Science Editor

By combining two nanoparticles into an "amplification system," scientists have managed to harness an endogenous biological cascade, activated by a signaling molecule, to serve as a homing beacon that directs a second molecule, the receiver, to the site of tumors.

Optimizing drug targeting is one of the basic issues faced by any sort of therapeutic. The new experiments, which were published in the June 19, 2011, issue of Nature Materials, could serve as a basic approach to improve such targeting.

"The field spends most of the time thinking about [targeting particles] individually," first author Geoffrey von Maltzahn told BioWorld Today.

"We are trying to build systems of particles, much like immune cells talk to each other," he said.

The basic idea is simple: von Maltzahn and his team developed a two-particle combination where the first particle's job is to find tumor sites and activate the coagulation cascade, which forms blood clots after tissue injury, within them.

Each signaling nanoparticle is thus able to create many biological signaling molecules, which are what draws the second particle – the receiver – and its payload to the tumor site.

Amplification cascades are a basic biological mechanism – in fact, von Maltzahn argued that any efficacious medication is typically performing a biological amplification of some sort, "even if we don't think of it that way." His team is planning to look at other amplification cascades, such as the complement cascade, to see whether they can be similarly harnessed.

In the work now published in Nature Materials, the scientists chose to activate the coagulation cascade with their messenger molecules because it had "a number of different desirable characteristics," including the fact that its signals stay localized during amplification: "If you have tremendous amplification that gets swept away in the bloodstream . . . that doesn't do you any good."

In the experiments, his team used two different signaling nanoparticles to activate the coagulation cascade. One was gold nanorods, which target tumor tissues and can activate the coagulation cascade when they are essentially heated using near-infrared light. The other signaling molecule was a protein, tumor-targeted tissue factor, which binds to receptors on tumor blood vessels. Both nanoparticles, through their activation of coagulation, increased the number of target binding sites for receivers by at least an order of magnitude.

The scientists also explored two different receivers. In some of their experiments, von Maltzahn and his colleagues used chemotherapy-loaded fat droplets – which could deliver up to 40 times more chemotherapy to tumor sites when they were targeted to coagulation sites via signaling particles than when they were targeted directly to the tumors. In others, they used so-called nanoworms, which are being developed as imaging nanoparticles.

The authors estimated that for each signaling molecule, their system was ultimately able to draw 150 nanoworms or more than 35,000 chemotherapy molecules to the tumor site; tumor-targeted tissue factor was not quite as spectacular, but still managed to draw 10 nanoworms. (Which does not imply that nanorod signaling will necessarily turn out to be the more useful method overall: von Maltzahn noted that one big advantage of the tissue factor is its ability to "autonomously" go after deep tumors. Nanorods need to be externally irradiated to activate clotting and thus, in practice, would be limited to superficial tumors.)

To prevent every bump and bruise from becoming an imaginary tumor to the nanoparticle system, the receivers bind to two components of the coagulation cascade. One is fibrin blankets, a structural component of blood clots – and other tissue sites, such as healing wounds. The other is Factor XIII, an enzyme of the coagulation cascade that is only active for a very brief time period when the coagulation cascade is activated.

Nevertheless, the amplification concept, by its nature, clearly has the potential to go spectacularly awry, meaning that amplification systems need to be very carefully targeted.

"The goal is to make it very precise – I think there's work that remains to be done there," von Maltzahn said.

But, he pointed out, usually erring on the side of caution in the form of more precise targeting means that a drug is ultimately less effective. Using an amplification cascade might allow that tradeoff to be avoided, or at least minimized, he said: "Our hope is that that by coupling precision and amplification, you could get the best of both worlds."

Von Maltzahn is currently inventor, entrepreneur, and new venture principal at Flagship VentureLabs, but was in the lab of senior author Sangeeta Bhatia at Massachusetts Institute of Technology when the work now published in Nature Materials was performed. He said that Flagship VentureLabs is not involved in funding or commercializing that work, which, for the time being, is being advanced academically.