Ferumoxides–protamine sulfate is more effective than ferucarbotran for cell labeling: implications for clinically applicable cell tracking using MRI

Buul, Gerben M. van; Farrell, Eric; Kops, Nicole; Tiel, Sandra T. van; Bos, P.K.; Weinans, Harrie; Krestin, Gabriël P.; Osch, Gerjo J.V.M. van; Bernsen, Monique R.

doi:10.1002/cmmi.289

Cited by 29 publications

(28 citation statements)

References 26 publications

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“…It was suggested that the additional carboxyl groups associated with ferucarbotran might lead to a higher affinity to the cell membrane so that cells could be labeled with it without need of an incorporation facilitator [48,49]. However, recent work showed that a higher percentage of labeled cells, a higher amount of intracellular iron and lower amount of extracellular iron aggregates were reached using FeProt complexes when compared to Resovist without incorporation facilitator [33]. Moreover, in a study on human MSC (hMSC), there was no difference in the total iron content (pg/cell) among cells incubated with Feridex or Resovist when both were added together with PLL; both Feridex and Resovist incorporation was superior to a third type of nanoparticle [monocrystalline iron oxide (MION), an ultrasmall superparamagnetic iron oxide] when added with PLL [58].…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, dextran-coated SPIONs do not show sufficient cellular uptake to enable tracking of nonphagocytic cells [29]. However, the cellular uptake of SPIONs by nonphagocytic cells can be facilitated by cationic compounds such as poly-L-lysine (PLL) [29,30] and protamine sulfate [31-33] due to their interaction with the negatively charged cell surface and subsequent endosomal uptake [29,34]. PLL is a synthetic cationic polymer commonly used to enhance cell adhesion to the surface of culture dishes.…”

Section: Introductionmentioning

confidence: 99%

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Optimized labeling of bone marrow mesenchymal cells with superparamagnetic iron oxide nanoparticles and in vivo visualization by magnetic resonance imaging

et al. 2011

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BackgroundStem cell therapy has emerged as a promising addition to traditional treatments for a number of diseases. However, harnessing the therapeutic potential of stem cells requires an understanding of their fate in vivo. Non-invasive cell tracking can provide knowledge about mechanisms responsible for functional improvement of host tissue. Superparamagnetic iron oxide nanoparticles (SPIONs) have been used to label and visualize various cell types with magnetic resonance imaging (MRI). In this study we performed experiments designed to investigate the biological properties, including proliferation, viability and differentiation capacity of mesenchymal cells (MSCs) labeled with clinically approved SPIONs.ResultsRat and mouse MSCs were isolated, cultured, and incubated with dextran-covered SPIONs (ferumoxide) alone or with poly-L-lysine (PLL) or protamine chlorhydrate for 4 or 24 hrs. Labeling efficiency was evaluated by dextran immunocytochemistry and MRI. Cell proliferation and viability were evaluated in vitro with Ki67 immunocytochemistry and live/dead assays. Ferumoxide-labeled MSCs could be induced to differentiate to adipocytes, osteocytes and chondrocytes. We analyzed ferumoxide retention in MSCs with or without mitomycin C pretreatment. Approximately 95% MSCs were labeled when incubated with ferumoxide for 4 or 24 hrs in the presence of PLL or protamine, whereas labeling of MSCs incubated with ferumoxide alone was poor. Proliferative capacity was maintained in MSCs incubated with ferumoxide and PLL for 4 hrs, however, after 24 hrs it was reduced. MSCs incubated with ferumoxide and protamine were efficiently visualized by MRI; they maintained proliferation and viability for up to 7 days and remained competent to differentiate. After 21 days MSCs pretreated with mitomycin C still showed a large number of ferumoxide-labeled cells.ConclusionsThe efficient and long lasting uptake and retention of SPIONs by MSCs using a protocol employing ferumoxide and protamine may be applicable to patients, since both ferumoxides and protamine are approved for human use.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Optimized labeling of bone marrow mesenchymal cells with superparamagnetic iron oxide nanoparticles and in vivo visualization by magnetic resonance imaging

et al. 2011

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“…Since the original concentration of applied cells is known in an ACI procedure, and seeded in a confined volume, it is possible to quantify the total amount of labeled cells and follow them in the same patient in subsequent MRI sessions. Since both hBMSCs and chondrocytes can be labeled using SPIO [25], [26], these findings indicate the potential of SPIO labeling for tracking cells in numerous orthopedic treatments and many other regenerative medicine fields [27]. Cell visualization and especially quantification using MRI can be a major step towards improvement in all these applications.…”

Section: Discussionmentioning

confidence: 98%

“…SPIO labeling was performed using ferumoxides (Endorem®, Guerbet S.A., Paris, France) complexed to protamine sulfate (LEO Pharma N.V., Wilrijk, Belgium) as described earlier [25]. For removal of extracellular iron, cells were washed with PBS containing heparin 10 U/ml (LEO Pharma B.V., Breda, the Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Clinically Translatable Cell Tracking and Quantification by MRI in Cartilage Repair Using Superparamagnetic Iron Oxides

et al. 2011

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BackgroundArticular cartilage has very limited intrinsic regenerative capacity, making cell-based therapy a tempting approach for cartilage repair. Cell tracking can be a major step towards unraveling and improving the repair process of these therapies. We studied superparamagnetic iron oxides (SPIO) for labeling human bone marrow-derived mesenchymal stem cells (hBMSCs) regarding effectivity, cell viability, long term metabolic cell activity, chondrogenic differentiation and hBMSC secretion profile. We additionally examined the capacity of synovial cells to endocytose SPIO from dead, labeled cells, together with the use of magnetic resonance imaging (MRI) for intra-articular visualization and quantification of SPIO labeled cells.Methodology/Prinicipal FindingsEfficacy and various safety aspects of SPIO cell labeling were determined using appropriate assays. Synovial SPIO re-uptake was investigated in vitro by co-labeling cells with SPIO and green fluorescent protein (GFP). MRI experiments were performed on a clinical 3.0T MRI scanner. Two cell-based cartilage repair techniques were mimicked for evaluating MRI traceability of labeled cells: intra-articular cell injection and cell implantation in cartilage defects. Cells were applied ex vivo or in vitro in an intra-articular environment and immediately scanned. SPIO labeling was effective and did not impair any of the studied safety aspects, including hBMSC secretion profile. SPIO from dead, labeled cells could be taken up by synovial cells. Both injected and implanted SPIO-labeled cells could accurately be visualized by MRI in a clinically relevant sized joint model using clinically applied cell doses. Finally, we quantified the amount of labeled cells seeded in cartilage defects using MR-based relaxometry.ConclusionsSPIO labeling appears to be safe without influencing cell behavior. SPIO labeled cells can be visualized in an intra-articular environment and quantified when seeded in cartilage defects.

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“…106 The authors and the use of "physicochemical labels" such as magnetic nanoparticles. 110,111 An important advantage of magnetic nanoparticles like "superparamagnetic iron oxide"-labeling over other labeling techniques is that it enables clinical noninvasive in vivo cell tracking using MRI, without the need for harvesting biopsies. This allows for continuous follow-up of biological repair of articular cartilage without influencing the repair tissue or jeopardizing the patient with repeated interventions.…”

Section: Mscs For Cartilage Repairmentioning

confidence: 99%

Articular cartilage repair and the evolving role of regenerative medicine

Bos¹

2010

OAS

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Among the growing applications of regenerative medicine, clinical articular cartilage repair has now been used for 2 decades and forms a successful example of translational medicine. Cartilage is characterized by a limited intrinsic repair capacity following injury. Articular cartilage defects cause symptoms, are not spontaneously repaired, and are generally believed to result in early osteoarthritis. Marrow stimulation techniques, osteochondral transplantation, and cell-based therapies, such as autologous chondrocyte implantation (ACI) and use of mesenchymal stem cells (MSCs), are used for tissue regeneration, symptom relief, and prevention of further joint degeneration. The exact incidence of cartilage defects and the natural outcome of joints with these lesions are unclear. Currently available cartilage repair techniques are designed for defect treatment in otherwise healthy joints and limbs, mostly in young adults. The natural history studies presented in this review estimated that the prevalence of cartilage lesions in this patient group ranges from 5% to 11%. The background and results from currently available randomized clinical trials of the three mostly used cartilage repair techniques are outlined in this review. Osteochondral transplantation, marrow stimulation, and ACI show improvement of symptoms with an advantage for cell-based techniques, but only a suggestion that risk for joint degeneration can be reduced. MSCs, characterized by their good proliferative capacity and the potential to differentiate into different mesenchymal lineages, form an attractive alternative cell source for cartilage regeneration. Moreover, MSCs provide a regenerative microenvironment by the secretion of bioactive factors. This trophic activity is believed to limit damage and stimulate intrinsic regenerative responses. Finally, important clinical issues are discussed, including techniques to study the role of implanted cells in tissue regeneration using cell labeling and cell tracking, the improvement of cartilage integration, the use of delayed gadolinium-enhanced magnetic resonance imaging of cartilage for early judgment of joint degeneration/regeneration, and the influence of regulatory rules for therapeutic application development.

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Ferumoxides–protamine sulfate is more effective than ferucarbotran for cell labeling: implications for clinically applicable cell tracking using MRI

Cited by 29 publications

References 26 publications

Optimized labeling of bone marrow mesenchymal cells with superparamagnetic iron oxide nanoparticles and in vivo visualization by magnetic resonance imaging

Optimized labeling of bone marrow mesenchymal cells with superparamagnetic iron oxide nanoparticles and in vivo visualization by magnetic resonance imaging

Clinically Translatable Cell Tracking and Quantification by MRI in Cartilage Repair Using Superparamagnetic Iron Oxides

Articular cartilage repair and the evolving role of regenerative medicine

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