Abstract
It has long been a dream to achieve tumor targeting therapy that can efficiently reduce the toxicity and severe side effects of conventional antitumor chemotherapeutic agents. Taking advantage of the abnormalities of tumor vasculature, we demonstrate here a new powerful tumor vascular-targeting therapeutic technique for solid cancers that applies advanced nanotechnology to cut off the nutrient supply of tumor cells by physically destroying the abnormal tumor blood vessels. Water soluble magnetic Gd@C82 nanocrystals of the chosen sizes are deliberately designed with abilities to penetrate into the leaky tumor blood vessels. By triggering the radiofrequency induced phase transition of gadofullerene nanocrystals while extravasating the tumor blood vessel, the explosive structural change of nanoparticles generates a devastating impact on abnormal tumor blood vessels, resulting in a rapid and extensive ischemia necrosis and shrinkage of the tumors. This unprecedented target-specific physiotherapy is found to work perfectly for advanced and refractory solid tumors.
中文摘要
本文报道了一种利用金属富勒烯纳米晶体快速高效治疗肿瘤的新技术. 从生物学上肿瘤血管和正常血管在结构上存在显著差异这一特点着手, 利用材料学上金属富勒烯纳米晶体在吸收射频能量后发生相变, 伴随着体积剧烈膨胀的特性, 高选择性地摧毁肿瘤血管. 研究表明, 经过1小时治疗后, 肿瘤部位血流即可发生快速阻断, 治疗2~4小时后, 肿瘤组织逐步发生出血性坏死, 肿瘤塌陷体积缩小; 并且对于多种实体肿瘤均有显著疗效. 该技术是一种快速、广谱、特异性高、毒副作用小的新型肿瘤治疗技术, 是一种具有巨大发展潜力的肿瘤治疗技术.
Article PDF
Similar content being viewed by others
References
Nagy JA, Chang SH, Dvorak AM, Dvorak HF. Why are tumour blood vessels abnormal and why is it important to know? Br J Cancer, 2009, 100: 865–869
Barinaga M. Designing therapies that target tumor blood vessels. Science, 1997, 275: 482–484
Heath VL, Bicknell R. Anticancer strategies involving the vasculature. Nat Rev Clin Oncol, 2009, 6: 395–404
Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer, 2005, 5: 423–435
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science, 2005, 307: 58–62
Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer, 2005, 5: 161–171
Kievit FM, Zhang M. Cancer nanotheranostics: improving imaging and therapy by targeted delivery across biological barriers. Adv Mater, 2011, 23: H217–H247
Greish K. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target, 2007, 15: 457–464
Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev, 2011, 63: 136–151
Liu X, Chen Y, Li H, et al. Enhanced retention and cellular uptake of nanoparticles in tumors by controlling their aggregation behavior. ACS Nano, 2013, 7: 6244–6257
Thakor AS, Gambhir SS. Nanooncology: the future of cancer diagnosis and therapy. CA-Cancer J Clin, 2013, 63: 395–418
Li Y, Lin TY, Luo Y, et al. A smart and versatile theranostic nanomedicine platform based on nanoporphyrin. Nat Commun, 2014, 5: 4712
Siemann DW, Horsman MR. Vascular targeted therapies in oncology. Cell Tissue Res, 2009, 335: 241–248
Wang M, Thanou M. Targeting nanoparticles to cancer. Pharm Res, 2010, 62: 90–99.
de Bono JS, Ashworth A. Translating cancer research into targeted therapeutics. Nature, 2010, 467: 543–549
Shu CY, Ma XY, Zhang JF, et al. Conjugation of a water-soluble gadolinium endohedral fulleride with an antibody as a magnetic resonance imaging contrast agent. Bioconjugate Chem, 2008, 19: 651–655
Shu C, Corwin FD, Zhang J, et al. Facile preparation of a new gadofullerene- based magnetic resonance imaging contrast agent with high 1H relaxivity. Bioconjugate Chem, 2009, 20: 1186–1193
Guo YG, Wan LJ, Li CJ, et al. The effects of annealing on the structures and electrical conductivities of fullerene-derived nanowires. J Mater Chem, 2004, 14: 914–918
Wang CR, Kai T, Tomiyama T, et al. Materials science: C66 fullerene encaging a scandium dimer. Nature, 2000, 408: 426–427
Wang T, Wu J, Xu W, et al. Spin divergence induced by exohedral modification: ESR study of Sc3C2@C80 fulleropyrrolidine. Angew Chem Int Ed, 2010, 49: 1786–1789
Li CJ, Guo YG, Li BS, et al. Template synthesis of Sc@C82(I) nanowires and nanotubes at room temperature. Adv Mater, 2005, 17: 71–73
Sitharaman B, Bolskar RD, Rusakova I, Wilson LJ. Gd@C60 [C(COOH)2]10 and Gd@C60(OH)x: nanoscale aggregation studies of two metallofullerene MRI contrast agents in aqueous solution. Nano Lett, 2004, 4: 2373–2378
Shu CY, Wang CR, Zhang JF, et al. Organophosphonate functionalized Gd@C82 as a magnetic resonance imaging contrast agent. Chem Mater, 2008, 20: 2106–2109
Husebo LO, Sitharaman B, Furukawa K, Kato T, Wilson LJ. Fullerenols revisited as stable radical anions. J Am Chem Soc, 2004, 126: 12055–12064
Zheng JP, 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: 175–180
Di Corato R, Béalle G, Kolosnjaj-Tabi J, et al. Combining magnetic hyperthermia and photodynamic therapy for tumor ablation with photoresponsive magnetic liposomes. ACS Nano, 2015, 9: 2904–2916
Tamarov KP, Osminkina LA, Zinovyev SV, et al. Radio frequency radiation-induced hyperthermia using Si nanoparticle-based sensitizers for mild cancer therapy. Sci Rep, 2014, 4: 7034
Chu KF, Dupuy DE. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer, 2014, 14: 199–208
Moran C, Wainerdi S, Cherukuri T, et al. Size-dependent Joule heating of gold nanoparticles using capacitively coupled radiofrequency fields. Nano Res, 2009, 2: 400–405
Gaya AM, Rustin GJS. Vascular disrupting agents: a new class of drug in cancer therapy. Clin Oncol, 2005, 17: 277–290
Hinnen P, Eskens FALM. Vascular disrupting agents in clinical development. Br J Cancer, 2007, 96: 1159–1165
Bhave M, Akhter N, Rosen ST. Cardiovascular toxicity of biologic agents for cancer therapy. Oncology-NY, 2014, 28: 482–490
Chen C, Xing G, Wang J, et al. Multihydroxylated [Gd@C82(OH)22]n nanoparticles: antineoplastic activity of high efficiency and low toxicity. Nano Lett, 2005, 5: 2050–2057
Yang D, Zhao Y, Guo H, et al. [Gd@C82(OH)22]n nanoparticles induce dendritic cell maturation and activate Th1 immune responses. ACS Nano, 2010, 4: 1178–1186
Kang SG, Zhou G, Yang P, et al. Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C82(OH)22 and its implication for de novo design of nanomedicine. Proc Natl Acad Sci USA, 2012, 109: 15431–15436
Author information
Authors and Affiliations
Corresponding author
Additional information
Acknowledgments This work was supported by the National Natural Science Foundation of China (51472248, 11179006 and 51372251) and the Key Research Program of the Chinese Academy of Sciences (KGZDEW- T02 and XDA09030302). We thank Prof. Yan Li of Zhongnan Hospital of Wuhan University for help with tissues histology and biochemical analysis. We also thank Yongtao Li, Zhentao Zuo, and Yuqing Wang for developing the RF set-ups.
Author contributions Wang C and Zhen M supervised the project and designed the experiments. Li J synthesized the GFNCs. Zhen M and Zhang G performed the in vivo experiments. Zhen M, Deng R and Zou T performed the in vitro characterization. Shu C and Wang T analyzed the nature of GFNCs. Fang F and Lei H performed the animal MRI studies. Wang C, Bai C and Luo Y contributed to the interpretation of the data. Zhen M, Luo Y and Wang C wrote the manuscript.
Conflict of interests The authors declare that they have no conflict of interest.
Supplementary information Supporting data are available in the online version of the paper.
Mingming Zhen was born in 1987. She received her PhD degree in physical chemistry from the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) in 2014. Currently, she is an assistant professor at 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 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.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Zhen, M., Shu, C., Li, J. et al. A highly efficient and tumor vascular-targeting therapeutic technique with size-expansible gadofullerene nanocrystals. Sci. China Mater. 58, 799–810 (2015). https://doi.org/10.1007/s40843-015-0089-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40843-015-0089-3