‘Homing' Nanoparticles Starve Tumors of Blood

A collaborative team of researchers has developed nanoparticles that search for tumors, bind to their blood vessels, and then attract more nanoparticles to the tumor target.

Utilizing this technology, the researchers, led by Erkki Ruoslahti, M.D., Ph.D., from the Burnham Institute for Medical Research at the University of California (UC) Santa Barbara (Burnham; USA), demonstrated that the homing nanoparticle could be used to deliver a "payload” of an imaging agent, and in the process act as a clotting compound, obstructing as much as 20% of the tumor blood vessels. These findings are pending publication in the Proceedings of the [U.S.] National Academy of Sciences and at the journal's website on January 8, 2007.

The promise of nanomedicine is based on the premise that a particle can perform more functions than a drug. Multifuncionality is demonstrated in this study, in which researchers from Burnham, UC San Diego, and Massachusetts Institute of Technology (Boston, MA, USA) devised a nanoparticle that combined tumor-homing, self-amplification of the homing, hindering tumor blood flow, and imaging.

Using a screening technique developed earlier in Dr. Ruoslahti's laboratory, the group identified a peptide that targeted the blood vessels, or vasculature, inside breast cancer tumors growing in mice. The peptide was comprised of five amino acids: cysteine-arginine-glutamic acid-lysine-alanine (CREKA).

The researchers then demonstrated that the CREKA peptide recognizes clotted blood, which is present in the lining of tumor vessels but not in vessels of healthy tissues. The researchers utilized a special mouse strain that lacks fibrinogen, the primary protein component of blood clots, to demonstrate that tumors growing in these fibrinogen-deficient mice did not attract the CREKA peptide, whereas the peptide was detected in the tumors of a control group of normal littermates.

Having established clotted blood as the binding site for CREKA, the team constructed nanoparticles from superparamagnetic amino dextran-coated iron oxide (SPIO); such particles are used in the clinic to enhance magnetic resonance imaging (MRI). They combined the CREKA peptide to the SPIO particles to give the particles a tumor-homing function and programmed an additional enhanced imaging functionality into their nanoparticle by making it fluorescent.

At first, CREKA-SPIO's tumor homing ability was hindered by a natural defense response, which activates the reticuloendothelial system (RES)--white blood cells that, together with the liver and spleen, comprise a protective screening system in mice (and humans). The investigators designed "decoy” molecules of liposomes coated with nickel, which sidetracked the RES response that would have otherwise been directed toward CREKA-SPIO. The use of decoy molecules extended the half-life of CREKA-SPIO in circulating blood five-fold, which significantly increased the nanoparticle's ability to narrow in on the tumors.

The CREKA-SPIO that gathered in the tumor enhanced blood clotting in tumor vessels created additional binding sites for the nanoparticles. This "self amplification” of the tumor homing greatly enhanced the researchers' ability to image the tumors. It also contributed to blocking as much as 20% of the blood vessels in the tumor. While occluding 20% of tumor vessels was not sufficient to decrease the rate of tumor growth, it remains a promising target for future studies.

"Having identified the principle of self-amplification, we are now optimizing the process, hoping to obtain a more complete shut-down of blood flow into the tumor to strangle it,” stated Dr. Ruoslahti. "We are also in the process of adding a drug delivery function to the particles. These two approaches are synergistic; the more particles we bring into the tumor, the greater the obstruction of the blood flow and more of the drug is delivered into the tumor.”



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Burnham Institute for Medical Research