Superparamagnetic contrast agents for magnetic resonance imaging.

SUPERPARAMAGNETIC CONTRAST AGENTS FOR MAGNETIC RESONANCE IMAGING Tueng Shen Submitted to the Harvard University-Massachusetts Institute of Technology Division of Health Sciences and Technology on April 29, 1994 in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Medical Engineering/Medical Physics Abstract Magnetic resonance imaging (MRI) is a non-invasive, sensitive diagnostic tool with high spatial resolution that provides detailed anatomic information. However, the diagnostic accuracy can be limited by the lack of inherent difference between normal and pathologic tissues. Under these circumstances, it is necessary to administer MR contrast agents which selectively alter the tissue characteristics by changing the magnetic environment of the region of interest. Currently, the only MR contrast agent approved for clinical use is gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA), a paramagnetic agent which non-specifically enhances the longitudinal relaxation rate of protons in tissues. However, Gd-DTPA requires high tissue concentrations to be detectable by MR, making it less suitable for target-specific MRI. Superparamagnetic iron oxides have much higher magnetic moments, and therefore require a lower dose for similar contrast enhancement. A prototype of a superparamagnetic monocrystalline iron oxide nanocompound (MION) has been synthesized and characterized as a universal magnetic label for target-specific MR imaging. The physicochemical properties of MION were characterized using high resolution transmission electron microscopy (HRTEM), X-ray diffraction, column chromatography, spectrophotometry, Mdssbauer spectroscopy, and relaxometry. MION fulfills the criteria for a targetable agent with its small size (size of central iron oxide containing core 4.6 + 1.2 nm) allowing passage through the capillary endothelium while still retaining superparamagnetic behavior. Further studies of pharmacological properties and in vivo MR imaging in animal models demonstrated that MION can be delivered to a variety of targets, including human receptor systems, antigenic sites, and intracellular structures. This approach opens new avenues to in vivo MR imaging in both medicine and research.Magnetic resonance imaging (MRI) is a non-invasive, sensitive diagnostic tool with high spatial resolution that provides detailed anatomic information. However, the diagnostic accuracy can be limited by the lack of inherent difference between normal and pathologic tissues. Under these circumstances, it is necessary to administer MR contrast agents which selectively alter the tissue characteristics by changing the magnetic environment of the region of interest. Currently, the only MR contrast agent approved for clinical use is gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA), a paramagnetic agent which non-specifically enhances the longitudinal relaxation rate of protons in tissues. However, Gd-DTPA requires high tissue concentrations to be detectable by MR, making it less suitable for target-specific MRI. Superparamagnetic iron oxides have much higher magnetic moments, and therefore require a lower dose for similar contrast enhancement. A prototype of a superparamagnetic monocrystalline iron oxide nanocompound (MION) has been synthesized and characterized as a universal magnetic label for target-specific MR imaging. The physicochemical properties of MION were characterized using high resolution transmission electron microscopy (HRTEM), X-ray diffraction, column chromatography, spectrophotometry, Mdssbauer spectroscopy, and relaxometry. MION fulfills the criteria for a targetable agent with its small size (size of central iron oxide containing core 4.6 + 1.2 nm) allowing passage through the capillary endothelium while still retaining superparamagnetic behavior. Further studies of pharmacological properties and in vivo MR imaging in animal models demonstrated that MION can be delivered to a variety of targets, including human receptor systems, antigenic sites, and intracellular structures. This approach opens new avenues to in vivo MR imaging in both medicine and research. Thesis Advisors: Thomas J. Brady, M.D. Ralph Weissleder, M.D., Ph.D. Thesis Committee: William H. Orme-Johnson, Ph.D. Robert S. Langer, Sc.D.