Superparamagnetic iron oxide nanoparticles (SPION) stabilized by alginate (SPION-alginate) have been developed as a contrast agent to improve the sensitivity of magnetic resonance imaging (MRI) in the detection of hepatocellular carcinoma (HCC) (1-3). MRI is an imaging modality that is used to construct images of the nuclear magnetic resonance (NMR) signal, primarily from the hydrogen atoms in an object. The image contrast is achieved by the differences in the NMR signal intensity in different areas within the object, and the NMR signal intensity largely depends on the nuclear density (proton spins), the relaxation times (T, T, and T*), and the magnetic environment of the tissues. Contrast agents serve to enhance the image contrast, thus improving the sensitivity and specificity of MRI in mapping information from tissues (4, 5). SPION comprise a class of novel MRI contrast agents that are composed of a ferric iron (Fe) and ferrous iron (Fe) core and a layer of dextran or other polysaccharide coating (4, 6). The iron nanoparticles have very large magnetic moment, which leads to local magnetic field inhomogeneity. Consequently, the NMR signal intensity is significantly decreased, appearing dark on T- and T*-weighted images. On the basis of size (i.e., diameter), SPION are commonly classified as oral SPIO (300 nm–3.5 µm), polydisperse SPIO (PSPIO, 50–150 nm), and ultrasmall SPIO (USPIO, <50 nm). In addition, USPIO nanoparticles with an iron oxide core that is monocrystalline in nature are referred to as monocrystalline iron oxide nanoparticles (MION), and MION with a chemically cross-linked and aminated polysaccharide shell are called cross-linked iron oxide nanoparticles (CLIO) (7). SPION are predominantly used as a T/T* contrast agent in the clinic, though it could shorten both T and T/T* relaxation processes. Successful application of a SPION-based contrast agent is dependent on its size, size distribution, shape, magnetic susceptibility, and surface modification. , nonspecific SPION are mainly captured by the reticuloendothelial system, and they are more suitable for liver, spleen, and lymph node imaging (8). Because of the long plasma half-life (hours), they are also used as blood pool agents in magnetic resonance angiography (9). Specific SPION are developed by conjugating the respective targeting agents directly onto the SPION surface or onto its hydrophilic coating. Specific accumulation of the agents at disease-specific sites is achieved because of the target overexpression (often cell surface receptors) and receptor-mediated endocytosis and recycling (4, 5). The signal decrease is much more obvious in the lesions than in the surrounding normal tissues. An inverse strategy of the SPION-based molecular imaging is also applied in some studies by designing molecules that bind to targets expressing on normal tissues. This strategy has been proved to be valuable in imaging pancreatic ductal adenocarcinomas and HCC by targeting the receptors of bombesin, cholecystokinin, or asialoglycoprotein (10, 11). In this case, by decreasing the T signal of normal tissue surrounding a tumor more than that of the tumor, the contrast between healthy and tumor tissues is enhanced. A SPION-based MRI contrast agent was developed by stabilizing the SPION with alginate (SPION-alginate) (1-3). application of this newly developed contrast agent improved the sensitivity of MRI in the detection of HCC in rat and rabbit HCC models.