MRI Contrast Agent
Magnetic Resonance Imaging (MRI), is a medical imaging technique commonly used in radiology to visualize the internal structure and function of every part of the body, and is particularly useful for neurological conditions, for disorders of the muscles and joints, for evaluating tumors, and for showing abnormalities in the heart and blood vessels. MRI provides greater contrast between the different soft tissues of the body than computer tomography (CT) making it very useful in neurological (brain), muskuloskeletal, cardiovascular, and oncological (cancer) imaging. It uses a powerful magnetic field to align the nuclear magnetization of hydrogen atoms in water in the body without the use of ionizing radiation. The alignment of this magnetization is usually altered with radio frequency (RF) fields causing the hydrogen nuclei to produce a rotating magnetic field signal that is detected by the scanner. This signal can be enhanced by additional magnetic fields to build up enough information to construct an image of the body or the tissue. Diseased tissue, such as tumors, can be detected because the protons in different tissues return to their equilibrium state at different rates. Changing the parameters on the scanner creates a contrast between different types of body tissues.
To enhance the appearance of tissues such as blood vessels, tumors, muscles, bones, neurons, etc., contrast agents may be injected intravenously. In certain cases such as problems of the joints, the contrast agents may be directly injected into tissue to generate MR images of joints. MRI is used to image every part of the body, and is particularly useful for neurological conditions, for disorders of the muscles and joints, for evaluating tumors, and for showing abnormalities in the heart and blood vessels.
While most conventional MRI contrast agents have difficulty in providing sufficient signal amplification and versatile functionalization that is essential for target-specific molecular imaging probes, magnetic nanocrystals hold great potential to fulfill these needs. Furthermore, these are well suited as contrast agents for in vivo MRI because of their unique superparamagnetic properties, which generate a significant susceptibility effect that results in strong T2 and T*2 contrasts, as well as a T1 effect at very low concentrations. In addition to these unique properties and advantages of nanocrystals, iron oxide nanocrystals usually have a long blood retention time, are generally biodegradable, and are considered to be tolerable at low concentrations.
Ocean’s superparamagnetic IO nanocrystals are suitable MRI contrast agents. These exhibit high efficient response to magnetic fields and have functional groups on the outer surface that can be linked to different types of molecules designed for target specific imaging. Ocean’s superparamagnetic IO nanocrystals offer the opportunity to design “smart” nanocrystals that can be used as target-specific contrast agents and multi-modality imaging probes. They also offer the possibility of multi-functionalization using multiple reagents for simultaneous imaging of different tissues for diagnostic applications. Extensive research has shown that nanocrystals in the size range of 5-100 nm are taken up and accumulate preferentially in various cell lines, including cancer and tumor cells, to allow magnetic labeling of the targeted cells because of enhanced permeability and retention effect associated with cancer or tumor growth. When internalized by cells, iron oxide nanocrystals are able to generate imaging contrasts that enable the detection of a single-cell by MRI. The uptake and accumulation of Ocean’s superparamagnetic IO nanocrystals are most promising for improving the sensitivity of molecular imaging and quantitative cellular analysis by 1-2 orders of magnitude.
In comparison with dextran-coated IO nanocrystals which consist of a 5-10 nm sized core and more than 20 nm dextran shell, Ocean NanoTech’s iron oxide nanocrystals that are 5-30 nm in diameter with a monolayer polymer coating show similar hydrodynamic size with dextran-coated IO nanocrystals. However, the inorganic core size is much larger than the core of dextran-coated nanocyrstals, increasing the magnetic contrast.
Ocean NanoTech is actively developing a new generation of iron oxide nanocrystals for target-specific MR imaging probes. Our recent development indicates that the effective converse relaxation rate of our 30 nm IO nanocrystals is 2.5 times higher than 10 nm nanocrystals. The in vivo studies also demonstrated that nanocrystals conjugated to affinity ligands can specifically target tumor sites (Figure 1). Detailed information can be found in our recent publication in Small, Gastroenterology and J. Phys.Chem. C.
Additional objectives that Ocean NanoTech is targeting to improve the application of superparamagnetic IO nanocrystals as MRI contrast agent include 1) a strong signal to increase the sensitivity of detection while exhibiting low toxicity to healthy organs and tissues; 2) identification of a target molecule that is unique to an over expressed receptor that will receive sufficient amount of the imaging probe; and 3) reduction of the reticuloendothelial system (RES) uptake to increase the detection sensitivity. Ocean NanoTech is actively working with collaborators to achieve the above objectives to move the application of superparamagnetic IO nanocrystals as MRI contrast agent from the research stage to clinical applications.
Examination of target specificity of ScFvEGFR-IO nanocrystals by MRI using an orthotopic human pancreatic xenograft model.
A) MRI of a tumor-bearing mouse. ScFvEGFR-IO nanocrystals (8 nmol kg_1 body weight) were injected into the mouse through the tail vein. Pre- and post-contrast MRI at 5 and 30 h were collected. Upper and lower panels showed the MRI from different sectional levels of the same mouse. The areas of the pancreatic tumor were marked as a dash-lined circle (pink). The pancreatic tumor area showed a bright signal before receiving the nanocrystals. After injection of the targeted IO nanocrystals, a marked MRI contrast decrease was detected in the tumor (darker), which delineated the area of the tumor lesion. MRI contrast change is also found in the liver (green arrow) and spleen. These MRIs are representative results of five mice that received ScFvEGFR-IO nanocrystals. Lower right is the picture of tumor and spleen tissues, showing sizes and locations of two intra-pancreatic tumor lesions (arrows) that correspond with the tumor images of MRI. B) MRI of a mouse that received non-targeted IO nanocrystals. The tumor area (pink dash-lined circle) did not show MRI signal decrease at 5 and 30 h after the injection of nanocrystals. The areas representing the liver and spleen had marked signal decrease due to the T2 contrast. Shown are representative MRIs of three mice that received control IO nanocrystals.