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Recent advancements in polymer-coated nanoparticles, designed to deliver therapeutic agents directly to tumors, exhibit significant potential in the fight against cancer, particularly ovarian cancer. These innovative particles enable targeted drug release, thereby minimizing the adverse effects commonly associated with conventional chemotherapy.
Over the past ten years, a team led by MIT Institute Professor Paula Hammond has successfully developed a variety of these nanoparticles through a method called layer-by-layer assembly. Their research has demonstrated the effectiveness of these particles against cancerous cells in mouse models.
To further transition these nanoparticles from laboratory research to clinical application, the team has devised a new manufacturing process that enhances the production rate of these particles, significantly reducing the time required for their creation.
“The nanoparticle systems we have engineered show tremendous promise, especially with the encouraging results we’ve witnessed in animal studies targeting ovarian cancer,” states Hammond, who also serves as MIT’s vice provost for faculty and is affiliated with the Koch Institute for Integrative Cancer Research. “It’s crucial that we scale this production to a level suitable for commercial manufacturing.”
Hammond and Darrell Irvine, a prominent immunology and microbiology professor from the Scripps Research Institute, are the senior authors of the study published in Advanced Functional Materials. Leading the research are Ivan Pires, a PhD graduate now conducting postdoctoral work at Brigham and Women’s Hospital, and undergraduate Ezra Gordon, with contributions from MIT research technician Heikyung Suh.
A streamlined process
Hammond’s lab pioneered a novel method over a decade ago that focuses on constructing nanoparticles with precisely controlled architectures. This technique facilitates the application of alternating layers of positively and negatively charged polymers, enabling the embedding of drug molecules or therapeutic agents within each layer.
These nanoparticle layers can also incorporate targeting agents which help direct the particles specifically to cancer cells. Traditionally, each polymer layer application necessitated a centrifugation step to remove surplus polymer, a process that proved to be labor-intensive and challenging to scale for mass production, according to the researchers.
Recently, a graduate student in Hammond’s laboratory introduced tangential flow filtration as a method to refine particle purification. Although this innovation sped up the process, it was still limited in terms of manufacturing scale and complexity.
“Even though tangential flow filtration is beneficial, it is still a small-batch technique, and for clinical applications, a larger supply is essential to accommodate a significant patient population,” Hammond explains.
In seeking a scalable manufacturing solution, the team utilized a microfluidic mixing device that streamlines the addition of polymer layers as the nanoparticles traverse a microchannel. This allows for precise calculations of polymer quantities required at each stage, eliminating the need for subsequent purification.
“This is crucial since purification processes often present the highest costs and time demands in such systems,” notes Hammond.
This innovative approach reduces the potential for human error and simplifies production while adhering to good manufacturing practices (GMP), which are vital for ensuring safety and consistency in product manufacturing. The microfluidic technology employed in this research is already being used for the GMP manufacturing of various nanoparticles, including mRNA vaccines.
“With our new method, the potential for operator error is significantly reduced,” remarks Pires. “This process can be easily implemented within GMP frameworks, which is a pivotal step allowing us to move toward clinical trials swiftly.”
Scaled-up production
Utilizing this novel approach, the researchers can produce 15 milligrams of nanoparticles, sufficient for about 50 patient doses, in mere minutes—previously, the older method would require close to an hour for the same quantity. This increased efficiency could facilitate the creation of the numerous particles required for clinical trials and patient treatment.
“To scale this process, we can simply keep running the chip, making it significantly easier to increase production,” Pires explains.
To validate their upgraded production technique, the researchers formulated nanoparticles embedded with a cytokine known as interleukin-12 (IL-12). Prior studies from Hammond’s lab have indicated that IL-12 delivered through layer-by-layer nanoparticles can activate vital immune cells and inhibit tumor growth in mice.
The latest findings show that IL-12-loaded nanoparticles created via this new manufacturing technique exhibited comparable efficacy to earlier versions. These nanoparticles not only bind effectively to cancerous tissues but also uniquely refrain from entering the cancer cells, allowing them to act as markers that activate the immune response within the tumor environment. In mouse models of ovarian cancer, this approach has resulted in significant tumor growth suppression and in some cases, complete cures.
The research team has pursued a patent on this innovative technology and is collaborating with MIT’s Deshpande Center for Technological Innovation to explore the establishment of a company for commercialization efforts. Initially, their research targets cancers prevalent in the abdominal region, such as ovarian cancer, with potential applications for other malignancies, including glioblastoma.
This research effort has received funding from multiple sources, including the U.S. National Institutes of Health, the Marble Center for Nanomedicine, the Deshpande Center for Technological Innovation, and the Koch Institute Support Grant from the National Cancer Institute.
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