May 2 2018
For 15 years, materials chemist Dale Huber from the Sandia National Laboratories has been involved in the challenge of creating iron-based nanoparticles measuring the exact same size.
Sandia National Laboratories materials chemist Dale Huber has worked to make nanoparticles the exact same size for 15 years. His long-term collaborators at Imagion Biosystems will use these magnetic nanoparticles for their first breast cancer clinical trial later this year. He is holding a microfluidic chip that can make tiny amounts of nanoparticles. The round-bottom flask beside him can be used for making much larger quantities of nanoparticles. (Photo by Randy Montoya)
Currently, he and his long-term collaborators at Imagion Biosystems will be using these magnetic nanoparticles for their first breast cancer clinical trial later in the year. The nanoparticles stick to breast cancer cells, enabling the detection and removal of even small metastases.
Imagion Biosystems and Huber have been collaborating to synthesize nanoparticles since the inauguration of the Center for Integrated Nanotechnologies in 2006.
Having access to the talent pool at CINT with experts like Dale Huber has been helpful. Additionally, the fact that CINT has a user program that allows industry to access the facilities and equipment that, otherwise, would be too expensive for a small company like ours was valuable. The initial work we did with CINT to develop a method to give precise control over the size of the nanoparticle was key for our MagSense magnetic relaxometry technology for the detection of cancer.
Bob Proulx, CEO, Imagion Biosystems
CINT is a user facility cooperatively operated by Sandia and Los Alamos National Laboratory for the U.S. Department of Energy’s Office of Science. CINT offers free access to high-tech equipment and world-renowned scientists for nanoscience researchers in academia and industry, provided they publish the findings in scientific journals.
The magnetic nanoparticles are coated with cancer antibodies, which stick particularly to cancerous cells. A small magnetic pulse—almost the strength of a refrigerator magnet and hundreds of times weaker than one generated by an MRI machine—can sense the difference between nanoparticles clinging to cancer cells and those that are floating at will, enabling the detection of tiny metastases.
Precision synthesis of magnetic nanoparticles
Nonetheless, for Imagion Biosystems’ cancer detection technique to work, each nanoparticle has to be virtually exactly the same size.
“A 2 percent variation is the difference between perfect and just about useless,” said Huber. He added laughing, “It was eye opening for me and if had I known that in the beginning, I might not have taken on the challenge.”
Erika Vreeland, who worked with Huber during her doctoral thesis to advance reproducible synthesis and was hired by Imagion Biosystems to be their chief nanoparticle scientist following her graduation said, “We eliminated all of the witchcraft of the reaction.”
The standard technique to create iron nanoparticles is to mix the ingredients and heat the mixture to about 650 °F. How rapidly the heat increases decides the size of the nanoparticle, said Huber. However, just like the oven at home, it will exceed the critical temperature and then cool down until it levels off. How much the temperature exceeds this critical temperature also influences the size, creating nanoparticles over 15% smaller or larger.
Instead, Vreeland and Huber developed a technique where they gradually add the ingredients to a molten metal bath whose temperature differs less than half a degree. This creates nanoparticles with less than 2% size variation. Huber said, “It’s not the easiest way to make particles, but that’s why they’re so much better.”
Not only did the team formulate an extremely reproducible technique to make the minuscule particles, they also moved the process twice—once to Imagion and once to ChemConnection, a nanoparticle manufacturer in the Netherlands that can make the nanoparticles under the stringent U.S. Food and Drug Administration and European Union regulations necessary for use in patient clinical trials.
The synthesis was transferred to the lab in the Netherlands while maintaining size control. This is huge. Everything changes, even the boiling points, because the Netherlands is basically at sea level.
Dale Huber, Materials Chemist, Sandia National Laboratories
Clinical trial to detect spread of breast cancer this fall
After ChemConnection makes a number of batches, Imagion Biosystems will perform some preclinical trials to verify the particles aren’t toxic. Then ChemConnection will create a small batch of nanoparticles—comparable to a half teaspoon of sugar—for Imagion Biosystems’ breast cancer clinical trials.
“Because the nanoparticles are uniform and have excellent magnetic properties, we don’t need a lot. We expect that a patient will be injected with at most 1 milligram of particles,” said Vreeland.
The patients for the first clinical trial will be chosen pertaining to their oncologists’ treatment procedure, which includes lymph node removal and biopsy. Before each patient has numerous lymph nodes taken out surgically, the magnetic nanoparticles, coated in the breast cancer-specific antibodies, will be injected at the site of the identified tumors. After the removal but prior to the biopsy, Imagion Biosystems’ detection system will analyze removed lymph nodes to check for the spread of cancer.
Vreeland said she hopes Imagion Biosystems’ technique will be as exact as a pathologist, with the ultimate goal of using this technique first to look for cancer and eradicate the need to remove cancer-free lymph nodes.
Our No. 1 aspiration is to see the nanoparticles make it into regular clinical use with our MagSense cancer detection technology. Beyond that we believe the nanoparticles can be instrumental in a wide variety of biomedical applications including uses in treatment of cancer or other diseases.
Bob Proulx, CEO, Imagion Biosystems
Continuing collaboration to characterize nanoparticles and solve problems
CINT and Imagion Biosystems continued the partnership beyond the effort to create identically-sized magnetic nanoparticles. Vreeland said, “We still run into all sorts of issues all the time so being able to talk with Dale or other scientists about some of the challenges we’re facing is really invaluable.”
Sandia bioengineer George Bachand helped with the initial toxicology and cell-targeting studies. Sandia researcher John Reno assisted in characterizing the shape and size of the nanoparticles, using small angle X-ray scattering.
Small-angle X-ray scattering is a technique to establish the size and size distribution of nanoscale materials. “With CINT’s X-ray scattering instrument we can figure out exactly how big the particles are in 15 minutes. Seven or eight years ago it would take a week to figure out the same thing using electron microscopy,” said Huber.
This nearly real-time size measurement allowed Vreeland to predict how the reaction would end and corroborate that they were on the correct path, she said. The team used other CINT instruments to characterize the coatings and magnetic strength of the nanoparticles.
Besides accessing the CINT experts and equipment via its user program, the collaboration with Imagion Biosystems was supported by a number of New Mexico Small Business Assistance Program grants, which can aid proprietary research.
Several papers have been published by the team from the collaboration including one in Chemistry of Materials in 2015.