Hypoxia-activatable nano-prodrug for fluorescently tracking drug release in mice

Abstract

Chemotherapy is one of the commonly used methods to treat various types of cancers in clinic by virtue of its high efficiency and universality. However, strong side effects and low concentration of conventional drugs at the tumor site have always been important factors that plague the chemotherapy effects of patients, further precluding their practical applications. Thereof, to solve the above dilemma, by integration of anticancer drug (nitrogen mustard, NM) into an NIR fluorophore (a dicyanoisophorone derivative), an intelligent prodrug NIR-NM was developed via molecular engineering strategy. Prodrug NIR-NM stimulated in hypoxia condition exhibits significantly higher toxicity to cancer cells than normal cells, essentially reducing the collateral damage to healthy cells and tissues of nitrogen mustard. More importantly, the nanoparticle prodrug FA-lip@NIR-NM showed the advantages of the high accumulation of drug at tumor site and long-circulation capacity in vivo, which endowed it the ability to track the release of the active chemotherapeutic drug and further treat solid tumors.

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References

  1. 1

    Boulikas T, Vougiouka M. Oncol Rep, 2004, 11: 559–595

    CAS  PubMed  Google Scholar 

  2. 2

    Eckford PDW, Sharom FJ. Chem Rev, 2009, 109: 2989–3011

    CAS  PubMed  Google Scholar 

  3. 3

    Oun R, Moussa YE, Wheate NJ. Dalton Trans, 2018, 47: 6645–6653

    CAS  PubMed  Google Scholar 

  4. 4

    Huang CY, Ju DT, Chang CF, Reddy PM, Velmurugan BK. BioMedicine, 2017, 7: 12–23

    Google Scholar 

  5. 5

    Yang QZ, Wang C, Lang L, Zhou Y, Wang H, Shang DJ. Arch Pharm Res, 2013, 36: 1302–1310

    CAS  PubMed  Google Scholar 

  6. 6

    Yue J, Liu S, Wang R, Hu X, Xie Z, Huang Y, Jing X. Mol Pharm, 2012, 9: 1919–1931

    CAS  PubMed  Google Scholar 

  7. 7

    Li S, Zhang Y, Wang J, Zhao Y, Ji T, Zhao X, Ding Y, Zhao X, Zhao R, Li F, Yang X, Liu S, Liu Z, Lai J, Whittaker AK, Anderson GJ, Wei J, Nie G. Nat Biomed Eng, 2017, 1: 667–679

    CAS  PubMed  Google Scholar 

  8. 8

    Xue T, Jia X, Wang J, Xiang J, Wang W, Du J, He Y. Chem Eur J, 2019, 25: 9634–9638

    CAS  PubMed  Google Scholar 

  9. 9

    Walsh JC, Lebedev A, Aten E, Madsen K, Marciano L, Kolb HC. Antioxid Redox Sign, 2014, 21: 1516–1554

    CAS  Google Scholar 

  10. 10

    Apte S. T. Chin F. E. Graves E. Curr Org Synth, 2011, 8: 593–603

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Brown JM, Wilson WR. Nat Rev Cancer, 2004, 4: 437–447

    CAS  PubMed  Google Scholar 

  12. 12

    Huang J, Wu Y, Zeng F, Wu S. Theranostics, 2019, 9: 7313–7324

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Yoon J, Li H, Kim D, Yao Q, Ge H, Chung J, Fan J, Wang J, Peng X. Angew Chem Int Ed, 2020, anie.202009796

  14. 14

    He H, Du L, Tan M, Chen Y, Lu L, An Y, Wang Y, Li X, Li B, Shen J, Wu J, Shuai X. Sci China Chem, 2020, 63: 936–945

    CAS  Google Scholar 

  15. 15

    Verwilst P, Han J, Lee J, Mun S, Kang HG, Kim JS. Biomaterials, 2017, 115: 104–114

    CAS  PubMed  Google Scholar 

  16. 16

    Liao D, Johnson RS. Cancer Metastasis Rev, 2007, 26: 281–290

    CAS  PubMed  Google Scholar 

  17. 17

    Vaupel P. Oncol, 2008, 13: 21–26

    CAS  Google Scholar 

  18. 18

    Chang Q, Jurisica I, Do T, Hedley DW. Cancer Res, 2011, 71: 3110–3120

    CAS  PubMed  Google Scholar 

  19. 19

    Yan C, Guo Z, Shen Y, Chen Y, Tian H, Zhu WH. Chem Sci, 2018, 9: 4959–4969

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Sharma A, Lee MG, Won M, Koo S, Arambula JF, Sessler JL, Chi SG, Kim JS. J Am Chem Soc, 2019, 141: 15611–15618

    CAS  PubMed  Google Scholar 

  21. 21

    Xue T, Shen J, Shao K, Wang W, Wu B, He Y. Chem Eur J, 2020, 26: 2521–2528

    CAS  PubMed  Google Scholar 

  22. 22

    Li Q, Cao J, Wang Q, Zhang J, Zhu S, Guo Z, Zhu WH. J Mater Chem B, 2019, 7: 1503–1509

    CAS  PubMed  Google Scholar 

  23. 23

    Denmeade SR, Jakobsen CM, Janssen S, Khan SR, Garrett ES, Lilja H, Christensen SB, Isaacs JT. J Natl Cancer Institute, 2003, 95: 990–1000

    CAS  Google Scholar 

  24. 24

    Denmeade SR, Mhaka AM, Rosen DM, Brennen WN, Dalrymple S, Dach I, Olesen C, Gurel B, DeMarzo AM, Wilding G, Carducci MA, Dionne CA, Moller JV, Nissen P, Christensen SB, Isaacs JT. Sci Translational Med, 2012, 4: 140ra86

    Google Scholar 

  25. 25

    Liu HW, Hu XX, Li K, Liu Y, Rong Q, Zhu L, Yuan L, Qu FL, Zhang XB, Tan W. Chem Sci, 2017, 8: 7689–7695

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Cancer Cell, 2003, 3: 347–361

    PubMed  Google Scholar 

  27. 27

    Ballinger JR. Seminars Nucl Med, 2001, 31: 321–329

    CAS  Google Scholar 

  28. 28

    Vaupel P, Schlenger K, Knoop C, Höckel M. Cancer Res, 1991, 51: 3316–3322

    CAS  PubMed  Google Scholar 

  29. 29

    Yang Z, Cao J, He Y, Yang JH, Kim T, Peng X, Kim JS. Chem Soc Rev, 2014, 43: 4563–4601

    CAS  PubMed  Google Scholar 

  30. 30

    Silvers WC, Prasai B, Burk DH, Brown ML, McCarley RL. J Am Chem Soc, 2013, 135: 309–314

    CAS  PubMed  Google Scholar 

  31. 31

    Kwon N, Cho MK, Park SJ, Kim D, Nam SJ, Cui L, Kim HM, Yoon J. Chem Commun, 2017, 53: 525–528

    CAS  Google Scholar 

  32. 32

    Peng X, Gao J, Yuan Y, Liu H, Lei W, Li S, Zhang J, Wang S. Bioconjugate Chem, 2019, 30: 2828–2843

    CAS  Google Scholar 

  33. 33

    Li Y, Sun Y, Li J, Su Q, Yuan W, Dai Y, Han C, Wang Q, Feng W, Li F. J Am Chem Soc, 2015, 137: 6407–6416

    CAS  PubMed  Google Scholar 

  34. 34

    Xu F, Li H, Yao Q, Ge H, Fan J, Sun W, Wang J, Peng X. Chem Sci, 2019, 10: 10586–10594

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Zhou Y, Maiti M, Sharma A, Won M, Yu L, Miao LX, Shin J, Podder A, Bobba KN, Han J, Bhuniya S, Kim JS. J Control Release, 2018, 288: 14–22

    CAS  PubMed  Google Scholar 

  36. 36

    Ding N, Li Z, Tian X, Zhang J, Guo K, Wang P. Chem Commun, 2019, 55: 13172–13175

    CAS  Google Scholar 

  37. 37

    Biswas S, Rajesh Y, Barman S, Bera M, Paul A, Mandal M, Pradeep Singh ND. Chem Commun, 2018, 54: 7940–7943

    CAS  Google Scholar 

  38. 38

    Kumar R, Kim EJ, Han J, Lee H, Shin WS, Kim HM, Bhuniya S, Kim JS, Hong KS. Biomaterials, 2016, 104: 119–128

    CAS  PubMed  Google Scholar 

  39. 39

    Zhao X, Ha W, Gao K, Shi Y. Anal Chem, 2020, 92: 9039–9047

    CAS  PubMed  Google Scholar 

  40. 40

    Feng W, Gao C, Liu W, Ren H, Wang C, Ge K, Li S, Zhou G, Li H, Wang S, Jia G, Li Z, Zhang J. Chem Commun, 2016, 52: 9434–9437

    CAS  Google Scholar 

  41. 41

    Li B, Liu P, Yan D, Zeng F, Wu S. J Mater Chem B, 2017, 5: 2635–2643

    CAS  PubMed  Google Scholar 

  42. 42

    Jangili P, Won M, Kim SJ, Chun J, Shim I, Kang C, Ren WX, Kim JS. ACS Appl Bio Mater, 2019, 2: 3532–3539

    CAS  Google Scholar 

  43. 43

    Lindahl LM, Fenger-Gron M, Iversen L. J Eur Acad Dermatol Venereol, 2013, 27: 163–168

    CAS  PubMed  Google Scholar 

  44. 44

    Kim YH, Martinez G, Varghese A, Hoppe RT. Arch Dermatol, 2003, 139: 165–173

    CAS  PubMed  Google Scholar 

  45. 45

    Li H, Yao Q, Sun W, Shao K, Lu Y, Chung J, Kim D, Fan J, Long S, Du J, Li Y, Wang J, Yoon J, Peng X. J Am Chem Soc, 2020, 142: 6381–6389

    CAS  PubMed  Google Scholar 

  46. 46

    Li H, Yao Q, Xu F, Xu N, Duan R, Long S, Fan J, Du J, Wang J, Peng X. Biomaterials, 2018, 179: 1–14

    PubMed  Google Scholar 

  47. 47

    Li H, Li Y, Yao Q, Fan J, Sun W, Long S, Shao K, Du J, Wang J, Peng X. Chem Sci, 2019, 10: 1619–1625

    CAS  PubMed  Google Scholar 

  48. 48

    Li H, Yao Q, Xu F, Xu N, Sun W, Long S, Du J, Fan J, Wang J, Peng X. Front Chem, 2018, 6: 485

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Shi C, Li M, Zhang Z, Yao Q, Shao K, Xu F, Xu N, Li H, Fan J, Sun W, Du J, Long S, Wang J, Peng X. Biomaterials, 2020, 233: 119755

    PubMed  Google Scholar 

  50. 50

    Kohn KW, Spears CL, Doty P. J Mol Biol, 1966, 19: 266–288

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Creative Research Initiative programs of the National Research Foundation of Korea (NRF), the Korean Government (MSIP) (2012R1A3A2048814), the National Natural Science Foundation of China (21421005, 21808028) and the Natural Science Foundation of Liaoning United Fund (U1608222, U1908202).

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Correspondence to Juyoung Yoon or Xiaojun Peng.

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The authors declare no conflict of interest.

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Li, H., Yao, Q., Pu, Z. et al. Hypoxia-activatable nano-prodrug for fluorescently tracking drug release in mice. Sci. China Chem. 64, 499–508 (2021). https://doi.org/10.1007/s11426-020-9880-7

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  • NIR fluorescent probe
  • activatable
  • hypoxia
  • prodrug
  • imaging