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FluidMAG iron nanoparticle-labeled mesenchymal stem cells for tracking cell homing to tumors Shan LMolecular Imaging and Contrast Agent Database (MICAD)-/-ä 2004[]; ä (ä): äPersonalized diagnosis and treatment with allogenic or autologous cells are becoming a reality in the field of medicine (1, 2). Cytotoxic or engineered T-cells are under clinical trial for the treatment of hematopoietic or other malignant diseases (3). Contrast agent-tagged macrophages are used as cellular probes to image the early inflammatory processes in macrophage-rich conditions such as inflammation, atherosclerosis, and acute cardiac graft rejection (4). The roles of stem cells are under intensive investigation in therapeutic and regenerative medicine, such as regenerating cardiomyocytes, neurons, bone, and cartilage (1). Genetically modified cells are used to treat genetic disorders (5). With promising results from these studies, a critical issue is how to monitor the temporal and spatial migration and the homing of these cells, as well as the engraftment efficiency and functional capability of the transplanted cells in vivo (6, 7). Histopathological techniques have only been used to obtain information on the fate of implanted cells at the time of animal euthanization or via biopsy or surgery. To track the real-time changes of cell location, viability, and functional status, cell imaging techniques have been introduced during the last few years. Cells of interest are labeled with reporter genes, fluorescent dyes, or other contrast agents that transform the tagged cells into cellular probes or imaging agents (2, 6, 7). The ability to monitor superparamagnetic iron oxide particles (SPIO) with magnetic resonance imaging (MRI) has been utilized in animal models as well as in a few clinical settings to investigate the fate of labeled cells (6-10). The advantages of using MRI for cell tracking include the high spatial resolution with high anatomic background contrast, the lack of exposure to ionizing radiation, and the ability to follow the cells for months, although it is difficult to measure the rate of cell division and to determine whether each progeny shares the SPIO in vivo. In addition, cell labeling with SPIO nanoparticles is generally nontoxic and does not affect the cell proliferation and differentiation capacity, although a few studies have reported that the stem cells labeled with SPIO lose part of their differentiation capacity in a SPIO concentration-dependent manner. An important limitation of MRI is the fact that MRI signals cannot indicate whether cells are dead or alive. It is also unknown whether the MRI signal comes from targeted or labeled cells or from macrophages. Basically, SPIO particles are used to label the target cells by systemic application or by injection into the tissue area of interest to monitor target cell migration after phagocytosis. SPIO are more frequently used to label the cells in vitro by incorporating into the cells directly. Furthermore, SPIO are usually encapsulated by organic polymers to increase their stability and biocompatibility and to allow the chemical modification of their surfaces. The fact is that the uptake of different particles varies largely between different cell types and between particle coatings (6, 7). Msenchymal stem cells (MSCs) represent a heterogeneous subset of pluripotent stromal cells that can be isolated from different adult tissues including adipose tissue, liver, muscle, amniotic fluid, placenta, umbilical cord blood, and dental pulp, although the bone marrow remains the principal source for most preclinical and clinical studies (1, 11, 12). Although MSCs account for only 0.001-0.01% of the total nucleated cells within isolated bone marrow aspirates, they can easily be isolated and expanded in vitro through as many as 40 population doublings after 8-10 weeks of culture (1, 13). These cells exhibit the potential to differentiate into cells of diverse lineages such as adipocytes, chondrocytes, osteocytes, myoblasts, cardiomyocytes, neurons, and astrocytes. In addition, MSCs show tropism or homing to tumors and thus have been used as vehicles for directed cancer delivery (14, 15). The mechanism responsible for the homing of MSCs to tumors is thought to involve chemokine ligands and receptors, as with the recruitment of leukocytes to areas of inflammation. However, unlike with leukocytes, the specific chemokines responsible for MSC migration are poorly characterized (14, 15). Nevertheless, homing to tumors has been confirmed with traditional immunohistochemistry and other methods in many studies. Loebinger et al. labeled MSCs with fluidMAG iron nanoparticles and imaged homing of the labeled MSCs to tumors with MRI (16). FluidMAG nanoparticles are commercially available ferrofluids consisting of an aqueous dispersion of magnetic iron oxides with a hydrodynamic diameter of 200 nm and a starch coating. The investigators showed that as few as 1,000 labeled MSCs were detected 1 month after their co-injection with breast cancer cells that formed subcutaneous tumors. The investigators further demonstrated that intravenously injected labeled cells could be tracked in vivo to home to multiple lung metastases (16).ä |
