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Nanoparticles hold promise of preventing tumor growth

Biologists have long known cancer cells spread through the body, but not on exactly how they spread, and how to inhibit them at a molecular level. Working with an international team of cell biologists, chemists, and computational biologists, IBM Research scientist Drs. Ruhong Zhou, Seung-gu Kang and Tien Huynh, have shown in simulations that nanoparticle gadolinium metallofullerenol (Gd@C82(OH)22) prevents the spread of pancreatic cancer cells by quarantining them (see animation). It binds to and blocks the enzyme responsible for tumor metastasis and survival.
Earlier this year, the team from China led by Prof. Yuliang Zhao of the China National Center for Nanoscience and Technology discovered that the metallofullerenol could bind to breast cancer and stop its metastasis, but did not know how it happened at a molecular level. IBM’s work, featured in September’s Proceedings of the National Academy of Sciences, reveals for the first time the molecular mechanism of this process. Gadolinium metallofullerenol acts as a nanomedicine via inhibition of the cancer-instigating matrix metalloproteinase enzymes (MMPs).
Finding cancer’s “off” switch
MMPs degrade the extracelluar matrix (ECM) that confines cancer cells and spurs blood vessel growth into the cancer cells. So, these enzymes not only help tumors grow and spread in the body, but also keep them healthy. Stopping this cycle was a three-fold challenge:
  1. Find the right MMP(s) (we have 27 MMPs in our bodies)
  2. Stop those MMPs’ capability to spread the tumor
  3. Stop those MMPs’ capability to feed the tumor
The China National Center for Nanoscience and Technology team’s experiments show that MMP9 is the most affected of these enzymes by metallofullerenol at a cellular level. IBM’s team ran molecular dynamics simulations for a few months on a Blue Gene supercomputer and found that gadolinium metallofullerenol inactivates the function of MMP9 through an exocite binding mode near its S1’ loop, which is responsible for ligand (molecular binding point) recognition.

Knowing how to block this exocite binding mode could provide a new route for future cancer drug development. Now, IBM is looking at the MMP2 enzyme (which also was also affected in experiments) for further validation of this novel molecular inhibition mechanism.

Video of Nanoparticle Gd@C82(OH)22 Attacking a Tumor Cell
Gadolinium metallofullerenol is found to inhibit pancreatic tumor growth by about 50 percent. Similarly, it shows more than 80 percent inhibition rate to metastasis of human breast cancer in previous work (Nanomedicine 8, 136-146, February 2012). These findings may provide a new route of development of specific MMP inhibitors and effective anti-cancer nanomedicine.

IBM’s collaborators will soon begin producing these nanoparticles for phase one clinical trials. While a commercial drug is still a few years away, this is the first time we’ve understood and shown how to effectively attack cancer cells with a nanoparticle.

IBM’s Computational Biology Center collaborated with the China National Center for Nanoscience and Technology in Beijing; the Environmental Molecular Sciences Laboratory at the Pacific Northwest National Lab, in Richland, Washington; and the Department of Chemistry at Columbia University.


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