SCIENCE CHINA Materials, Volume 60, Issue 9: 866-880(2017) https://doi.org/10.1007/s40843-017-9079-6

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

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  • ReceivedJun 11, 2017
  • AcceptedJul 17, 2017
  • PublishedAug 14, 2017


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.

Funded by

National Natural Science Foundation of China(51472248,51372251,51502301)

National Major Scientific Instruments and Equipments Development Project(ZDYZ2015-2)

Key Research Program of the Chinese Academy of Sciences(QYZDJ-SSW-SLH025,KGZD-EW-T02,XDA09030302)


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-EW-T02 and XDA09030302).

Interest statement

The authors declare that they have no conflict of interest.

Contributions statement

Zhang Y, Zhen M and Wang C performed the experiments, collected and analyzed the data, and wrote the manuscript; Shu C provided critical comments on the design of the study and the writing of the manuscript; Li J and Yu T performed the preparation of gadofullerenes nanocrystals (GFNCs); Jia W, Li X, Deng R, and Zhou Y provided essential technical assistance with experiments; Wang C conceived of and designed the study, supervised the research and wrote the manuscript. All authors discussed the results and approved the manuscript.

Author information

Ying Zhang was born in 1989. She received her PhD degree in physical chemistry from the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) in 2017. Her research interests include biomedical applications of fullerenes and gadofullerenes.

Mingming Zhen was born in 1987. She received her PhD degree in physical chemistry from the ICCAS in 2014. Currently, she is an assistant professor at the ICCAS. Her research interests include biomedical applications of fullerenes and gadofullerenes.

Chunru Wang was born in 1965. He received his PhD degree in physical chemistry from Dalian Institute of Chemistry Physics, Chinese Academy of Sciences in 1992. Currently, he is a professor at the ICCAS. His research interests include fullerenes and endohedral fullerenes, mainly focusing on their industrialization and applications. He discovered the metal carbide fullerenes for the first time, researched on high efficiency MRI contrast agents and developed a novel tumor vascular-targeting therapy technique using gadofullerenes.


Supplementary information

Experimental details and supporting data are available in the online version of the paper.


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  • Figure 1

    Characteristics of GFNCs in vitro. (a) Schematic diagram of the as-synthesized GFNCs by hydroxylation and a photograph of the GFNCs aqueous solution. (b) AFM study of GFNCs to show the core size of the samples. (c) Average hydrodynamic diameter distributions of GFNCs in saline. (d) The ESR spectra of the hydroxyl radicals captured by DMPO after treatment with 50 μmol L−1 of GFNCs (red line). The saline was used as a blank (black line). The hydroxyl radical was generated by the H2O2 exposure to UV light for 8 min. (e) The cell viability of mice bone marrow FDC-P1 cells incubated with the GFNCs (0.5‒30 μmol L−1) for 24 h. It shows no toxicity of GFNCs towards the FDC-P1 cells. (f) Cytoprotective effects of the GFNCs (0.5‒30 μmol L−1) against H2O2-induced damage on the FDC-P1 cells (n = 6; *, P< 0.05).

  • Figure 2

    The biodistribution of GFNCs in vivo. (a) The GFNCs distribution in blood plasma of the test mice at different time points (5 min, 15 min,30 min, 45 min, 1 h, 4 h, and 24 h) after a single i.v. injection of GFNCs (expressed as ng Gd3+ mg−1 blood). (b) The GFNCs distribution in sclerotin and bone marrow of the test mice at 1 h and 24 h after administration with GFNCs (n = 5; *, P< 0.05). (c) Schematic illustration of the electron microprobe used to analyze the distribution of GFNCs in the mice bones. (d) The electron microprobe study about the time dependence of Gd3+ in mice bone marrow after GFNCs injection (0.5, 1, 4 and 24 h).

  • Figure 3

    The myelosuppression protective tests. (a) Schematic illustration of bone marrow protective process of the GFNCs. (b‒e) Hematological parameters including WBC, HGB, LY and MO% in the control group, the CTX group and the GFNCs + CTX group during the chemoprotective tests. (n = 6; *, P< 0.05). (f) Activities of MDA, SOD, GST, CAT and GPx in mice plasma on the day 18.

  • Figure 4

    The antitumor activity of CTX and the GFNCs protection against CTX-induced toxicity in mice. (a) The growth inhibitory curves of tumors (left) and body weight changes (right) in the control group, CTX group and GFNCs + CTX group (n = 6; *, P< 0.05, compared with the control group). (b) Photos of tumors of 18 tested mice after chemotherapy in three different groups. (c) Typical biochemical parameters: ALT, AST, ALP, LDH, BUN and UA, which are relevant to liver (ALT, AST and ALP), heart (LDH) and kidney functions (BUN and UA) (n = 6; *, P< 0.05). (d) Selected H&E sections of major organs (heart, liver, spleen, lung and kidney) and tumor tissues from the tested mice in different groups.

  • Figure 5

    Oxidative stress-related enzymes activities and H&E, ESEM analysis of mice tissues on the fourth day of CTX chemotherapy. (a) Activities of MDA, SOD, CAT, GPx, and GST in control, CTX, and GFNCs + CTX groups of mice (n = 4; *, P< 0.05). (b) Light microscopy of H&E sections of mice femur bone, in which the bone (Bo) and bone marrow (BM) labeled different bone sections; (► in red) labeled the normal bone marrow cells and hematopoietic cells, (► in black) labeled the fatty infiltration of hematopoietic tissues. (c) Light microscopy of H&E sections of mice spleen, in which (→ in black) labeled the splenic red pulp and (→ in red) the splenic white pulp. (d) ESEM images of mice bone marrow, in which (→ in blue) labeled the adipocytes and (→ in red) labeled the necrotic cells by the CTX injury. (e) ESEM images of mice blood red cells. Many shriveled and abnormal red cells were observed in the CTX group of mice, and the blood red cells in the GFNCs + CTX group showed normal morphology as that in controls.

  • Figure 6

    Oxidative stress-related enzyme activities and H&E, ESEM analyses of mice tissues on the eighth day of the CTX therapy. (a) Activities of MDA, SOD, CAT, GPx and GST in control, CTX, and GFNCs + CTX groups. (n = 4; *, P< 0.05). (b) Light microscopy of H&E sections of mice femur bone on the eighth day, in which the bone (Bo) and bone marrow (BM) labeled different bone sections; (► in red) labeled the normal bone marrow cells and hematopoietic cells, (► in black) labeled the fatty infiltration of hematopoietic tissues. (c) Light microscopy of H&E sections of mice spleen, in which (→ in black) labeled the splenic red pulp and (→ in red) the splenic white pulp. (d) ESEM images of mice bone marrow, in which (→ in blue) labeled the adipocytes and (→ in red) labeled the necrotic cells by the CTX injury. (e) ESEM images of mice blood red cells, in which the shriveled and abnormal red cells were mainly observed in the CTX group of mice.

  • Figure 7

    The schematic representation of the GFNCs protective mechanism related to bone marrow enrichment and free radical scavenging.

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