Polymer-coated nanoparticles loaded with therapeutic drugs hold significant potential for treating cancers, including ovarian cancer. These particles can be precisely directed to tumors, delivering their drug payload directly while minimizing the side effects commonly associated with traditional chemotherapy. Over the past decade, researchers at the Massachusetts Institute of Technology (MIT, Cambridge, MA, USA) have developed various versions of these particles using a method known as layer-by-layer assembly, and have demonstrated their effectiveness in fighting cancer in mouse models. To bring these nanoparticles closer to clinical application in humans, the researchers have now devised a manufacturing technique that allows for the rapid production of larger quantities of these particles.

The researchers had earlier developed a novel method for creating nanoparticles with highly controlled structures, where they layer different properties onto the nanoparticle’s surface by alternately applying positively and negatively charged polymers. These layers can contain therapeutic molecules or drugs, and can also include targeting molecules to help the particles specifically reach and enter cancer cells. In the original method, each layer is added individually, and after every application, the nanoparticles are centrifuged to remove excess polymer. While effective, this step-wise process is time-consuming and not feasible for large-scale production. In response to this challenge, the team introduced tangential flow filtration, a more efficient approach to particle purification, though it still had limits in terms of manufacturing complexity and scalability.

To further enhance the manufacturing process, the researchers turned to a microfluidic mixing device. This device allows for sequential polymer layer additions as the particles flow through a microchannel, enabling precise control over the amount of polymer added at each stage. This technique eliminates the need for post-layer purification, manual polymer mixing, and enhances overall production efficiency. It also integrates processes that comply with good manufacturing practice (GMP) standards, which are necessary to ensure the safety and consistency of products, a requirement that was difficult to meet using the previous batch process. The microfluidic device used in this research is already employed for GMP manufacturing of other nanoparticle types, including mRNA vaccines.

According to findings published in Advanced Functional Materials, this new manufacturing method allows the team to produce 15 milligrams of nanoparticles—enough for approximately 50 doses—in just a few minutes, compared to nearly an hour using the original method. This advancement could facilitate the production of sufficient quantities of nanoparticles for clinical trials and eventual patient treatments. To validate their new production method, the researchers created nanoparticles coated with interleukin-12 (IL-12), a cytokine known to activate immune cells. Previous studies by the team have demonstrated that IL-12 delivered by layer-by-layer nanoparticles can activate immune responses and slow ovarian tumor growth in mice.

The new study showed that IL-12-loaded nanoparticles manufactured using the improved technique were as effective as the original layer-by-layer nanoparticles. These nanoparticles were able to bind to cancer tissue without entering the cancer cells themselves, thus serving as markers for immune system activation directly at the tumor site. In mouse models of ovarian cancer, this treatment led to tumor growth delays and, in some cases, complete cures. The team has filed for a patent for the new technology and is actively working on its commercialization. While their current focus is on cancers of the abdominal cavity, such as ovarian cancer, the researchers believe this approach could also be applied to other cancer types, including glioblastoma.

“With the new approach, there’s much less chance of any sort of operator mistake or mishaps,” said researcher Ivan Pires PhD ’24. “This is a process that can be readily implemented in GMP, and that’s really the key step here. We can create an innovation within the layer-by-layer nanoparticles and quickly produce it in a manner that we could go into clinical trials with. “To scale up with this system, you just keep running the chip, and it is much easier to produce more of your material.” 

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