Gadolinium metallofullerenol nanoparticles inhibit cancer metastasis through matrix metalloproteinase inhibition: imprisoning instead of poisoning cancer cells.

UNLABELLED The purpose of this work is to study the antimetastasis activity of gadolinium metallofullerenol nanoparticles (f-NPs) in malignant and invasive human breast cancer models. We demonstrated that f-NPs inhibited the production of matrix metalloproteinase (MMP) enzymes and further interfered with the invasiveness of cancer cells in tissue culture condition. In the tissue invasion animal model, the invasive primary tumor treated with f-NPs showed significantly less metastasis to the ectopic site along with the decreased MMP expression. In the same animal model, we observed the formation of a fibrous cage that may serve as a physical barrier capable of cancer tissue encapsulation that cuts the communication between cancer- and tumor-associated macrophages, which produce MMP enzymes. In another animal model, the blood transfer model, f-NPs potently suppressed the establishment of tumor foci in lung. Based on these data, we conclude that f-NPs have antimetastasis effects and speculate that utilization of f-NPs may provide a new strategy for the treatment of tumor metastasis. FROM THE CLINICAL EDITOR In this study utilizing metallofullerenol nanoparticles, the authors demonstrate antimetastasis effects and speculate that utilization of these nanoparticles may provide a new strategy in metastatic tumor therapy.

[1]  L. Coussens,et al.  Tumor stroma and regulation of cancer development. , 2006, Annual review of pathology.

[2]  Chad A Mirkin,et al.  Multiplexed detection of protein cancer markers with biobarcoded nanoparticle probes. , 2006, Journal of the American Chemical Society.

[3]  G. Pasterkamp,et al.  Matrix metalloproteinase inhibition reduces adventitial thickening and collagen accumulation following balloon dilation. , 2002, Cardiovascular research.

[4]  C. Fombrun,et al.  Matrix , 1979, Encyclopedic Dictionary of Archaeology.

[5]  H. Dai,et al.  In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. , 2020, Nature nanotechnology.

[6]  Xingfa Gao,et al.  Periodical Variation of Electronic Properties in Polyhydroxylated Metallofullerene Materials , 2006 .

[7]  Weibo Cai,et al.  Circulation and long-term fate of functionalized, biocompatible single-walled carbon nanotubes in mice probed by Raman spectroscopy , 2008, Proceedings of the National Academy of Sciences.

[8]  Feng Zhao,et al.  Multihydroxylated [Gd@C82(OH)22]n nanoparticles: antineoplastic activity of high efficiency and low toxicity. , 2005, Nano letters.

[9]  Z. Werb,et al.  New functions for the matrix metalloproteinases in cancer progression , 2002, Nature Reviews Cancer.

[10]  Z. Chai,et al.  Tuning electronic properties of metallic atom in bondage to a nanospace. , 2005, The journal of physical chemistry. B.

[11]  F. Shen,et al.  Resveratrol inhibits matrix metalloproteinase-9 transcription in U937 cells. , 2003, Acta pharmacologica Sinica.

[12]  Gengfeng Zheng,et al.  Multiplexed electrical detection of cancer markers with nanowire sensor arrays , 2005, Nature Biotechnology.

[13]  Yingjin Yuan,et al.  Inhibition of tumor metastasis in vivo by combination of paclitaxel and hyaluronic acid. , 2006, Cancer letters.

[14]  Michael M. Gottesman,et al.  Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis , 2010, Proceedings of the National Academy of Sciences.

[15]  Long-Sen Chang,et al.  Caffeine induces matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 down‐regulation in human leukemia U937 cells via Ca2+/ROS‐mediated suppression of ERK/c‐fos pathway and activation of p38 MAPK/c‐jun pathway , 2010, Journal of cellular physiology.

[16]  K. Yamada Cell biology: Tumour jailbreak , 2003, Nature.

[17]  H. Dvorak,et al.  Fibrin as a component of the tumor stroma: origins and biological significance , 2004, Cancer and Metastasis Reviews.

[18]  S. Weiss,et al.  Membrane Type I Matrix Metalloproteinase Usurps Tumor Growth Control Imposed by the Three-Dimensional Extracellular Matrix , 2003, Cell.

[19]  P. Fatouros,et al.  Organophosphonate Functionalized Gd@C 82 as a Magnetic Resonance Imaging Contrast Agent , 2008 .

[20]  L. Liotta,et al.  Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation , 1991, Cell.

[21]  D. Welch,et al.  Metastasis of hormone-independent breast cancer to lung and bone is decreased by α-difluoromethylornithine treatment , 2005, Breast Cancer Research.

[22]  Z. Chai,et al.  Antioxidative function and biodistribution of [Gd@C82(OH)22]n nanoparticles in tumor-bearing mice. , 2006, Biochemical pharmacology.

[23]  Xing-Jie Liang,et al.  Inhibition of Tumor Growth by Endohedral Metallofullerenol Nanoparticles Optimized as Reactive Oxygen Species Scavenger , 2008, Molecular Pharmacology.

[24]  Noam Brown,et al.  The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapies , 2002, The Journal of pathology.

[25]  H. Maeda The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. , 2001, Advances in enzyme regulation.

[26]  Y. Liu,et al.  The effect of Gd@C82(OH)22 nanoparticles on the release of Th1/Th2 cytokines and induction of TNF-alpha mediated cellular immunity. , 2009, Biomaterials.

[27]  May D. Wang,et al.  In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags , 2008, Nature Biotechnology.

[28]  Yan Song,et al.  Potent angiogenesis inhibition by the particulate form of fullerene derivatives. , 2010, ACS nano.

[29]  Andrew V. Nguyen,et al.  Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy , 2001, The Journal of experimental medicine.

[30]  H. Shinohara,et al.  Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents. , 2001, Bioconjugate chemistry.

[31]  Ferdinando Mannello,et al.  Natural bio-drugs as matrix metalloproteinase inhibitors: new perspectives on the horizon? , 2006, Recent patents on anti-cancer drug discovery.

[32]  S. Ran,et al.  The vascular-ablative agent VEGF(121)/rGel inhibits pulmonary metastases of MDA-MB-231 breast tumors. , 2005, Neoplasia.

[33]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[34]  F. Zhao,et al.  Modulation of structural and electronic properties of fullerene and metallofullerenes by surface chemical modifications. , 2007, Journal of nanoscience and nanotechnology.

[35]  Z. Chai,et al.  The strong MRI relaxivity of paramagnetic nanoparticles. , 2008, Journal of Physical Chemistry B.

[36]  B. Fingleton,et al.  Matrix Metalloproteinase Inhibitors and Cancer—Trials and Tribulations , 2002, Science.

[37]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[38]  M. Ferrari Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.