biological SO2 derivatives in living cells. Chemical Communications, 2015, 51 (50): 10236–10239

    Article  CAS  PubMed  Google Scholar 

  42. Li D P, Wang Z Y, Cao X J, Cui J, Wang X, Cui H Z, Miao J Y, Zhao B X. A mitochondria-targeted fluorescent probe for ratiometric detection of endogenous sulfur dioxide derivatives in cancer cells. Chemical Communications, 2016, 52(13): 2760–2763

    Article  CAS  PubMed  Google Scholar 

  43. Puckett C A, Barton J K. Methods to explore cellular uptake of ruthenium complexes. Journal of the American Chemical Society, 2007, 129(1): 46–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li Y, Tao L, Zuo Z, Zhou Y, Qian X, Lin Y, Jie H, Liu C, Li Z, Zhang H, et al. ZY0511, a novel, potent and selective LSD1 inhibitor, exhibits anticancer activity against solid tumors via the DDIT4/mTOR pathway. Cancer Letters, 2019, 454: 179–190

    Article  CAS  PubMed  Google Scholar 

  45. Ko S K, Chen X, Yoon J, Shin I. Zebrafish as a good vertebrate model for molecular imaging using fluorescent probes. Chemical Society Reviews, 2011, 40(5): 2120–2130

    Article  CAS  PubMed  Google Scholar 

  46. Deniz Koç N, Yüce R. A light-and electron microscopic study of primordial germ cells in the zebra fish (Danio rerio). Biological Research, 2012, 45(4): 331–336

    Article  PubMed  Google Scholar 

  47. Kang Y F, Li Y H, Fang Y W, Xu Y, Wei X M, Yin X B. Carbon quantum dots for zebrafish fluorescence imaging. Scientific Reports, 2005, 5(1): 11835

    Article  Google Scholar 

  48. Liang D, Zhang Y, Wu Z, Chen Y J, Yang X, Sun M, Ni R, Bian J, Huang D. A near infrared singlet oxygen probe and its applications in in vivo imaging and measurement of singlet oxygen quenching activity of flavonoids. Sensors and Actuators. B, Chemical, 2018, 266: 645–654

    Article  CAS  Google Scholar 

  49. Ding F, Zhan Y, Lu X, Sun Y. Recent advances in near-infrared II fluorophores for multifunctional biomedical imaging. Chemical Science (Cambridge), 2018, 9(19): 4370–4380

    Article  CAS  Google Scholar 

  50. Han X, Wang R, Song X, Yu F, Chen L. Evaluation selenocysteine protective effect in carbon disulfide induced hepatitis with a mitochondrial targeting ratiometric near-infrared fluorescent probe. Analytical Chemistry, 2018, 90(13): 8108–8115

    Article  CAS  PubMed  Google Scholar 

  51. Hu M, Yang C, Luo Y, Chen F, Yang F, Yang S, Chen H, Cheng Z, Li K, Xie Y. A hypoxia-specific and mitochondria-targeted anticancer theranostic agent with high selectivity for cancer cells. Journal of Materials Chemistry. B, Materials for Biology and Medicine, 2018, 6(16): 2413–2416

    Article  CAS  PubMed  Google Scholar 

  52. Qu X, Yuan F, He Z, Mai Y, Gao J, Li X, Yang D, Cao Y, Li X, Yuan Z. A rhodamine-based single-molecular theranostic agent for multiple-functionality tumor therapy. Dyes and Pigments, 2019, 166: 72–83

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was financially supported by Science and Technology Department of Sichuan Province (Nos. 2020YJ0237, 2018SZ0030, 2019YFH0119), National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z20191006) and the 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (Nos. ZYJC18025 and ZYJC18003).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Weihong Kuang or Zhihui Li.

Ethics declarations

Compliance with Ethics Guidelines Xiuli Chen, Feng Liu, Bin Chen, Haiying Wu, Kun Li, Yongmei Xie, Weihong Kuang and Zhihui Li declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Liu, F., Chen, B. et al. Novel lysosome-targeted anticancer fluorescent agents used in zebrafish and nude mouse tumour imaging. Front. Chem. Sci. Eng. 16, 112–120 (2022). https://doi.org/10.1007/s11705-021-2075-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11705-021-2075-5

Keywords

Navigation