Magnetic Resonance Imaging Tracking Research Articles

Abstract B44: Enabling in vivo visualization of cellular therapies in the clinic: Maturation of αDC1 data sets.

Abstract Cellular therapies are increasingly being used in the clinic to modify a patient's immune function. Human dendritic cells (DC) have great clinical promise as an immunotherapeutic intervention against cancer, but questions concerning the dispersion and persistence of these cells, as well as correlations to therapeutic potency remain. Here we utilize a perfluoropolyether (PFPE) magnetic resonance imaging (MRI) tracer agent that aims to address these questions in the assessment of α-type-1-polarized dendritic cells (αDC1). αDC1 cells, producing high levels of interleukin-12p70 with putative strong lymph node homing capabilities, have been evaluated in support of an IND incorporating post-transfer MR imaging of the therapeutic cells. Important therapeutic functions, such as cytokine production, cellular phenotype, and antigen processing are maintained. Transitioning the protocol from the laboratory into clinical production, taking into account GMP procedural changes, resulted in both maintained cellular properties and detectable signal by 3T MRI. In vivo results demonstrate the capability of MRI to detect and quantify labeled cells with a high degree of specificity. With nominal exogenous fluorine naturally present in tissue, labeled cells appear with little background. Pairing this signal with conventional proton MRI from the same imaging session, cells are able to be traced to their precise anatomical location. The MRI tracking capabilities, safety profiles, and use of 19F labeling in preclinical data sets demonstrate the ability of 19F to be used in clinical applications to strengthen the understanding of cellular therapeutics. Citation Format: Brooke M. Helfer, Anthony Balducci, Julie Urban, Lisa Butterfield, Eric Ahrens, Pawel Kalinski, Amy Wesa. Enabling in vivo visualization of cellular therapies in the clinic: Maturation of αDC1 data sets. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B44.

In vivo and in vitro imaging tracing of dual-labeled bone mesenchymal stem cells transplanted into myocardium of F344 rats.

To investigate the feasibility of in vitro and in vivo magnetic resonance imaging (MRI) and fluorescence imaging tracking of transplanted bone mesenchymal stem cells (BMSCs) dual-labeled with ultrasmall superparamagnetic iron oxide (USPIO) and red fluorescence protein (RFP). BMSCs were incubated with culture medium containing USPIO for 24 hours. The Prussian-blue staining, transmission electron microscopy and trypan-blue staining were used to study the efficacy and safety of labeling. F344 rat model of acute myocardial infarction was established by ligating the left anterior descending coronary artery. The dual-labeled BMSCs were injected into the margin of the infraction myocardium. Then MRI and fluorescence imaging were performed to trace the cells both in vitro and in vivo. Postmortal study was carried out to observe the distribution of transplanted cells in myocardium. The percentage of dual-labeled BMSCs reached 99% after co-incubating with USPIO for 24 hours. USPIO particles were mainly located in lysosomes. As demonstrated by trypan-blue staining, there was no significant deference in viability between labeled and unlabeled groups (P>0.05). All dual-labeled transplanted BMSCs showed a significant decreasing signal on MRI, and the signal intensity changes had no significant difference over 4 weeks (P=0.66). In vitro cell tracing with fluorescence imaging of isolated heart from F344 rats was successful,while in vivo cell tracing with fluorescence imaging failed. Prussian blue staining showed that USPIO distributed near the infarcted myocardium, corresponding with the fluorescence imaging. MRI can be used to trace the dual-labeled BMSCs transplanted into F344 rat hearts in vivo, while fluorescence imaging and pathological fluorescence imaging can trace the transplanted cells in vitro.

Assessment of left ventricular systolic function in aortic stenosis and prognostic implications

This editorial refers to ‘Global longitudinal strain is a strong independent predictor of all-cause mortality in patients with aortic stenosis’ by L.G. Kearney et al ., doi:10.1093/ehjci/jes115. Left ventricular (LV) ejection fraction, most commonly assessed with two-dimensional echocardiography, is an important prognostic determinant of many cardiovascular diseases. The decision of implanting specific cardiovascular devices, such as cardiac resynchronization therapy or implantable cardioverter defibrillator, recommending valvular surgery or chemotherapy relies on the LV ejection fraction. However, the accumulating evidence shows that LV ejection fraction is an imperfect measure of LV systolic function since it simply reflects the changes in the LV cavity volume and does not take into consideration the complex architecture of the LV.1,2 The LV myocardial fibre changes the three-dimensional spatial orientation from a right-handed helix in the subendocardial region to a left-handed helix in the subepicardium.1 This counterclockwise and clockwise spiral muscle configuration results in a characteristic three-dimenisonal LV deformation with shortening in the longitudinal and circumferential directions, thickening in the radial direction, and twist in the circumferential-longitudinal plane and permits LV emptying and filling with optimal mechanical efficiency. Thus, 15% of myofibre shortening during systole results in 40% myocardial wall thickening and >60% change in the LV ejection fraction in the normal heart.3 In addition, the extracellular collagen matrix of the myocardium supporting this myofibre arrangement is key to maintain the LV shape and size. Any change in the myofibre alignment or extracellular matrix may lead to LV dysfunction. Current imaging techniques, such as diffusion tensor and tagged magnetic resonance imaging and speckle tracking, permit non-invasive evaluation of the LV spiral muscle configuration and quantification of LV shortening, thickening, and twisting deformations. Particularly, speckle tracking echocardiography permits accurate assessment of multidirectional LV …

Migration of iron-labeled KHYG-1 natural killer cells to subcutaneous tumors in nude mice, as detected by magnetic resonance imaging

A novel cell line of cytotoxic natural killer (NK) cells, KHYG-1, was examined in vivo for immunotherapy against prostate cancer. The feasibility of using magnetic resonance imaging (MRI) tracking to monitor the fate of injected NK cells following intravenous (i.v.), intraperitoneal (i.p.) and subcutaneous (s.c.) administration was assessed. PC-3M human prostate cancer cells were injected s.c. into the flank of nude mice (day 0). KHYG-1 NK cells were labeled with an iron oxide contrast agent and injected s.c., i.v. or i.p. on day 8. Mice were imaged by MRI on days 7, 9 and 12. Tumor sections were examined with fluorescence microscopy and immunohistologic staining for NK cells. NK cells were detected in the tumors by histology after all three administration routes. NK cells and fluorescence from the iron label were co-localized. Signal loss was seen in the areas around the tumors and between the tumor lobes in the s.c. group. We are the first to label this cell line of NK cells with an iron oxide contrast agent. Accumulation of NK cells was visualized by MRI after s.c. injection but not after i.v. and i.p. injection.

In vivo magnetic resonance imaging tracking of C6 glioma cells labeled with superparamagnetic iron oxide nanoparticles

The aim of the current study was to monitor the migration of superparamagnetic iron oxide nanoparticle (SPION)-labeled C6 cells, which were used to induce glioblastoma tumor growth in an animal model, over time using magnetic resonance imaging (MRI), with the goal of aiding in tumor prognosis and therapy. Two groups of male Wistar rats were used for the tumor induction model. In the first group (n=3), the tumors were induced via the injection of SPION-labeled C6 cells. In the second group (n=3), the tumors were induced via the injection of unlabeled C6 cells. Prussian Blue staining was performed to analyze the SPION distribution within the C6 cells in vitro. Tumor-inducing C6 cells were injected into the right frontal cortex, and subsequent tumor monitoring and SPION detection were performed using T2- and T2*-weighted MRI at a 2T field strength. In addition, cancerous tissue was histologically analyzed after performing the MRI studies. The in vitro qualitative evaluation demonstrated adequate distribution and satisfactory cell labeling of the SPIONs. At 14 or 21 days after C6 injection, a SPION-induced T2- and T2*-weighted MRI signal reduction was observed within the lesion located in the left frontal lobe on parasagittal topography. Moreover, histological staining of the tumor tissue with Prussian Blue revealed a broad distribution of SPIONs within the C6 cells. MRI analyses exhibit potential for monitoring the tumor growth of C6 cells efficiently labeled with SPIONs.

Labelling of olfactory ensheathing cells with micron‐sized particles of iron oxide and detection by MRI

A crucial issue in transplant-mediated repair of the damaged central nervous system (CNS) is serial non-invasive imaging of the transplanted cells, which has led to interest in the application of magnetic resonance imaging (MRI) combined with designated intracellular magnetic labels for cell tracking. Micron-sized particles of iron oxide (MPIO) have been successfully used to track cells by MRI, yet there is relatively little known about either their suitability for efficient labelling of specific cell types, or their effects on cell viability. The purpose of this study was to develop a suitable MPIO labelling protocol for olfactory ensheathing cells (OECs), a type of glia used to promote the regeneration of CNS axons after transplantation into the injured CNS. Here, we demonstrate an OEC labelling efficiency of >90% with an MPIO incubation time as short as 6 h, enabling intracellular particle uptake for single-cell detection by MRI without affecting cell proliferation, migration and viability. Moreover, MPIO are resolvable in OECs transplanted into the vitreous body of adult rat eyes, providing the first detailed protocol for efficient and safe MPIO labelling of OECs for non-invasive MRI tracking of transplanted OECs in real time for use in studies of CNS repair and axon regeneration.

MRI Tracking of FePro Labeled Fresh and Cryopreserved Long Term In Vitro Expanded Human Cord Blood AC133+ Endothelial Progenitor Cells in Rat Glioma

BackgroundEndothelial progenitors cells (EPCs) are important for the development of cell therapies for various diseases. However, the major obstacles in developing such therapies are low quantities of EPCs that can be generated from the patient and the lack of adequate non-invasive imaging approach for in vivo monitoring of transplanted cells. The objective of this project was to determine the ability of cord blood (CB) AC133+ EPCs to differentiate, in vitro and in vivo, toward mature endothelial cells (ECs) after long term in vitro expansion and cryopreservation and to use magnetic resonance imaging (MRI) to assess the in vivo migratory potential of ex vivo expanded and cryopreserved CB AC133+ EPCs in an orthotopic glioma rat model.Materials, Methods and ResultsThe primary CB AC133+ EPC culture contained mainly EPCs and long term in vitro conditions facilitated the maintenance of these cells in a state of commitment toward endothelial lineage. At days 15–20 and 25–30 of the primary culture, the cells were labeled with FePro and cryopreserved for a few weeks. Cryopreserved cells were thawed and in vitro differentiated or IV administered to glioma bearing rats. Different groups of rats also received long-term cultured, magnetically labeled fresh EPCs and both groups of animals underwent MRI 7 days after IV administration of EPCs. Fluorescent microscopy showed that in vitro differentiation of EPCs was not affected by FePro labeling and cryopreservation. MRI analysis demonstrated that in vivo accumulation of previously cryopreserved transplanted cells resulted in significantly higher R2 and R2* values indicating a higher rate of migration and incorporation into tumor neovascularization of previously cryopreserved CB AC133+ EPCs to glioma sites, compared to non-cryopreserved cells.ConclusionMagnetically labeled CB EPCs can be in vitro expanded and cryopreserved for future use as MRI probes for monitoring the migration and incorporation to the sites of neovascularization.

Highly efficient magnetic stem cell labeling with citrate-coated superparamagnetic iron oxide nanoparticles for MRI tracking

Tracking of transplanted stem cells is essential to monitor safety and efficiency of cell-based therapies. Magnetic resonance imaging (MRI) offers a very sensitive, repetitive and non-invasive in vivo detection of magnetically labeled cells but labeling with commercial superparamagnetic iron oxide nanoparticles (SPIONs) is still problematic because of low labeling efficiencies and the need of potentially toxic transfection agents. In this study, new experimental citrate-coated SPIONs and commercial Endorem and Resovist SPIONs were investigated comparatively in terms of in vitro labeling efficiency, effects on stem cell functionality and in vivo MRI visualization. Efficient labeling of human mesenchymal stem cells (MSCs) without transfection agents was only achieved with Citrate SPIONs. Magnetic labeling of human MSCs did not affect cell proliferation, presentation of typical cell surface marker antigens and differentiation into the adipogenic and osteogenic lineages. However, chondrogenic differentiation and chemotaxis were significantly impaired with increasing SPION incorporation. Transplanted SPION-labeled MSCs were visualized in vivo after intramuscular injection in rats by 7T-MRI and were retrieved ex vivo by Prussian Blue and immunohistochemical stainings. Though a careful titration of SPION incorporation, cellular function and MRI visualization is essential, Citrate SPIONs are very efficient intracellular magnetic labels for in vivo stem cell tracking by MRI.

MRI-Guided Nanorobotic Systems for Therapeutic and Diagnostic Applications

This review presents the state of the art of magnetic resonance imaging (MRI)-guided nanorobotic systems that can perform diagnostic, curative, and reconstructive treatments in the human body at the cellular and subcellular levels in a controllable manner. The concept of an MRI-guided nanorobotic system is based on the use of an MRI scanner to induce the required external driving forces to propel magnetic nanocapsules to a specific target. It is an active targeting mechanism that provides simultaneous propulsion and imaging capabilities, which allow the implementation of real-time feedback control of the targeting process. The architecture of the system comprises four main modules: (a) the nanocapsules, (b) the MRI propulsion module, (c) the MRI tracking module (for image processing), and (d) the controller module. A key concept is the nanocapsule technology, which is based on carriers such as liposomes, polymer micelles, gold nanoparticles, quantum dots, metallic nanoshells, and carbon nanotubes. Descriptions of the significant challenges faced by the MRI-guided nanorobotic system are presented, and promising solutions proposed by the involved research community are discussed. Emphasis is placed on reviewing the limitations imposed by the scaling effects that dominate within the blood vessels and also on reviewing the control algorithms and computational tools that have been developed for real-time propulsion and tracking of the nanocapsules.

Neural correlates of spatial orienting in the human superior colliculus

A natural visual scene contains more information than the visual system has the capacity to simultaneously process, requiring specific items to be selected for detailed analysis at the expense of others. Such selection and inhibition are fundamental in guiding search behavior, but the neural basis of these mechanisms remains unclear. Abruptly appearing visual items can automatically capture attention, but once attention has been directed away from the salient event, return to that same location is slowed. In non-human primates, signals associated with attentional capture (AC) and subsequent inhibition of return (IOR) have been recorded from the superior colliculus (SC)--a structure known to play a pivotal role in reflexive spatial orienting. Here, we sought to establish whether similar signals could be recorded from the human SC, as well as early retinotopic cortical visual areas, where signals associated with AC and IOR have yet to be investigated with respect to oculomotor responses. Using an optimized oculomotor paradigm together with high-field, high-spatial resolution functional magnetic resonance imaging and high-speed eye tracking, we demonstrate that BOLD signal changes recorded from the human SC correlate strongly with our saccadic measures of AC and IOR. A qualitatively similar pattern of responses was found for V1, but only the inhibitory response associated with IOR persisted through V2 and V3. Although the SC plays a role in mediating these automatic attentional biasing signals, the source of these signals is likely to lie in higher cortical areas.

Gerstmann Meets Geschwind

That disconnection causes clinical symptoms is a very influential concept in behavioral neurology. Criteria for subcortical disconnection usually are symptoms that are distinct from those following cortical lesions and damage to a single, long-range fiber tract. Yet, a recent study combining functional magnetic resonance imaging and fiber tracking concluded that a focal lesion in left parietal white matter provides the only tenable explanation for pure Gerstmann’s syndrome, an enigmatic tetrad of acalculia, agraphia, finger agnosia, and left-right disorientation. Such a lesion would affect not only a single fiber tract but crossing or “kissing” of different fiber tracts and hence disconnect separate cortical networks. As fiber crossing is prominent in the cerebral white matter, the authors propose an extension to the subcortical disconnection framework that opens the door to ascribing a more diversified clinical phenomenology to white matter damage and ensuing disconnection than has been the case so far.

Long-TermIn VivoMagnetic Resonance Imaging Tracking of Endothelial Progenitor Cells Transplanted in Rat Ischemic Limbs and Their Angiogenic Potential

Stem cell therapy has been used to repair ischemic tissues in the limbs, in myocardial infarctions, and in the brain. To understand the mechanisms of healing, a contrast agent capable of inducing sufficient magnetic resonance (MR) contrast would be useful in providing fundamental information about the cell migration and incorporation into the ischemic tissue. A magnetic resonance imaging contrast agent composed of dextran and gadolinium chelate was synthesized. Hydroxyl groups of dextran were activated with 1,1'-carbonylbis-1H-imidazole and reacted with propanediamine to obtain aminated dextran. This modified polymer was then reacted with mono-N-succinimidyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate, then with fluorescein isothiocyanate, and finally reacted with gadolinium chloride solution (Dex-DOTA-Gd3(+)). Endothelial progenitor cells (EPCs) were selected as a stem cell model for magnetic resonance imaging tracking. Cells were isolated from the bone marrow harvested from the femurs and tibias of rats. Dex-DOTA-Gd3(+) was then introduced into the EPCs by electroporation. The intracellular stability and cytotoxicity of Dex-DOTA-Gd3(+) were evaluated in vitro. Dex-DOTA-Gd3(+)-labeled EPCs were transplanted into a rat model of ischemic limb, and MR images were acquired. Dex-DOTA-Gd3(+) was found to efficiently label EPCs over a long duration without significant cytotoxicity. This provides an MR signal sufficient for tracking the EPCs intramuscularly injected into the limb.

Magnetic resonance imaging tracking of human adipose derived stromal cells within three-dimensional scaffolds for bone tissue engineering

For bone tissue engineering, human Adipose Derived Stem Cells (hADSCs) are proposed to be associated with a scaffold for promoting bone regeneration. After implantation, cellularised scaffolds require a non-invasive method for monitoring their fate in vivo. The purpose of this study was to use Magnetic Resonance Imaging (MRI)-based tracking of these cells, labelled with magnetic agents for in vivo longitudinal assessment. hADSCs were isolated from adipose tissue and labelled with USPIO-rhodamine (Ultrasmall SuperParamagnetic Iron Oxide). USPIO internalisation, absence of toxicity towards hADSCs, and osteogenic differentiation of the labelled cells were evaluated in standard culture conditions. Labelled cells were then seeded within a 3D porous polysaccharide-based scaffold and imaged in vitro using fluorescence microscopy and MRI. Cellularised scaffolds were implanted subcutaneously in nude mice and MRI analyses were performed from 1 to 28 d after implantation. In vitro, no effect of USPIO labelling on cell viability and osteogenic differentiation was found. USPIO were efficiently internalised by hADSCs and generated a high T2* contrast. In vivo MRI revealed that hADSCs remain detectable until 28 d after implantation and could migrate from the scaffold and colonise the area around it. These data suggested that this scaffold might behave as a cell carrier capable of both holding a cell fraction and delivering cells to the site of implantation. In addition, the present findings evidenced that MRI is a reliable technique to validate cell-seeding procedures in 3D porous scaffolds, and to assess the fate of hADSCs transplanted in vivo.

Fiber density between rhinal cortex and activated ventrolateral prefrontal regions predicts episodic memory performance in humans

The prefrontal cortex (PFC) is assumed to contribute to goal-directed episodic encoding by exerting cognitive control on medial temporal lobe (MTL) memory processes. However, it is thus far unclear to what extent the contribution of PFC-MTL interactions to memory manifests at a structural anatomical level. We combined functional magnetic resonance imaging and fiber tracking based on diffusion tensor imaging in 28 young, healthy adults to quantify the density of white matter tracts between PFC regions that were activated during the encoding period of a verbal free-recall task and MTL subregions. Across the cohort, the strength of fiber bundles linking activated ventrolateral PFC regions and the rhinal cortex (comprising the peri- and entorhinal cortices) of the MTL correlated positively with free-recall performance. These direct white matter connections provide a basis through which activated regions in the PFC can interact with the MTL and contribute to interindividual differences in human episodic memory.

Co-encapsulation of magnetic nanoparticles and doxorubicin into biodegradable microcarriers for deep tissue targeting by vascular MRI navigation

Magnetic tumor targeting with external magnets is a promising method to increase the delivery of cytotoxic agents to tumor cells while reducing side effects. However, this approach suffers from intrinsic limitations, such as the inability to target areas within deep tissues, due mainly to a strong decrease of the magnetic field magnitude away from the magnets. Magnetic resonance navigation (MRN) involving the endovascular steering of therapeutic magnetic microcarriers (TMMC) represents a clinically viable alternative to reach deep tissues. MRN is achieved with an upgraded magnetic resonance imaging (MRI) scanner. In this proof-of-concept preclinical study, the preparation and steering of TMMC which were designed by taking into consideration the constraints of MRN and liver chemoembolization are reported. TMMC were biodegradable microparticles loaded with iron-cobalt nanoparticles and doxorubicin (DOX). These particles displayed high saturation magnetization (Ms = 72 emu g −1), MRI tracking compatibility (strong contrast on T2∗-weighted images), appropriate size for the blood vessel embolization (∼50 μm), and sustained release of DOX (over several days). The TMMC were successfully steered in vitro and in vivo in the rabbit model. In vivo targeting of the right or left liver lobes was achieved by MRN through the hepatic artery located 4 cm beneath the skin. Parameters such as flow velocity, TMMC release site in the artery, magnetic gradient and TMMC properties, affected the steering efficiency. These data illustrate the potential of MRN to improve drug targeting in deep tissues.

Mesoporous silica-coated hollow manganese oxide nanoparticles as positive T1 contrast agents for labeling and MRI tracking of adipose-derived mesenchymal stem cells.

Mesoporous silica-coated hollow manganese oxide (HMnO@mSiO2) nanoparticles were developed as a novel T1 magnetic resonance imaging (MRI) contrast agent. We hypothesized that the mesoporous structure of the nanoparticle shell enables optimal access of water molecules to the magnetic core, and consequently, an effective longitudinal (R1) relaxation enhancement of water protons, which value was measured to be 0.99 (mM−1s−1) at 11.7 T. Adipose-derived mesenchymal stem cells (MSCs) were efficiently labeled using electroporation, with much shorter T1 values as compared to direct incubation without electroporation, which was also evidenced by signal enhancement on T1-weighted MR images in vitro. Intracranial grafting of HMnO@mSiO2-labeled MSCs enabled serial MR monitoring of cell transplants over 14 days. These novel nanoparticles may extend the arsenal of currently available nanoparticle MR contrast agents by providing positive contrast on T1-weighted images at high magnetic field strengths.

In vivo magnetic resonance imaging of cell tropsim, trafficking mechanism, and therapeutic impact of human mesenchymal stem cells in a murine glioma model

Stem cells have offered much promise as delivery vehicles for brain tumor therapy, with the development of modalities to track the tumor tropism of stem cells receiving intense focus. Cellular magnetic resonance imaging (MRI) allows serial high-resolution in vivo detection of transplanted stem cells’ tropism toward gliomas in the mouse brain once these cells are internally labeled with iron oxide particles, but has been impeded by low labeling efficiencies. In this study, we describe the use of ferucarbotran and protamine (Fer-Pro) complexes for labeling human mesenchymal stem cells (hMSCs) for MRI tracking of glioma tropism in vivo. We found that Fer-Pro was not toxic and was highly efficient for labeling in vitro. Cell labeling with Fer-Pro promoted the migration of hMSCs toward glioma U87MG cells in vitro, which was mediated by stromal-derived factor-1/CXCR4 (SDF-1/CXCR4) signaling. Fer-Pro-labeled hMSCs could migrate specifically toward gliomas in vivo, which was observed with a clinical 1.5-T MRI system. The efficient labeling of Fer-Pro also allowed a tropic mechanism mediated by SDF-1/CXCR4 signaling to be detected by MRI in vivo. Additionally, the potential intrinsic inhibitory effect of hMSCs on glioma progression was estimated simultaneously. This is the first report to have used a clinical MRI modality to simultaneously study the migration, the therapeutic impact on tumors, and above all the trafficking mechanism of bone marrow-derived mesenchymal stem cells from human in a murine glioma xenograft model. The use of Fer-Pro for stem cell labeling may have potential clinical applications in stem cell guided therapy.

Surface functionalization of superparamagnetic nanoparticles for the development of highly efficient magnetic resonance probe for macrophages

In vivo magnetic resonance imaging (MRI) tracking of macrophages plays an important role in monitoring and understanding numerous human diseases with high macrophage activity. In this work, superparamagnetic iron oxide nanoparticles (SPIONs) of ∼12 nm were surface-functionalized with poly(DL-lactic acid-co-malic acid) copolymer (PLMA) via a nanoprecipitation method. The r(1), r(2) and r(2) /r(1) values of the PLMA-SPIONs obtained at a magnetic field of 3 T were 0.38, 196 and 516 mM(-1) s(-1) , respectively. The high r(2)/r(1) ratio can be expected to provide enhanced MR contrast. The PLMA-SPIONs were readily taken in by macrophages and the high iron uptake was confirmed via Prussian Blue staining and quantified by inductively coupled plasma mass spectrometry (ICP-MS). No significant cytotoxicity was found even at a high nanoparticle loading of 67.7 pg Fe per cell. A linear relationship between R(2) and R2* values and the number of PLMA-SPIONs labeled cells was observed in vitro. As a result of the significantly higher R2* than R(2) effects, an in vitro detection threshold of about 2820 labeled cells was achieved with short labeling time and low nanoparticle concentration using a clinical 3 T MRI scanner. Thus, the PLMA-SPIONs can be potentially useful as magnetic resonance probes for targeting and tracking macrophages.

A highly sensitive magnetite nanoparticle as a simple and rapid stem cell labelling agent for MRI tracking

A superparamagnetic iron oxide nanoparticle (SPION) was coupled to 2-aminoethyl-trimethyl ammonium (TMA) in a 2-step ligand exchange reaction to produce TMA–SPION. This particle, which has a strong positive charge, was investigated as the basis for a simple and efficient method for labelling human mesenchymal stem cells (hMSCs) for noninvasive monitoring by magnetic resonance imaging (MRI). TMA–SPION has a ζ potential of +40 mV and a hydrodynamic size of 101 nm. In addition to its long-term stability in an aqueous solution, TMA–SPION has a low cytotoxicity and favourable magnetic properties as a T2 contrast agent due to its high relaxivity. The T2 relaxivity of TMA–SPION is 4.4 times greater than the commercially available Feridex® I.V. magnetic resonance agent. Despite a short labelling time of 4 h, hMSCs are efficiently labelled with TMA–SPION without the need for a transfection agent. An in vivo MRI study of a brain infarction model confirmed the utility of TMA–SPION as an MRI tracking marker of administered hMSCs.

Magnetic Resonance Imaging Tracking of Stem Cells in Vivo Using Iron Oxide Nanoparticles as a Tool for the Advancement of Clinical Regenerative Medicine

National Cell Bank, Pasteur Institute of Iran, Tehran 1316943551, Iran, Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York 10029, United States, Department of General, Organic, and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Avenue Maistriau, 19, B-7000 Mons, Belgium, Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran 14588, Iran, Department of Biomedical Engineering, National Yang Ming University, No 155, Sec. 2, LiNong Street, Taipei 112, Taiwan, Nanotechnology Toxicology Consulting & Training, Inc., Nova Scotia, Canada, Faculty of Medicine, Dalhousie Medical School, Dalhousie University, Halifax, Nova Scotia, Canada, and Institute for Nanoscale Science and Technology (INSAT), University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7ER, U.K., Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran