Using nanoaggregates against cancer starts with control. Here's how:

September 17, 2015 | by City of Hope

nanoaggregates To use nanoaggregates effectively against cancer starts with control. City of Hope researchers have taken an important step.

Nanoparticles’ unique size – much larger than drug molecules but much smaller than cells – explains the potential to use them to fight cancer.

Many researchers, including teams at City of Hope, are working toward loading nanoparticles with drug cargos and then using the nanoparticles to selectively deliver those cargos selectively into tumor cells. This would dramatically increase the efficacy of most therapies while sharply reducing side effects. In the ideal, the nanoparticles would function almost like little mail trucks driving their cargo right to the tumor.

There’s one big problem with this vision: The nanoparticles’ unique size is also the right size for filtration by the liver. Nearly all current nanoparticles show more uptake in the liver than in tumors. It is as if most of the mail trucks were stopped at customs and never allowed to go to their intended destination.

Now researchers at City of Hope report an important breakthrough in developing new nanoparticles to tackle this problem.

The paper detailing that work, “Controlled Assembly of Biocompatible Metallic Nanoaggregates Using a Small Molecule Crosslinker,” was first published online on July 24 in the prestigious journal Advanced Materials and was published in print Sept. 16. It was authored by Desiree Van Haute, Julia M. Longmate and Jacob M. Berlin, Ph.D., an assistant professor of molecular medicine at City of Hope.

The goal: Persist in the tumor, leave the liver

“The goal was to develop a nanoparticle system that can accumulate and persist in the tumor, and at the same time be easily expelled from the liver,” said study co-author Van Haute, a student in the Irell & Manella Graduate School of Biological Sciences in Beckman Research Institute of City of Hope. “We knew this would require a system that could change its properties based on where it goes.”

To build such a system, Van Haute, Longmate, a student in the Eugene and Ruth Roberts Summer Student Academy at City of Hope, and Berlin started with the idea of assembling tiny building blocks into larger nanoparticle aggregates. These particles would be the right size for tumor targeting (and liver filtration), but in the liver they would disassemble into the tiny building blocks and clear out of the body.

But they had to overcome one small problem – finding a way to make aggregates out of tiny building blocks in a controlled manner.

“You face a variety of challenges with nanoparticle aggregates, including that the building blocks you’re using are themselves inherently unstable and often uncontrollably reactive,” said Berlin.

Although the problem of uncontrolled growth in nanoaggregates has been previously addressed via the use of sophisticated materials such as DNA, these solutions bring their own sets of problems. DNA, for example, can set off an immune response within the body.

Controlled assembly through a controlled ratio

Instead, the City of Hope team sought a method for controlling the assembly using only small molecules. The team found that by controlling the ratio between the building blocks and a small molecule called a “crosslinker,” the size of the resulting aggregates could be controlled and tuned. Using a unique surface coating step, the aggregates could be rendered highly stable and biocompatible.

While researchers in Berlin’s lab are now primarily focused on testing these aggregates for tumor accumulation and liver clearance, future uses of the homogeneous, stable nanoaggregates go far beyond imaging and drug delivery, Van Haute and Berlin said.

“These nanoaggregates have very interesting photophysical properties – they absorb and scatter light in interesting ways,” Berlin said. “We are collaborating with Caltech and Northwestern for applications in a noncancer setting; the future of this work is very exciting.”

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Learn more about Beckman Research Institute of City of Hope.

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