Nanoparticles coated with polymers and infused with therapeutic agents exhibit considerable potential for cancer therapy, particularly in the case of ovarian cancer. These nanoparticles can be precisely directed to tumors, facilitating the release of their therapeutic load while minimizing numerous adverse effects commonly associated with conventional chemotherapy.
In recent years, MIT Institute Professor Paula Hammond, alongside her students, has fabricated a diverse array of these nanoparticles utilizing a method termed layer-by-layer assembly. Their findings demonstrate that these nanoparticles can successfully fight cancer in animal studies.
To assist in advancing these nanoparticles towards human application, the researchers have developed a manufacturing technique that enables them to produce larger volumes of nanoparticles in a significantly reduced time frame.
“The nanoparticle systems we are developing hold tremendous promise, and we have become increasingly encouraged by the successes observed in animal models, particularly for our ovarian cancer treatments,” states Hammond, who also serves as MIT’s vice provost for faculty and is affiliated with the Koch Institute for Integrative Cancer Research. “Ultimately, it is essential that we can scale this up so that a company can produce these in substantial quantities.”
Hammond and Darrell Irvine, a professor of immunology and microbiology at the Scripps Research Institute, are the senior authors of the recent study, which is published today in Advanced Functional Materials. Ivan Pires PhD ’24, currently a postdoctoral researcher at Brigham and Women’s Hospital and a visiting scientist at the Koch Institute, along with Ezra Gordon ’24, are the principal authors of the paper. Heikyung Suh, a research technician at MIT, is also listed as an author.
A streamlined process
Over a decade ago, Hammond’s laboratory pioneered an innovative methodology for constructing nanoparticles with meticulously regulated architectures. This technique permits layers with differing characteristics to be deposited on a nanoparticle’s surface by successively exposing it to positively and negatively charged polymers.
Each layer can be infused with drug molecules or other therapeutic agents. Additionally, these layers can incorporate targeting molecules that assist the nanoparticles in locating and penetrating cancer cells.
In accordance with the strategy pioneered by Hammond’s laboratory, one layer is applied at a time, and post-application, the nanoparticles undergo a centrifugation process to eliminate any surplus polymer. Researchers note that this procedure is labor-intensive and would pose challenges for large-scale production.
More recently, a graduate student in Hammond’s lab devised a different method for purifying the nanoparticles, identified as tangential flow filtration. However, although this method simplified the process, it remained restricted by its manufacturing intricacies and the maximum production scale.
“While utilizing tangential flow filtration is advantageous, it still functions as a very limited batch process, and a clinical trial necessitates that we have many doses prepared for a substantial number of patients,” Hammond explains.
To establish a larger-scale production technique, the researchers employed a microfluidic mixing apparatus that permits the gradual addition of new polymer layers as the nanoparticles travel through a microchannel in the device. For each layer, researchers can determine the precise amount of polymer required, eliminating the necessity for purification after each application.
“This is crucial since separations are the most expensive and time-consuming aspects of these kinds of processes,” Hammond emphasizes.
This approach removes the need for manual mixing of polymers, optimizes production, and incorporates good manufacturing practice (GMP)-compliant procedures. The FDA’s GMP guidelines ensure products adhere to safety regulations and can be manufactured consistently, a challenging and costly endeavor using the prior step-wise batch method. The microfluidic device used in this study is already being utilized for GMP production of other nanoparticle types, including mRNA vaccines.
“With this new method, there is significantly less risk of any operator error or mishaps,” Pires remarks. “This is a process that can be seamlessly implemented in GMP, and that’s the essential step forward. We can innovate within the layer-by-layer nanoparticles and quickly produce them in a manner suitable for clinical trials.”
Scaled-up production
By employing this method, the researchers can produce 15 milligrams of nanoparticles (sufficient for approximately 50 doses) in only a few minutes, whereas the original technique would require nearly an hour for the same quantity. This advancement could facilitate the production of more than adequate particles for clinical trials and patient applications, according to the researchers.
To illustrate their new production method, the researchers formulated nanoparticles coated with a cytokine known as interleukin-12 (IL-12). Hammond’s lab has previously demonstrated that IL-12 delivered via layer-by-layer nanoparticles can activate crucial immune cells and impede ovarian tumor growth in mice.
In this investigation, the researchers found that particles loaded with IL-12 produced using the new technique exhibited comparable performance to the original layer-by-layer nanoparticles. Furthermore, these nanoparticles not only adhere to cancer tissue but also exhibit a distinctive capability to evade entry into cancer cells, allowing them to function as markers on the cancer cells that stimulate the immune system locally within the tumor. This treatment has shown potential for both delaying tumor growth and even achieving cures in mouse models of ovarian cancer.
The researchers have filed for a patent regarding the technology and are currently collaborating with MIT’s Deshpande Center for Technological Innovation with the aim of potentially establishing a company to commercialize the technology. While their initial focus is on cancers affecting the abdominal cavity, such as ovarian cancer, they believe the methodology could also be adapted for other cancer types, including glioblastoma.
The research received funding from the U.S. National Institutes of Health, the Marble Center for Nanomedicine, the Deshpande Center for Technological Innovation, and the Koch Institute Support (core) Grant from the National Cancer Institute.