In Vitro Evaluation of Magnetic Resonance Imaging Contrast Agents for Labeling Human Liver Cells: Implications for Clinical Translation

Raschzok, Nathanael; Muecke, David A.; Adonopoulou, Michaela K.; Billecke, Nils; Werner, Wiebke; Kammer, Nora N.; Zielinski, Anja; Behringer, Peter A.; Ringel, Frauke; Huang, Mingming; Neuhaus, P.; Teichgräber, Ulf; Sauer, Igor M.

doi:10.1007/s11307-010-0405-y

Cited by 19 publications

(19 citation statements)

References 39 publications

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“…The polymer coat of the MPIO described above means that they are not broken down in vivo and instead accumulate in the reticuloendothelial system (RES) as they are cleared from the circulation 3. Although MPIO administered to human liver cells in vitro did not suggest any detrimental effects of the particles on cellular iron homeostasis or cell performance,14 first generation, ‘off‐the‐shelf’ MPIO are not suitable for use in humans due to the potential long‐term toxicity. However, a range of biodegradable MPIO are being developed and indeed some have already been synthesized 15,16.…”

Section: Types Of Mpiomentioning

confidence: 99%

Development and application of endothelium‐targeted microparticles for molecular magnetic resonance imaging

Jefferson

Wijesurendra

McAteer

et al. 2012

WIREs Nanomed Nanobiotechnol

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Molecular imaging of disease states can enhance diagnosis allowing for accurate and more effective treatment. By specifically targeting molecules differentially expressed in disease states, researchers and clinicians have a means of disease characterization at a cellular or tissue level. Targeted micron‐sized particles of iron oxide (MPIO) have been used as molecule‐specific contrast agents for use with magnetic resonance imaging (MRI), and early evidence suggests they may be suitable for use with other imaging modalities. Targeting of MPIO to markers of disease is commonly achieved through the covalent attachment of antibodies to the surface of the particles, providing an imaging agent that is both highly specific and which binds with high affinity. When comparing micron‐sized particles with nanometre‐sized particles, the former provide substantial signal dropout in MRI and confer the sensitivity to detect low levels of target. Furthermore, larger particles appear to bind to targets more potently than smaller particles. Animal models have also demonstrated favorable blood clearance characteristics of MPIO, which are important in achieving favorable signal over background and to attain clearance and disposal. Although the current generation of commercially available MPIO are not suitable for administration into humans, future work may focus on the development of biodegradable and nonimmunogenic MPIO that may allow the use of these imaging agents in a clinical setting. WIREs Nanomed Nanobiotechnol 2012, 4:247–256. doi: 10.1002/wnan.1164 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease

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Section: Types Of Mpiomentioning

confidence: 99%

Development and application of endothelium‐targeted microparticles for molecular magnetic resonance imaging

Jefferson

Wijesurendra

McAteer

et al. 2012

WIREs Nanomed Nanobiotechnol

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“…However, utilizing a detailed in-vitro tissue evaluation and importantly, advanced super-paramagnetic agents such as micron-sized, Dragon-green fluorochrome co-labeled iron-oxide particles [28], [29], [36], we were able to proof the MRI findings and to confirm the presence of the transplanted cells within the fetal myocardium. Using specific antibodies to either detect human cells, the fluorochrome co-labeled MPIOs or both, we were able to clearly detect the transplanted cells highlighting the efficacy of this cell-tracking approach.…”

Section: Discussionmentioning

confidence: 95%

“…Using novel micron-sized, Dragon-green fluorochrome labelled iron-oxide particles (MPIO) that had so far been used in the field of liver research [28], [29], we were able to evaluate human cell-fate after intra-myocardial stem cell transplantation on MRI which was then followed by detailed Flow Cytometry, PCR and IHC assessment highlighting the advantage of the fluorochrome co-labelled MPIOs. On MRI, the MPIO labeled cell-clusters were clearly visible within the septal and anterior-lateral ventricular-wall corresponding to the injection sites.…”

Section: Discussionmentioning

confidence: 99%

Intramyocardial Transplantation and Tracking of Human Mesenchymal Stem Cells in a Novel Intra-Uterine Pre-Immune Fetal Sheep Myocardial Infarction Model: A Proof of Concept Study

et al. 2013

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Although stem-cell therapies have been suggested for cardiac-regeneration after myocardial-infarction (MI), key-questions regarding the in-vivo cell-fate remain unknown. While most available animal-models require immunosuppressive-therapy when applying human cells, the fetal-sheep being pre-immune until day 75 of gestation has been proposed for the in-vivo tracking of human cells after intra-peritoneal transplantation. We introduce a novel intra-uterine myocardial-infarction model to track human mesenchymal stem cells after direct intra-myocardial transplantation into the pre-immune fetal-sheep. Thirteen fetal-sheep (gestation age: 70–75 days) were included. Ten animals either received an intra-uterine induction of MI only (n = 4) or MI+intra-myocardial injection (IMI;n = 6) using micron-sized, iron-oxide (MPIO) labeled human mesenchymal stem cells either derived from the adipose-tissue (ATMSCs;n = 3) or the bone-marrow (BMMSCs;n = 3). Three animals received an intra-peritoneal injection (IPI;n = 3; ATMSCs;n = 2/BMMSCs;n = 1). All procedures were performed successfully and follow-up was 7–9 days. To assess human cell-fate, multimodal cell-tracking was performed via MRI and/or Micro-CT, Flow-Cytometry, PCR and immunohistochemistry. After IMI, MRI displayed an estimated amount of 1×105–5×105 human cells within ventricular-wall corresponding to the injection-sites which was further confirmed on Micro-CT. PCR and IHC verified intra-myocardial presence via detection of human-specific β-2-microglobulin, MHC-1, ALU-Sequence and anti-FITC targeting the fluorochrome-labeled part of the MPIOs. The cells appeared viable, integrated and were found in clusters or in the interstitial-spaces. Flow-Cytometry confirmed intra-myocardial presence, and showed further distribution within the spleen, lungs, kidneys and brain. Following IPI, MRI indicated the cells within the intra-peritoneal-cavity involving the liver and kidneys. Flow-Cytometry detected the cells within spleen, lungs, kidneys, thymus, bone-marrow and intra-peritoneal lavage, but not within the heart. For the first time we demonstrate the feasibility of intra-uterine, intra-myocardial stem-cell transplantation into the pre-immune fetal-sheep after MI. Utilizing cell-tracking strategies comprising advanced imaging-technologies and in-vitro tracking-tools, this novel model may serve as a unique platform to assess human cell-fate after intra-myocardial transplantation without the necessity of immunosuppressive-therapy.

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“…However, SPIOs may not stay inside the transplanted cells over time (26), but may be phagocytized by macrophages, resulting in an uncoupling between the MRI signal and the viability of stem cells (26, 27). Furthermore, considerations should be given to the potential toxicity of ferromagnetic compounds and transfection agents (28, 30) as well as the potential interaction between certain SPIOs with metalloproteins (28). As MRI has high spatial resolution, this strategy appears as a good modality to define cardiac delivery and short-term (e.g., 1–2 days) homing of transplanted cells (Figure 1B) (23, 25).…”

Section: Short Term Assessment Of Transplanted Cellsmentioning

confidence: 99%

Cell Tracking and the Development of Cell-Based Therapies

Rodriguez-Porcel

Kronenberg

Henry

et al. 2012

JACC: Cardiovascular Imaging

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Cell-based therapies are being developed for myocardial infarction (MI) and its consequences (e.g. heart failure) as well as refractory angina and critical limb ischemia. The promising results obtained in pre-clinical studies led to the translation of this strategy to clinical studies. To date, the initial results have been mixed: some studies showed benefit, while in others no benefit was observed. There is a growing consensus among the scientific community that a better understanding of the fate of transplanted cells (e.g., cell homing and viability over time) will be critical for the long term success of these strategies and that future studies should include an assessment of cell homing, engraftment and fate as an integral part of the trial design. In this review, different imaging methods and technologies will be discussed within the framework of the physiological answers that the imaging strategies can provide, with special focus on the inherent regulatory issues.

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In Vitro Evaluation of Magnetic Resonance Imaging Contrast Agents for Labeling Human Liver Cells: Implications for Clinical Translation

Abstract: Our findings suggest that MPIO are suited for clinical translation of strategies for cellular imaging with MRI. Attention should be paid to iron release and oxidative stress caused by biodegradable contrast agents.

Cited by 19 publications

References 39 publications

Development and application of endothelium‐targeted microparticles for molecular magnetic resonance imaging

Development and application of endothelium‐targeted microparticles for molecular magnetic resonance imaging

Intramyocardial Transplantation and Tracking of Human Mesenchymal Stem Cells in a Novel Intra-Uterine Pre-Immune Fetal Sheep Myocardial Infarction Model: A Proof of Concept Study

Cell Tracking and the Development of Cell-Based Therapies

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