Engineers develop methods to mass-produce nanoparticles that will directly supply cancer drugs to tumors

Nanoparticles coated with therapeutic agents show great promise in cancer treatments, including ovarian cancer. These particles can directly target tumors, where they release the payload while avoiding many of the side effects of traditional chemotherapy.

Over the past decade, Professor Paula Hammond of the MIT Institute and her students have used a technique known as layer-by-layer assembly to create a variety of particles of these particles. They showed that particles can effectively combat cancer in mouse studies.

To help bring these nanoparticles closer to human use, researchers have now come up with manufacturing techniques that can produce large quantities of particles in just a fraction of the time.

“There is a lot of promise in the nanoparticle systems we’ve been developing, and we’ve been excited lately about the success we’ve seen in animal models, especially for the treatment of ovarian cancer,” says Hammond, a professor at MIT and a member of the Koch Institute for Integrated Cancer Research. “In the end, we need to be able to bring this to a scale where companies can produce these at a large level.”

Hammond and Darrell Irvine, professors of immunology and microbiology at the Scripps Research Institute, are senior authors of new research published in Advanced Functional Materials. Ivan Pires, Ph.D. ’24, currently a postdoctoral at Brigham and Women’s Hospital, visiting scientist at Koch Institute, and Ezra Gordon ’24 is the paper’s lead author. Heikyung Suh, a research technician at MIT, is also the author.

A streamlined process

More than a decade ago, Hammond’s lab developed new technologies for building nanoparticles with highly controlled architectures. This approach allows layers with different properties to be laid on the surface of nanoparticles by alternating surface exposure to positive and negative polymers.

Each layer can be implanted with drug molecules or other therapeutic agents. The layer can also carry targeting molecules that help particles find and enter cancer cells.

Using the strategy originally developed by Hammond’s lab, one layer is applied at a time, and after each application, the particles undergo a centrifugation step to remove excess polymer. This is a time of day and it is difficult to expand to large-scale production, the researchers say.

More recently, graduate students in Hammond’s lab have developed an alternative approach to purifying particles known as tangential flow filtration. However, this streamlined the process, but was still limited by manufacturing complexity and maximum production scale.

“The use of tangential flow filtration is useful, but it is still a very small batch process, and clinical research requires that more doses be available to a considerable number of patients,” says Hammond.

To create a large-scale manufacturing method, researchers used microfluidic mixing devices to allow particles to sequentially add new polymer layers as they flow through microchannels within the device. For each layer, researchers can accurately calculate the amount of polymer needed. This eliminates the need to purify the particles after each addition.

“It’s really important because separation is the most expensive and time-consuming step in these types of systems,” says Hammond.

This strategy eliminates the need for manual polymer mixing, streamlines production and integrates the process of integrating into superior manufacturing (GMP). FDA GMP requirements ensure that products meet safety standards and can be manufactured in a consistent manner. The microfluidic devices used by the researchers in this study are already used for the GMP production of other types of nanoparticles, including mRNA vaccines.

“With a new approach, there is much less chance of mistakes and misfortunes for all kinds of operators,” Piers said. “This is a process that can be easily implemented with GMP, and it’s a really important step here. Innovations can be created within layered nanoparticles and generated quickly in a way that allows them to participate in clinical trials.”

Scaled Production

Using this approach, researchers can produce 15 milligrams of nanoparticles (approximately 50 doses are sufficient) in just a few minutes, but the original technique takes nearly an hour to create the same amount. This could potentially produce enough particles for clinical trials and patient use, researchers say.

“It’s much easier to produce more material just by continuing to run the chips to scale up with this system,” Pires says.

To demonstrate new production techniques, researchers created nanoparticles coated with a cytokine called interleukin-12 (IL-12). Hammond’s lab has previously shown that IL-12 delivered by layer-by-layer nanoparticles activates major immune cells and slows the growth of ovarian tumors in mice.

In this study, the researchers found that IL-12 loaded particles manufactured using new techniques exhibited similar performance to the original layer-by-layer nanoparticles. And these nanoparticles not only bind to cancer tissues, but also show their unique ability to not enter cancer cells. This allows nanoparticles to function as markers for cancer cells that activate the immune system locally of the tumor. In mouse models of ovarian cancer, this treatment can lead to both tumor growth retardation and treatment.

Researchers have filed a patent for the technology and are currently hoping to form a company to commercialize the technology, in collaboration with MIT’s Deshpande Center for Technology Innovation. They initially focus on abdominal cancers, such as ovarian cancer, but researchers can also apply to other types of cancer, including glioblastoma, the researchers say.

This story has been republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and education.