This Small Business Innovation Research (SBIR) Phase I project is a feasibility assessment of using ultrathin magnetic iron oxide nanowires as positive contrast agent for magnetic resonance imaging (MRI). Each year, approximately 30 million MRI scans are performed for diagnostic or therapeutic purpose. Two types of contrast agents are routinely administrated to alter the image contrast: T1 positive contrast agents-gadolinium (Gd) complexes and T2 negative contrast agents-iron oxide nanoparticles. The brighter MR image of a T1 contrast agent is clinically preferred over the darker image of the T2 contrast agent. The current problems with the T1 Gd-based contrast agents is the health risk to patients with liver and kidney diseases, and babies, and are difficult to retain at target locations. Because iron oxide -based T2 contrast agents are generally accepted to be safe and can be reabsorbed through normal iron metabolic pathways, if they can be used as T1 contras agents, it could provide safety and imaging efficacy. The unique magnetic property of ultrathin nanowires offers great potential as positive contrast agent. The research objective is to evaluate the potential of these nanowires in clinical relevant conditions, leading to a safe and effective MRI contrast agent.
The broader impact/commercial potential of this project is significant. As the leading imaging modality, MRI generates contrast agent revenues of over $1.87 bn in the U.S. alone with growth rate of 12%. The MRI contrast agent market is driven by the increased demand on new applications, faster scan times and better quality, aging population, and increased cancer incident. The potential commercialization of such a MRI contrast agent offer a solution to patients with live and kidney diseases. The targeting capability of the nanoparticles will significantly improve the imaging efficiency at a much lower dose. This contrast agent will ultimately improve disease detection, therapeutic monitoring and treatment efficacy, potentially leading to the advancement of human health.
Each year, approximately 30 million MRI scans are performed for diagnostic or therapeutic purposes. During a MRI scan, contrast agents are routinely administrated to improve the image contrast. Two types of contrast agents are clinically used: T1 positive contrast agents (e.g., gadolinium (Gd) complexes) and T2 negative contrast agents (e.g., iron oxide nanoparticles). MR images of a tumor inside a brain clearly demonstrate the differences (Figure 1). Without contrast agents, the image is blurry and the tumor site is hard to differentiate (Figure 1a); the whole image with T1 contrast agents is much brighter and with clear difference between the tumor and surrounding tissues (Figure 1b, red circle); the whole darker image with T2 contrast agents also shows the variation between the tumor and the nearby tissues, but the identified tumor region is erroneously bigger, indicating the low diagnostic accuracy of T2 contrast agents (Figure 1c, red circle). The clinically available contrast agents are primarily Gd-complexes, which are positive contrast agents generating brighter MR images. The current challenges with the Gd-based contrast agents are the potential health risks to patients. It was shown that the use of Gd-based contrast agents poses health risks to patients with renal and kidney diseases. In the United States, the incidence of Nephrogenic systemic fibrosis (NSF) was estimated to be 0.4% in 200 million administrations patients, which is approximately 800,000 affected Americans per year. In 2009, the World Health Organization issued a restriction on the application of 5 out of 7 Gd-based contrast agents utilized in the United States due to adverse effects when administered to those with severe kidney problems, who have received a liver transplants, and newborn babies up to 4 weeks of age. Thus, an alternative to Gd-based contrast agents is needed to overcome undesired side effects. The objective of our SBIR Phase I project was to demonstrate a highly innovative concept of using ultrathin (diameter, d < 4 nm) magnetic iron oxide nanowires as positive (T1) contrast agents for magnetic resonance imaging (MRI). We have successfully completed the proposed studies and demonstrated the feasibility of the two proposed tasks: (1) we have demonstrated the feasibility of using ultrathin nanowires as positive MRI contrast agents on both phantom cellular MR imaging in vitro and on mice in vivo (Figure 2). (2) We have successfully synthesized ultrathin iron oxide nanowires using our scaled-up reactors. Figure 2a-c shows the T1-weighted MR images of cell pallets on a 3T research MRI scanner. Cellular samples were prepared by incubating nanoparticles with human monocyte immune cells for 4 hours, and subsequently, the nanoparticle-treated cells were collected. Compared to the image of the control cell pallet, the T1-weighted MR image of the cells treated with nanowires is much brighter, suggesting the positive contrast enhancement of iron oxide nanonwires. In contrast, the cells treated with 12 nm spherical iron oxide nanoparticles showed a darker image, consistent with the known negative contrast of 12 nm spherical iron oxide nanoparticles. The T1-weighted MR images of mouse abdomen collected on a 3T animal MRI scanner 30 min after intraperitoneal (IP) injection of the nanoparticles were compared with the image of the pre injection control. The image with our nanowire injection showed evident brightening with clear boundaries. In contrast, the image with the injection of 12 nm spherical nanoparticles did not show much positive enhancement; instead, the image became darker. In conclusion, our preliminary tests on both cellular samples in vitro and on mice in vivo showed positive results and demonstrated the feasibility of the proposed nanowires to act as a T1 MRI contrast agent and have the potential to replace Gd based agents Another objective of our Phase I project was to scale up the production of ultrathin iron oxide nanowires. The synthesis of ultrathin nanowires was initially developed on laboratory scale using 250 mL flask. During our study, we have successfully scaled up the reaction to 10 L reactors. With the scale-up reactions, we can produce 30 grams of iron oxide nanowires. The nanowires generated from one batch can potentially be used for 100 MRI scans. Most importantly, the product from the scale-up reaction has similar quality to that from the laboratory scale, in terms of size, shape, and crystallinity.
