Friday, December 4, 2009

Magnetic microdiscs target and initiate cell death in tumors

Issue date: 12/3/09

Scientists working at Argonne National Laboratory in Chicago and The University of Chicago have developed an effective method to target and kill cancer cells using tiny magnetic discs.

The microdiscs, only one micron in diameter, work by disrupting the outer membranes and initiating chemical pathways that lead to apoptosis, or cell death. In laboratory tests, the microdiscs destroyed up to 90 percent of cancer cells after being activated for only 10 minutes.

One major drawback of chemotherapy drugs, widely used to treat cancers, is that they cannot be targeted to tumor cells. These drugs affect the entire body and often cause painful side effects such as hair loss, nausea, fatigue and a weakened immune system.

For several decades, scientists have been trying to develop nanoparticles that can deliver drugs specifically to cancer cells. Although several such methods are now being tested in clinical trials, practical hurdles still remain.

Up until now, effective treatments required high concentrations of magnetic particles and high levels of power to activate them. Both could cause harmful side effects in patients.

The new research offers a potential solution to many of these problems. The team studied an aggressive brain cancer called glioblastoma multiforme. The surfaces of these cancer cells, called glioma cells, contain a much higher concentration of a protein called IL13 than normal cells do.

The microdiscs, each 60 nm wide and 1000 nm in diameter, were made of an iron and nickel alloy, then coated with a thin gold veneer. Gold is both nontoxic to living tissues and easy to modify with organic molecules. The gold-covered microdiscs were then coated with antibodies that would recognize and bind to the overexpressed protein on glioma cells.

Once introduced into the body, or in this case a cell culture, the antibodies guide the microdiscs to attach to the surface of the cancerous glioma cells, but not healthy cells. About 10 microdiscs attached to each cancer cell.

Because they are discs instead of particles, and much wider than they are thick, the microdiscs have a magnetic property known as a spin-vortex ground state, and they oscillate when an alternating current is applied.

The cell membrane consists of a fluid double layer of lipid molecules, more like the film that forms over a bowl of cold soup. This fluid membrane is easily disrupted by the twisting and turning motion of the microdiscs attached to its surface.

"The spin-vortex-mediated stimulus creates two dramatic effects: compromised integrity of the cellular membrane . . . and initiation of programmed cell death," said Elena Rozhkova, a research scientist at Argonne National Laboratory who worked on the study.

After they activated the microdiscs, the researchers noticed that most of the cancer cells looked like they were undergoing apoptosis, the controlled pathway towards death that normal cells are programmed to follow once they reach the end of their useful lives.

Cancer cells have developed mutations that allow them to escape cell cycle control and apoptosis. Instead of dying when they should, they divide and grow continuously, forming tumors.

However, the microdisc-treated glioma cells had fragmented DNA and nuclei, rounded shapes and irregular surface bulges (scientific term: blebs), all classic signs of cells undergoing apoptosis.

But the force the microdiscs exerted could not have caused such striking changes in the cells alone. In fact, the torque exerted by the microdiscs was less than one tenth of the torque needed even to break the outer membrane.

It was clear that the surface disruptions that the discs created were activating a signaling pathway inside the cell that led to apoptosis.

The researchers found that microdisc-treated cells had much higher concentrations of calcium than usual. Calcium plays a major role in many cell pathways and is known to be a key signaling molecule in apoptotic pathways.

Previous studies had also shown that even minor, temporary cell membrane disturbances can raise calcium levels within cells. It seems likely that the mechanical stimulus provided by the microdiscs is then amplified as a chemical signal inside the cell, leading the cell to begin apoptosis.

One key advancement in the team's research was that because of the material used to make the discs, a relatively low frequency and short treatment time was enough to kill most cancer cells. The relative mildness of the treatment may help decrease side effects in vivo.

"Using the unique 'soft' magnetic material allows application of a low-frequency field of a few tens of hertz applied for only ten minutes, [which] was sufficient to achieve approximately 90% cancer-cell destruction in vitro," Rozhkova said. "This is 10-100,000 times weaker magnetic field that it is used for superparamagnetic particles."

Although these new findings offer a promising new way that nanotechnology can be used to treat cancer, more work needs to be done before clinical trials can begin.

Ferromagnetic microdisks as carriers for biomedical applications
J. Appl. Phys. 105, 07B306 (2009); doi:10.1063/1.3061685

Published 5 March 2009
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E. A. Rozhkova,1 V. Novosad,2 D.-H. Kim,2 J. Pearson,2 R. Divan,1 T. Rajh,1 and S. D. Bader2
1Center for Nanoscale Materials, Argonne National Laboratory, Argonne, Illinois 60439, USA
2Materials Sciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA

We report the fabrication process, magnetic behavior, as well as the surface modification of ferromagnetic microdisks suspended in aqueous solution. They posses unique properties such as high magnetization of saturation, zero remanence due to spin vortex formation, intrinsic spin resonance at low frequencies, and the capability of delivering various biomolecules at once. Furthermore, because of their anisotropic shape, our magnetic particles rotate under alternating magnetic fields of small amplitude. This can be used to promote the idea of advanced therapies, which include combined drug delivery and magnetomechanical cell destruction when targeting tumor cells. The approach enables us to fabricate suitable magnetic carriers with excellent size tolerances, and then release them from the wafer into solution, ready for surface modification and therapeutic use. The particles have a magnetic core and are covered with few nanometers of gold on each side to provide stability at ambient conditions as well as biocompatibility and selective adhesion functions. A successful attempt to bind thiolates, including SH-modified antibody, to the disk's surface was demonstrated. ©2009 American Institute of Physics
History:Presented 12 November 2008; received 13 October 2008; accepted 23 October 2008; published 5 March 2009