A Magnetic Switch for Cancer Cell Death

A Magnetic Switch for Cancer Cell Death

Triggering the death of tumor cells is an area of cancer research being pursued with interest. Some approaches look to a biochemical trigger – a molecule administered to patients that will activate the death program in unhealthy cells – yet their action is not confined to the region of the tumor and may not last long in the body. A possible solution to both of these problems may lie in magnetic nanoparticles targeted to death receptors on cancer cells; using magnets, these particles can be activated where and when they are required. A new study has demonstrated, for the first time in a living vertebrate, the use of this non-invasive system to “turn on” cell death.

Triggering the death of tumor cells is an area of cancer research being pursued with interest. Some approaches look to a biochemical trigger – a molecule administered to patients that will activate the death program in unhealthy cells – yet their action is not confined to the region of the tumor and may not last long in the body. A possible solution to both of these problems may lie in magnetic nanoparticles targeted to death receptors on cancer cells; using magnets, these particles can be activated where and when they are required. A new study has demonstrated, for the first time in a living vertebrate, the use of this non-invasive system to “turn on” cell death.

 

A team in South Korea has taken an important step towards using magnets to target anti-cancer treatments to tumor cells. Much work is invested in developing compounds to kill such cells, but often they lack specificity in where and when they act: drugs may exert their negative effects throughout the body, or the therapeutic substance may break down before it can act on its intended target. In a study published online, 7 October 2012, in Nature Materials, the group demonstrates not only the use of magnetic nanoparticles to trigger tumor cell death in vitro, but that the action of these same particles can be finely controlled with magnets in vivo, in zebrafish.

The magnetic aspect of the system consists of 15-nanometer zinc and iron oxide particles (Zn0.4 Fe2.6 O4). The tumor-targeting element is an antibody specific to the cell surface death receptor 4 (DR4) of a type of colon cancer cell. When activated, this receptor initiates apoptosis, or programmed cell death, a process that rids the body of unhealthy or aged cells. In cancer cells, apoptosis is disrupted, allowing them to proliferate without control.

The team led by Jeon-Soo Shin and Jinwoo Cheon, of the Yonsei University College of Medicine, linked the magnetic nanoparticles (MNPs) to the DR4-targeting antibody (Ab) and applied them to cultures of colon cancer cells. In the absence of a magnetic field, the Ab-MNP complexes were distributed evenly over the surface of the cells. To activate the system, the researchers placed two magnets 200 micrometers apart, generating a magnetic field of 0.64 Tesla between them. This magnetic field was applied to the cancer cells in culture, focusing on a micrometer-sized area. When the magnetism of the particles was “turned on”, the Ab-MNP complexes, bound to the death receptors, clustered together in small groups on the cell surface. It is this clustering of DR4 that sends the signal to initiate apoptosis.

Magnetic nanoparticles targeted to a cell death receptor are "turned on" using magnets. (Copyright: Nature Publishing Group)
Magnetic nanoparticles targeted to a cell death receptor are "turned on" using magnets.

The researchers confirmed that an apoptosis signal had indeed been sent by looking for caspase-3, a molecule activated during the process. Apoptosis itself was measured by staining the colon cancer cells; when the cell membrane is damaged, a result of the apoptotic process, cells take up the blue dye. With a magnetic field treatment of 4 hours, using increasing concentrations of Ab-MNP complexes, between 20% and 65% of cancer cells were killed.

Proof of principle, in vivo

These in vitro experiments showed the cell-killing efficacy of the magnetic nanoparticle system. A similar technique had actually been developed in 2008 by Robert J. Mannix et al; the real step forward provided by the South Korean team was in demonstrating their ability to control the nanoparticles in a live vertebrate.

Apoptosis, in addition to clearing the body of old and damaged cells, plays a role in development: some cells produced are destined to die off in a sort of “pruning” process, as the organism assumes its adult form. In this study, zebrafish development was used to test the ability of the researchers to control their apoptosis-inducing particles in vivo, both in space and time. The genetic similarity between the zebrafish apoptosis signaling receptor and human DR4 made them a relevant choice, and the appropriate antibody-magnetic nanoparticle complexes were produced for the experiment.

"A schematic representation of the magnetic switch for apoptosis signalling in in vitro cells and in a zebrafish. MNPs first bind to the death receptors, and subsequent aggregation on the application of a focused magnetic field triggers extrinsic apoptosis signalling. Magnetic switching On of death receptor clustering results in the death of in vitro cells and also causes morphological changes in in vivo zebrafish." (Copyright: Nature Publishing Group)
A magnetic switch for apoptosis in vitro and in vivo in the zebrafish

Fish embryos were injected with Ab-MNPs at the one-cell stage of development, and were treated with a magnetic field of up to 0.5T. The magnetically activated apoptosis resulted in changes in their development, leading to bending of the tail: the stronger the magnetic field, the greater the angle of the bend. The authors note that “a bent tail is regarded as one of the most representative traits of apoptosis”; observation of clustered MNPs and tell-tale apoptotic molecule caspase-3 in the tail added further support to the conclusion.

These results, while “only” building incrementally on previous research, represent an important move into a living organism. If magnetic nanoparticles and a non-invasive magnetic switch can be used to turn on apoptosis in zebrafish development, perhaps the technique will prove to be an equally controllable method of activating the cell death process in human cancer cells, where and when it is needed.

Find out more:

Nanoparticles: size and charge matter http://www.sciencenews.org/view/generic/id/36709/title/Nanoparticles_size_and_charge_matter

Cell death (apoptosis) - A to Z http://www.cancerresearchuk.org/cancer-info/utilities/atozindex/atoz-cell-death

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