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Nanoparticles target cancer by mimicking platelet cells

BioPhotonics
Mar 2007
Peptide that self-amplifies is key to technique

Hank Hogan

It’s not only art that imitates life. So too does a new technique that could be useful in nanoparticle-based diagnostics and therapeutics such as tumor imaging and targeted drug delivery. Researchers have devised a scheme in which nanoparticles flowing in the bloodstream home in on tumors and amplify their targeting, mimicking the action of platelet cells during the formation of a clot.

“A couple of years ago, we came up with the idea that we might be able to increase the homing of nanoparticles by making the homing self-amplifying,” said Erkki Ruoslahti, professor at the Burnham Institute for Medical Research at the University of California, Santa Barbara. He added that the details turned out to be different than anticipated, but that the concept worked.

Others in the team were from the Burnham Institute for Medical Research at La Jolla, Calif.; the University of California, San Diego; AntiCancer, Inc. of San Diego; and the Harvard-MIT Division of Health Sciences and Technology in Cambridge, Mass. Ruoslahti noted that Dmitri Simberg, a postdoctoral researcher in his lab, contributed greatly to transforming the idea into reality.

Key to the technique is coating the nanoparticles with a peptide that provides homing and amplification. The self-amplification leads to positive feedback; as the nanoparticles flock to a target, more are attracted.

The researchers used the CREKA peptide, first identified using mouse cancers. The peptide was a good candidate for nanoparticle use because it is linear — unlike the cyclic arrangement of other peptides — and is only five amino acids long, which is shorter than other peptides. In addition, it can be conjugated with other functional groups without affecting its binding activity. Although targeting can be done with other peptides, Ruoslahti said that CREKA is the only one thus far that provides self-amplification.

The researchers synthesized the peptide, attaching the fluorescent dye fluorescein or Alexa Fluor 647. Optical inspection found that the peptide was essentially undetectable in normal tissue, but that it formed a distinct meshwork in tumors and highlighted tumor blood vessels.

Mouse experiments

The team coupled the fluorescently labeled peptides onto the surface of 50-nm-diameter superparamagnetic amino dextran-coated iron oxide nanoparticles, which have been extensively studied and used as MRI contrast agents. The resulting particles were strongly fluorescent and were employed in a series of in vivo mouse experiments.

BRMIMETIC.jpg
Homing in on tumors thanks to an attached peptide, superparamagnetic amino dextran-coated iron oxide (SPIO) nanoparticles enhance magnetic resonance tumor imaging and could someday be used to deliver therapeutics directly to tumors. In these images, CD31 (top two left) and CD41 (bottom left) antibodies, SPIO nanoparticles (middle) and cell nuclei (right) are fluorescently labeled with different colors. The column on the right is a merger of those in the middle and left, along with cell nuclei (blue). In experiments, most nanoparticles ended up collocalized with tumor blood vessels in mice bearing a cancer xenograft (top right). Staining for fibrin indicated that the blood clots were impregnated with nanoparticles, which means that the particles were incorporated into the growing clot after the blood was flowing freely (middle right). In some cases, the nanoparticles are distributed along a meshwork (middle right inset). The nanoparticles, however, did not collocalize with platelets (bottom right), which indicates that platelets are not involved in the homing and amplification process. Reprinted with permission of PNAS.

The scientists used an Olympus intravital laser scanning microscope to observe human breast cancer tissue that had been xenografted onto mice that were immune deficient and thus incapable of rejecting the foreign cells. They found mechanisms in the mice that sequestered the nanoparticles, removing them from the blood and preventing them from reaching the tumor formed by the human cells.

To get around this effect, the researchers injected decoy particles — either plain liposomes or nickel-chelated liposomes — into the blood. These prolonged the blood lifetime of the nanoparticles, with the nickel liposomes increasing the nanoparticle concentration fivefold.

They found that the nanoparticles ended up in the mouse xenograft tumors and tumor blood vessels. Up to 20 percent of tumor vessels were filled with fluorescent masses. Measurements of tumor magnetization and fluorescence showed that mice that were pretreated with the nickel-chelated liposomes had a sixfold greater accumulation of nanoparticles in the tumor than those that were not treated. This accretion was cut by more than half if a strong clotting inhibitor was injected first. Thus the nanoparticles not only were homing in but also were amplifying their homing. The work was reported in the Jan. 16 issue of PNAS.

The researchers also did some work with a CREKA liposome and discovered that it also selectively homed in on tumors. Without the peptide, neither the nanoparticles nor the liposomes caused clotting.

These initial findings are a proof of principal, noted Ruoslahti, and need to be extended to additional tumor types. Because CREKA homes in on various kinds of tumors, he does not believe that this will be a problem. It also will be necessary to develop a better pretreatment because the nickel presents toxicity issues. Cutting the concentration may help, but more work needs to be done.

As for future research, the group is working toward using the technique for therapy in addition to diagnostics. To do that, the nanoparticles would carry a drug and deliver it directly to a tumor. In addition, if the vessel occlusion rate were higher, then the blood flow feeding a tumor would be reduced and the tumor starved.

Achieving such a blockage would entail getting more particles into the area, which also would mean that more of any drug would end up in the tumor. “The two approaches, improving the homing/vessel occlusion aspect and adding a drug delivery function, are synergistic,” said Ruoslahti.


GLOSSARY
nanoparticle
A small object that behaves as a whole unit or entity in terms of it’s transport and it’s properties, as opposed to an individual molecule which on it’s own is not considered a nanoparticle.. Nanoparticles range between 100 and 2500 nanometers in diameter.  
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