Polyethylene glycol–coated and folic acid–conjugated superparamagnetic iron oxide nanoparticles

The polyethylene glycol (PEG)–coated and folic acid (FA)–conjugated superparamagnetic iron oxide (SPIO) nanoparticles (SPIO-PEG-FA) were developed by Chen et al. as a magnetic resonance imaging (MRI) contrast agent for molecular imaging of tumors overexpressing folate receptor (1). 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; the NMR signal intensity 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 and thus improve the sensitivity and specificity of MRI in mapping information from tissues (2, 3). SPIO nanoparticles 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 (2, 4). 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 molecular diameter, SPIO nanoparticles 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 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) (5). Clinically, SPIO nanoparticles are predominantly used as a T/T* contrast agent, though it could shorten both T and T/T* relaxation processes. Successful application of a SPIO-based contrast agent is dependent on its size, size distribution, shape, magnetic susceptibility, and surface modification. , nonspecific SPIO nanoparticles are mainly captured by the reticuloendothelial system (RES), and they are more suitable for liver, spleen, and lymph node imaging (6). Because of their long plasma half-life (hours), SPIO are also used as blood pool agents in magnetic resonance angiography (7). Accumulation of the nonspecific SPIO in tumors relies on the enhanced permeation and retention effect defined by the tumor's leaky vasculature and poor lymphatic drainage. Specific SPIO nanoparticles are developed by conjugating the respective targeting agents directly onto the SPIO surface or onto its hydrophilic coating. Specific accumulation of the agents at the disease-specific sites is achieved because of the target overexpression (often cell surface receptors) and receptor-mediated endocytosis and recycling (2, 3). The signal decrease is much more obvious in the lesions than in the surrounding normal tissues. An inverse strategy of SPIO-based molecular imaging is also applied in some studies by designing molecules that bind to targets expressing on normal tissues. This strategy has been proven to be valuable in imaging pancreatic ductal adenocarcinomas and hepatocellular carcinomas by targeting the receptors of bombesin, cholecystokinin, or asialoglycoprotein in normal tissue (8, 9). By decreasing the T signal of the normal tissue surrounding a tumor more than that of the tumor, the contrast between healthy and tumor tissues is enhanced. Chen et al. developed a SPIO-based MRI contrast agent by immobilizing the PEG and FA on the surface of SPIO nanoparticles (SPIO-PEG-FA) (1). PEG was used to increase the blood circulation time of the nanoparticles, and FA was designed to target the cancer cells and to increase the cell internalization the folate receptor–mediated endocytosis and recycling. The folate receptor is a high-affinity, glycosylphosphatidylinositol-anchored protein that is overexpressed in various types of human tumors. Folate is vital for the rapid proliferation of tumor cells. In contrast, nonproliferating healthy cells are severely restricted in possessing folate receptors. Folate receptors provide highly selective sites that differentiate tumor cells from normal cells. In addition, folate has no immunotoxicity. Because of these unique features, folate conjugates have been intensively investigated as drugs, drug carriers, and imaging agents (10-12).