Conquering the Dark Side: Colloidal Iron Oxide Nanoparticles

Abstract

Nanomedicine approaches to atherosclerotic disease will have significant impact on the practice and outcomes of cardiovascular medicine. Iron oxide nanoparticles have been extensively used for nontargeted and targeted imaging applications based upon highly sensitive T2* imaging properties, which typically result in negative contrast effects that can only be imaged 24 or more hours after systemic administration due to persistent blood pool interference. Although recent advances involving MR pulse sequences have converted these dark contrast voxels into bright ones, the marked delays in imaging from persistent magnetic background interference and prominent dipole blooming effects of the magnetic susceptibility remain barriers to overcome. We report a T1-weighted (T1w) theranostic colloidal iron oxide nanoparticle platform, CION, which is achieved by entrapping oleatecoated magnetite particles within a cross-linked phospholipid nanoemulsion. Contrary to expectations, this formulation decreased T2 effects thus allowing positive T1w contrast detection down to low nanomolar concentrations. CION, a vascular constrained nanoplatform administered in vivo permitted T1w molecular imaging 1 hour after treatment without blood pool interference, although some T2 shortening effects on blood, induced by the superparamagnetic particles persisted. Moreover, CION was shown to encapsulate antiangiogenic drugs, like fumagillin, and retained them under prolonged dissolution, suggesting significant theranostic functionality. Overall, CION is a platform technology, developed with generally recognized as safe components, that overcomes the temporal and spatial imaging challenges associated with current iron oxide nanoparticle T2 imaging agents, and which has theranostic potential in vascular diseases for detecting unstable ruptured plaque or treating atherosclerotic angiogenesis.Keywords iron oxide; molecular imaging; drug delivery; angiogenesis; ruptured plaque; MRI Iron oxide crystals have long been used as superparamagnetic T2* contrast agents for magnetic resonance imaging (MRI). [1][2][3][4] Superparamagnetic iron oxide (SPIO, particle diameter > 50nm) Corresponding Author Address: Gregory M. Lanza, M.D. Ph.D., Professor of Medicine and Bioengineering, Division of Cardiology, Washington University Medical School, 4320 Forest Park Avenue, Cortex Building, Suite 101, Saint Louis, MO 63108, greg.lanza@mac.com. † ASP and SDC contributed equally to this research project Brief Statement: Oleate-coated magnetite (20-30nm) particles suspended in oil and encapsulated with a partially cross-linked phospholipid surfactant transforms a typical T2* MR contrast agent into a T1w platform capable of rapid, targeted "positive" contrast imaging without magnetic bloom artifacts as well as targeted drug delivery. and ultrasmall superparamagnetic oxide (USPIO, particle diameter < 50nm) particles have nonstoichiometric microcrystalline magnetite core(s) and are typically coated with dextran (e.g., ferumoxide) or siloxane (e.g., ferumoxsil). 5 At...

Superparamagnetic Iron Oxide Nanoparticles in Biomedicine: Applications and Developments in Diagnostics and Therapy

“…Hohenberg (HPI Hamburg)), e, f commercially available monodisperse polymers SPIO from Ocean NanoTech (www.oceannanotech.com), e SHP-15 (15 ± 1.5 nm, scale 50 nm) and f SHP-40 (40 ± 4 nm). Table 1 Superparamagnetic iron oxide particles in clinical application and clinical and preclinical evaluation (modified according to [43] and [28] form for simultaneous imaging and treatment (theranostics) is proposed [46]. An overview of the SPIO currently used in clinical application and testing is provided in • " Table 1.…”

Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents

“…17,25,27 The resulting nanoparticles have greater paramagnetic metal surface payloads that rotate or tumble more slowly than small-molecule organometallic compounds typically used as blood-pool agents. 28 …”

“…Once they are coated with a layer of polycrystalline Fe 3 O 4 or a graphitic shell, these metallic nanoparticles are more stable and provide better contrast in MRI. FePt nanoparticles are chemically more stable than Fe and FeCo nanoparticles, and have been shown to have great potential as contrast agents for MRI and CT. 28 However, it is worth pointing out that such systems could be used for preclinical experiments, but clinical assessment of their acute and long-term toxicity is required.…”

“…However, a new generation of USPIONs, with diameters less than 10 nm, has also been reported to have excellent T 1 -enhancing properties. 28,66 Compared with paramagnetic ions, SPIONs have higher molar relaxivities, and, when used as blood-pool and tissue-specific agents, may offer advantages at low concentrations. 67 As indicated above, SPIONs generate dark or negative contrast at the target site with a marked blooming effect from magnetite susceptibility artifacts.…”

Functionalized nanomaterials: their use as contrast agents in bioimaging: mono- and multimodal approaches

“…To solve this problem, specific methods based on either pulse sequences [101,102] , design [103] , or size control [76] of NPs have been developed by researchers to generate a bright contrast from the IONPs.…”