Science China Materials

, Volume 60, Issue 9, pp 866–880 | Cite as

A novel bone marrow targeted gadofullerene agent protect against oxidative injury in chemotherapy

  • Ying Zhang (张莹)
  • Chunying Shu (舒春英)
  • Mingming Zhen (甄明明)Email author
  • Jie Li (李杰)
  • Tong Yu (于童)
  • Wang Jia (贾旺)
  • Xue Li (李雪)
  • Ruijun Deng (邓睿君)
  • Yue Zhou (周悦)
  • Chunru Wang (王春儒)Email author


Chemotherapy as an effective cancer treatment technique has been widely used in tumor therapy. However, it is still a challenge to overcome the serious side effects of chemotherapy, especially for its myelotoxicity. Here we report a novel strategy using the water soluble gadofullerene nanocrystals (GFNCs) to protect against chemotherapy injury in hepatocarcinoma bearing mice, which was induced by the commonly chemotherapeutic agent cyclophosphamide (CTX). The GFNCs were revealed to specifically accumulate in the bone marrow after intravenously injecting to mice and they exhibited excellent radical scavenging function, resulting in a prominent increase of mice blood cells and pathological improvements of the primary organs in the GFNCs (15 mg kg−1) treated mice after the CTX (60 mg kg−1) therapy. Moreover, the GFNCs maintained and even strengthened the antineoplastic activity of the CTX agent. Therefore, the GFNCs would be the promising chemoprotective agents in chemotherapy based on their high efficiency, low toxicity and metabolizable property.


gadofullerene nanocrystals chemopreventive agent myelosuppression radical scavenging chemotherapy drug 



本文报道了一种利用金属富勒烯纳米材料实现肿瘤化疗骨髓保护的新技术. 肿瘤化疗往往会带来严重的骨髓抑制等毒副作用, 给患者 造成极大的创伤. 利用金属富勒烯纳米材料高效清除自由基、高选择性且快速富集在小鼠骨髓中的特性, 开发了基于金属富勒烯的新型化疗 辅助药物. 研究表明, 金属富勒烯实现了多方面的化疗保护效果, 对白细胞计数最高可提升166%, 对淋巴细胞最高可提升285%, 对于骨髓以及 脾脏多器官均有显著保护效果, 且未影响化疗药物的肿瘤治疗效果. 该材料是一种快速、高效、毒副作用小的新型肿瘤化疗辅助药物, 具有巨 大的发展潜力.



This work was financially supported by the National Natural Science Foundation of China (51472248, 51372251 and 51502301), the National Major Scientific Instruments and Equipments Development Project (ZDYZ2015-2), and the Key Research Program of the Chinese Academy of Sciences (QYZDJ-SSW-SLH025, KGZD-EWT02 and XDA09030302).

Supplementary material

40843_2017_9079_MOESM1_ESM.pdf (2.7 mb)
A novel bone marrow targeted gadofullerene agent protect against oxidative injury in chemotherapy


  1. 1.
    André N, Carré M, Pasquier E. Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol, 2014, 11: 413–431CrossRefGoogle Scholar
  2. 2.
    Kurtova AV, Xiao J, Mo Q, et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature, 2014, 517: 209–213CrossRefGoogle Scholar
  3. 3.
    Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer, 2012, 52Google Scholar
  4. 4.
    Helleday T, Petermann E, Lundin C, et al. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer, 2008, 8: 193–204CrossRefGoogle Scholar
  5. 5.
    Costa L, Major PP. Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Clin Prac Oncol, 2009, 6: 163–174CrossRefGoogle Scholar
  6. 6.
    Lachmann N, Czarnecki K, Brennig S, et al. Deoxycytidine-kinase knockdown as a novel myeloprotective strategy in the context of fludarabine, cytarabine or cladribine therapy. Leukemia, 2015, 29: 2266–2269CrossRefGoogle Scholar
  7. 7.
    Das UB, Mallick M, Debnath JM, Ghosh D. Protective effect of ascorbic acid on cyclophosphamide-induced testicular gametogenic and androgenic disorders in male rats. Asian J androl, 2002, 4: 201–207Google Scholar
  8. 8.
    Lucas D, Scheiermann C, Chow A, et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med, 2013, 19: 695–703CrossRefGoogle Scholar
  9. 9.
    Levesque JP, Winkler IG. It takes nerves to recover from chemotherapy. Nat Med, 2013, 19: 669–671CrossRefGoogle Scholar
  10. 10.
    Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov, 2009, 8: 579–591CrossRefGoogle Scholar
  11. 11.
    Dvash E, Har-Tal M, Barak S, et al. Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage. Nat Commun, 2015, 6: 10112CrossRefGoogle Scholar
  12. 12.
    Macleod KF. The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system. Nat Rev Cancer, 2008, 8: 769–781CrossRefGoogle Scholar
  13. 13.
    Lin W, Yuan N, Wang Z, et al. Autophagy confers DNA damage repair pathways to protect the hematopoietic system from nuclear radiation injury. Sci Rep, 2015, 5: 12362–12373CrossRefGoogle Scholar
  14. 14.
    Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer, 2004, 4: 423–436CrossRefGoogle Scholar
  15. 15.
    Manda K, Bhatia AL. Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice. Cell Biol Toxicol, 2003, 19: 367–372CrossRefGoogle Scholar
  16. 16.
    Patra K, Bose S, Sarkar S, et al. Amelioration of cyclophosphamide induced myelosuppression and oxidative stress by cinnamic acid. Chemico-Biol Interactions, 2012, 195: 231–239CrossRefGoogle Scholar
  17. 17.
    Xue Y, Lim S, Yang Y, et al. PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells. Nat Med, 2011, 18: 100–110CrossRefGoogle Scholar
  18. 18.
    Passegué E, Ernst P. IFN-α wakes up sleeping hematopoietic stem cells. Nat Med, 2009, 15: 612–613CrossRefGoogle Scholar
  19. 19.
    Finkel T. Oxidant signals and oxidative stress. Curr Opin Cell Biol, 2003, 15: 247–254CrossRefGoogle Scholar
  20. 20.
    Winterbourn C. Oxidative denaturation in congenital hemolytic anemias: the unstable hemoglobins. Semin Hematol, 1990, 27: 41–50Google Scholar
  21. 21.
    Lee J, Lim KT. Protection against cyclophosphamide-induced myelosuppression by ZPDC glycoprotein (24 kDa). Immunol Invest, 2013, 42: 61–80CrossRefGoogle Scholar
  22. 22.
    Kawano M, Mabuchi S, Matsumoto Y, et al. The significance of GCSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer. Sci Rep, 2016, 5: 18217CrossRefGoogle Scholar
  23. 23.
    Bakanay M, Demirer T. Novel agents and approaches for stem cell mobilization in normal donors and patients. Bone Marrow Transplant, 2012, 47: 1154–1163CrossRefGoogle Scholar
  24. 24.
    Afifi S, Adel NG, Devlin S, et al. Upfront plerixafor plus G-CSF versus cyclophosphamide plus G-CSF for stem cell mobilization in multiple myeloma: efficacy and cost analysis study. Bone Marrow Transplant, 2016, 51: 546–552CrossRefGoogle Scholar
  25. 25.
    Barreto JA, O’Malley W, Kubeil M, et al. Nanomaterials: applications in cancer imaging and therapy. Adv Mater, 2011, 23: H18–H40CrossRefGoogle Scholar
  26. 26.
    Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer, 2005, 5: 161–171CrossRefGoogle Scholar
  27. 27.
    Wicki A, Witzigmann D, Balasubramanian V, et al. Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J Control Release, 2015, 200: 138–157CrossRefGoogle Scholar
  28. 28.
    Sayes CM, Marchione AA, Reed KL, et al. Comparative pulmonary toxicity assessments of C60 water suspensions in rats: few differences in fullerene toxicity in vivo in contrast to in vitro profiles. Nano Lett, 2007, 7: 2399–2406CrossRefGoogle Scholar
  29. 29.
    Aschberger K, Johnston HJ, Stone V, et al. Review of fullerene toxicity and exposure—appraisal of a human health risk assessment, based on open literature. Regul Toxicol Pharmacol, 2010, 58: 455–473CrossRefGoogle Scholar
  30. 30.
    Yan L, Zhao F, Li S, et al. Low-toxic and safe nanomaterials by surface-chemical design, carbon nanotubes, fullerenes, metallofullerenes, and graphenes. Nanoscale, 2011, 3: 362–382CrossRefGoogle Scholar
  31. 31.
    Wang J, Chen C, Li B, et al. Antioxidative function and biodistribution of [Gd@C82(OH)22]n nanoparticles in tumor-bearing mice. Biochem Pharmacol, 2006, 71: 872–881CrossRefGoogle Scholar
  32. 32.
    Zhen M, Shu C, Li J, et al. A highly efficient and tumor vasculartargeting therapeutic technique with size-expansible gadofullerene nanocrystals. Sci China Mater, 2015, 58: 799–810CrossRefGoogle Scholar
  33. 33.
    Cagle DW, Kennel SJ, Mirzadeh S, et al. In vivo studies of fullerene- based materials using endohedral metallofullerene radiotracers. Proc Natl Acad Sci USA, 1999, 96: 5182–5187CrossRefGoogle Scholar
  34. 34.
    Gharbi N, Pressac M, Hadchouel M, et al. Fullerene is a powerful antioxidant in vivo with no acute or subacute toxicity. Nano Lett, 2005, 5: 2578–2585CrossRefGoogle Scholar
  35. 35.
    Yin JJ, Lao F, Fu PP, et al. The scavenging of reactive oxygen species and the potential for cell protection by functionalized fullerene materials. Biomaterials, 2009, 30: 611–621CrossRefGoogle Scholar
  36. 36.
    Duarte JH. Experimental arthritis: fullerene nanoparticles ameliorate disease in arthritis mouse model. Nat Rev Rheumatol, 2015, 11: 319–319CrossRefGoogle Scholar
  37. 37.
    Xu JY, Su YY, Cheng JS, et al. Protective effects of fullerenol on carbon tetrachloride-induced acute hepatotoxicity and nephrotoxicity in rats. Carbon, 2010, 48: 1388–1396CrossRefGoogle Scholar
  38. 38.
    Milic VD, Stankov K, Injac R, et al. Activity of antioxidative enzymes in erythrocytes after a single dose administration of doxorubicin in rats pretreated with fullerenol C60(OH)24. Toxicol Mech Methods, 2009, 19: 24–28CrossRefGoogle Scholar
  39. 39.
    Baati T, Bourasset F, Gharbi N, et al. The prolongation of the lifespan of rats by repeated oral administration of fullerene. Biomaterials, 2012, 33: 4936–4946CrossRefGoogle Scholar
  40. 40.
    Ji ZQ, Sun H, Wang H, et al. Biodistribution and tumor uptake of C60(OH)x in mice. J Nanopart Res, 2006, 8: 53–63CrossRefGoogle Scholar
  41. 41.
    Zheng J, Zhen MM, Ge JC, et al. Multifunctional gadofulleride nanoprobe for magnetic resonance imaging/fluorescent dual modality molecular imaging and free radical scavenging. Carbon, 2013, 65: 175–180CrossRefGoogle Scholar
  42. 42.
    Markovic Z, Trajkovic V. Biomedical potential of the reactive oxygen species generation and quenching by fullerenes (C60). Biomaterials, 2008, 29: 3561–3573CrossRefGoogle Scholar
  43. 43.
    Andrievsky GV, Bruskov VI, Tykhomyrov AA, et al. Peculiarities of the antioxidant and radioprotective effects of hydrated C60 fullerene nanostuctures in vitro and in vivo. Free Radical Biol Med, 2009, 47: 786–793CrossRefGoogle Scholar
  44. 44.
    Karakoti A, Singh S, Dowding JM, et al. Redox-active radical scavenging nanomaterials. Chem Soc Rev, 2010, 39: 4422–4432CrossRefGoogle Scholar
  45. 45.
    Lee HJ, Selesniemi K, Niikura Y, et al. Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol, 2007, 25: 3198–3204CrossRefGoogle Scholar
  46. 46.
    Wang H, Agarwal P, Zhao S, et al. Combined cancer therapy with hyaluronan-decorated fullerene-silica multifunctional nanoparticles to target cancer stem-like cells. Biomaterials, 2016, 97: 62–73CrossRefGoogle Scholar
  47. 47.
    Sun M, Kiourti A, Wang H, et al. Enhanced microwave hyperthermia of cancer cells with fullerene. Mol Pharm, 2016, 13: 2184–2192CrossRefGoogle Scholar
  48. 48.
    Naveiras O, Nardi V, Wenzel PL, et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature, 2009, 460: 259–263CrossRefGoogle Scholar
  49. 49.
    Cao S, Durrani FA, Tóth K, et al. Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models. Br J Cancer, 2014, 110: 1733–1743CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Ying Zhang (张莹)
    • 1
    • 2
  • Chunying Shu (舒春英)
    • 1
    • 2
  • Mingming Zhen (甄明明)
    • 1
    • 2
    Email author
  • Jie Li (李杰)
    • 1
    • 2
  • Tong Yu (于童)
    • 1
    • 2
  • Wang Jia (贾旺)
    • 1
    • 2
  • Xue Li (李雪)
    • 1
    • 2
  • Ruijun Deng (邓睿君)
    • 1
    • 2
  • Yue Zhou (周悦)
    • 1
    • 2
  • Chunru Wang (王春儒)
    • 1
    • 2
    Email author
  1. 1.Beijing National Laboratory for Molecular Sciences, Key Laboratory of Molecular Nanostructure and Nanotechnology, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of ChemistryChinese Academy of SciencesBeijingChina
  2. 2.University of Chinese Academy of SciencesBeijingChina

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