Publications by authors named "Meser M Ali"

34 Publications

Glioblastoma: Targeting Angiogenesis and Tyrosine Kinase Pathways.

Nov Approaches Cancer Study 2020 29;4(5):398-401. Epub 2020 May 29.

Cellular and Molecular Imaging Lab, Department of Neurosurgery, Henry Ford Hospital, USA.

Angiogenesis is a hallmark of glioblastoma (GBM) and remains an important therapeutic target in its treatment, especially for recurrent GBM. GBMs are characterized by the release of vascular endothelial growth factor (VEGF), an important regulator and promoter of angiogenesis. Therefore, antiangiogenic therapies (AATs) targeting VEGF or VEGF receptors (VEGFRs) were designed and thought to be an effective tool for controlling the growth of GBM. However, recent results of different clinical trials using humanized monoclonal antibodies against VEGF (bevacizumab), as well as tyrosine kinase inhibitors (TKIs) that target different VEGFRs alone or in combination with other therapeutic agents demonstrated mixed results, with the majority of reports indicating that GBM developed resistance against antiangiogenic treatments.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486014PMC
May 2020

Enhancing the Performance of Dye Sensitized Solar Cells Using Silver Nanoparticles Modified Photoanode.

Molecules 2020 Sep 3;25(17). Epub 2020 Sep 3.

Center for Nanotechnology, Department of Natural Sciences, Coppin State University, 2500 W. North Ave, Baltimore, MD 21216, USA.

In this study, silver nanoparticles were synthesized, characterized, and applied to a dye-sensitized solar cell (DSSC) to enhance the efficiency of solar cells. The synthesized silver nanoparticles were characterized with UV-Vis spectroscopy, dynamic light scattering, transmission electron microscopy, and field emission scanning electron microscopy. The silver nanoparticles infused titanium dioxide film was also characterized by Fourier transform infrared and Raman spectroscopy. The performance of DSSC fabricated with silver nanoparticle-modified photoanode was compared with that of a control group. The current and voltage characteristics of the devices as well as the electrochemical impedance measurements were also carried out to assess the performance of the fabricated solar cells. The solar-to-electric efficiency of silver nanoparticles based DSSC was 1.76%, which is quite remarkable compared to the 0.98% realized for DSSC fabricated without silver nanoparticles.
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http://dx.doi.org/10.3390/molecules25174021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504805PMC
September 2020

MiR-17-92 enriched exosomes derived from multipotent mesenchymal stromal cells enhance axon-myelin remodeling and motor electrophysiological recovery after stroke.

J Cereb Blood Flow Metab 2020 Aug 18:271678X20950489. Epub 2020 Aug 18.

Department of Neurology, Henry Ford Health System, Detroit, MI, USA.

MiR-17-92 cluster enriched exosomes derived from multipotent mesenchymal stromal cells (MSCs) increase functional recovery after stroke. Here, we investigate the mechanisms underlying this recovery. At 24 h (h) post transient middle cerebral artery occlusion, rats received control liposomes or exosomes derived from MSCs infected with pre-miR-17-92 expression lentivirus (Exo-miR-17-92) or control lentivirus (Exo-Con) intravenously. Compared to the liposomes, exosomes significantly reduced the intracortical microstimulation threshold current of the contralateral cortex for evoking impaired forelimb movements (day 21), increased the neurite and myelin density in the ischemic boundary area, and contralesional axonal sprouting into the caudal forelimb area of ipsilateral side and in the denervated spinal cord (day 28), respectively. The Exo-miR-17-92 further enhanced axon-myelin remodeling and electrophysiological recovery compared with the EXO-Con. Ex vivo cultured rat brain slice data showed that myelin and neuronal fiber density were significantly increased by Exo-miR-17-92, while significantly inhibited by application of the PI3K/Akt/mTOR pathway inhibitors. Our studies suggest that the miR-17-92 cluster enriched MSC exosomes enhanced neuro-functional recovery of stroke may be attributed to an increase of axonal extension and myelination, and this enhanced axon-myelin remodeling may be mediated in part via the activation of the PI3K/Akt/mTOR pathway induced by the downregulation of PTEN.
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http://dx.doi.org/10.1177/0271678X20950489DOI Listing
August 2020

Photophysical Studies of Ruthenium-Based Complexes and the Performance of Nanostructured TiO Based Dye Sensitized Solar Cells.

J Nanomed Nanotechnol 2019 7;10(6). Epub 2019 Dec 7.

Center for Nanotechnology, Department of Natural Sciences, Coppin State University, 2500 W. North Ave, Baltimore, MD, USA.

Dye-sensitized solar cells (DSSCs) have attracted enormous attention in the last couple of decades due to their relatively small size, low cost and minimal environmental impact. DSSCs convert solar energy to electrical energy with the aid of a sensitizing dye. In this work, two ruthenium-based dyes, tris(bipyridine)ruthenium(II) chloride (Rubpy) and ruthenium(II)2,2'-bis(benzimidazol-2-yl)-4,4'-bipyridine (RubbbpyH), were synthesized, characterized, and investigated for use as dye sensitizers in the fabrication of DSSCs. The photovoltaic performance of the ruthenium-based DSSCs was assessed. The solar-to-electric power efficiency of the RubbbpyH DSSC was 0.2% and that of the Rubpy was 0.03%. The RubbbpyH was also deprotonated and analyzed to study the effect of deprotonation on the efficiency of the solar cell. The deprotonated species, Rubbbpy, recorded an average efficiency of 0.12%. Thus, a change in pH did not enhance the efficiency of the solar cell. The cells were further characterized by impedance measurements. The photocurrent-photovoltage results were not consistent with the absorption spectra since Rubbbpy showed a more prominent band than RubbbpyH but had a lower efficiency.
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http://dx.doi.org/10.35248/2157-7439.19.10.538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986734PMC
December 2019

Lipoic Acid Decorated Gold Nanoparticles and Their Application in the Detection of Lead Ions.

J Nanomed Nanotechnol 2019 12;10(6). Epub 2019 Dec 12.

Center for Nanotechnology, Department of Natural Sciences, Coppin State University, 2500 W. North Ave, Baltimore, MD, USA.

A simple colorimetric method has been developed for the detection of lead (Pb) in water samples using lipoic acid-functionalized gold nanoparticles. The lipoic acid-functionalized gold nanoparticles are induced to aggregate in the presence of the Pb which results in a change in the color of the functionalized gold nanoparticles. The change in color and the amount of Pb producing the change could be monitored via UV-visible spectrophotometry. A good correlation coefficient of 0.9927 was obtained for the calibration curve of the colorimetric method. The method was applied in the determination of Pb in water samples and the results compared to that of measurement carried out with Atomic Absorption Spectroscopy.
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http://dx.doi.org/10.35248/2157-7439.19.10.539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986728PMC
December 2019

Terahertz Reflectometry Imaging of Carbon Nanomaterials for Biological Application.

J Nanomed Nanotechnol 2019 26;10(4). Epub 2019 Aug 26.

Department of Natural Sciences, Center for Nanotechnology, Coppin State University, 2500 W. North Ave, Baltimore, MD, USA.

The multiwalled carbon nanotubes has a myriad of applications due to its unique electrical and mechanical properties. The biomedical application of multiwalled carbon nanotubes that have been reported include drug delivery, medical imaging, gene delivery, tissue regeneration, and diagnostics. Proper characterization is required to enhance the potential application of the multiwalled carbon nanotubes. Terahertz technology is a relatively unfamiliar spectrometric technique that show promise in efficiently characterizing multiwalled carbon nanotubes. In this paper, terahertz imaging was used to characterize multiwalled carbon nanotube in comparison with other characterization techniques, including transmission electron microscopy and field emission scanning electron microscopy. The average diameter of the carbon nanotubes from the reconstructed terahertz images was 48.54 nm, while the average length of a fiber was found to be approximately 1.2 μm. The multiwalled carbon nanotubes were additionally characterized by FTIR, Raman spectroscopy, and Energy-dispersive X-ray spectroscopy.
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http://dx.doi.org/10.35248/2157-7439.19.10.535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738974PMC
August 2019

MRI Monitoring of Cerebral Blood Flow after the Delivery of Nanocombretastatin across the Blood Brain Tumor Barrier.

J Nanomed Nanotechnol 2018 25;9(5). Epub 2018 Oct 25.

Department of Neurosurgery, Cellular and Molecular Imaging Laboratory, Henry Ford Hospital, USA.

Introduction of polymeric nanoparticles in cancer therapeutics is widely investigated since nanomedicine often enables the intratumoral delivery of drugs with increased efficacy with minimal side effects. In this study MRI monitoring was employed to study the therapeutic effect of nanocombretastatin (G3-CA4) in an orthotopic glioma model. Water insoluble combretastatin (CA4) was conjugated to a small-sized water soluble G3-succinamic acid PAMAM dendrimer. Nanoconstruct sizes were determined by TEM to be 3 to 5 nm. Intravenous (i.v.) delivery of G3-CA4 in an orthotopic glioma model produced a long-lived ischemia accompanied by necrosis at the core of the tumor but leaving a rim of viable tissue. In contrast, delivery of CA4 alone has no therapeutic effect in an experimental rat model of glioma.
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http://dx.doi.org/10.4172/2157-7439.1000516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333422PMC
October 2018

Dendrimer-based Nanoparticle for Dye Sensitized Solar Cells with Improved Efficiency.

J Nanomed Nanotechnol 2018 13;9(2). Epub 2018 Apr 13.

Department of Neurosurgery, Cellular and Molecular Imaging Laboratory, Henry Ford Hospital, Detroit, MI, USA.

Dye sensitized solar cells were fabricated with DyLight680 (DL680) dye and its corresponding europium conjugated dendrimer, DL680-Eu-G5PAMAM, to study the effect of europium on the current and voltage characteristics of the DL680 dye sensitized solar cell. The dye samples were characterized by using Absorption Spectroscopy, Emission Spectroscopy, Fluorescence lifetime and Fourier Transform Infrared measurements. Transmission electron microscopy imaging was carried out on the DL680-Eu-G5PAMAM dye and DL680-Eu-G5PAMAM dye sensitized titanium dioxide nanoparticles to analyze the size of the dye molecules and examine the interaction of the dye with titanium dioxide nanoparticles. The DL680-Eu-G5PAMAM dye sensitized solar cells demonstrated an enhanced solar-to-electric energy conversion of 0.32% under full light illumination (100 mWcm, AM 1.5 Global) in comparison with that of DL680 dye sensitized cells which recorded an average solar-to-electric energy conversion of only 0.19%. The improvement of the efficiency could be due to the presence of the europium that enhances the propensity of dye to absorb sunlight.
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http://dx.doi.org/10.4172/2157-7439.1000496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976458PMC
April 2018

Fluorinated Eu-based multimodal contrast agent for temperature- and redox-responsive magnetic resonance imaging.

Chem Sci 2017 Dec 26;8(12):8345-8350. Epub 2017 Oct 26.

Department of Chemistry , Wayne State University , 5101 Cass Avenue , Detroit , Michigan 48202 , USA . Email:

Magnetic resonance imaging (MRI) using redox-active, Eu-containing complexes is one of the most promising techniques for noninvasively imaging hypoxia . In this technique, positive (-weighted) contrast enhancement persists in areas of relatively low oxidizing ability, such as hypoxic tissue. Herein, we describe a fluorinated, Eu-containing complex in which the redox-active metal is caged by intramolecular interactions. The position of the fluorine atoms enables temperature-responsive contrast enhancement in the reduced form of the contrast agent and detection of the oxidized contrast agent MRI . Positive contrast is observed in H-MRI with Eu in the +2 oxidation state, and chemical exchange saturation transfer and F-MRI signal are observed with Eu in the +3 oxidation state. Contrast enhancement is controlled by the redox state of Eu, and modulated by the fluorous interactions that cage a bound water molecule reduce relaxivity in a temperature-dependent fashion. Together, these advancements constitute the first report of , redox-responsive imaging using F-MRI.
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http://dx.doi.org/10.1039/c7sc03142dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933353PMC
December 2017

Application of Dendrimer-based Nanoparticles in Glioma Imaging.

J Nanomed Nanotechnol 2017 Jun 14;8(3). Epub 2017 Jun 14.

Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.

Dendritic polymers or dendrimers present an alternate template for the development of nanoparticulate-based drug delivery and imaging systems. The smaller size (~7-12 nm) of dendrimers have the advantage over the other particles, because its smaller size can possibly improve tumor penetration and the inclusion of tumor specific drug release mechanisms. A Paramagnetic Chemical Exchange Saturation Transfer (PARACEST) MRI contrast agent, Eu-DOTA-Gly4 or a clinical relevant Gd-DOTA was conjugated on the surface of a G5 PAMAM dendrimer. To create a dual mode MRI-optical imaging nanoparticle, Dylight680 was also incorporated on the amines surface of a G5 dendrimer. The particle was detected with MRI in preclinical glioma animal model. Furthermore, noninvasive imaging results were validated with in vivo and optical imaging.
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http://dx.doi.org/10.4172/2157-7439.1000444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573247PMC
June 2017

Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH.

Sci Rep 2017 08 11;7(1):7865. Epub 2017 Aug 11.

Magnetic Resonance Research Center, Yale University, New Haven, CT, USA.

Gliomas maintain an acidic extracellular pH (pH), which promotes tumor growth and builds resistance to therapy. Given evidence that acidic pH beyond the tumor core indicates infiltration, we hypothesized that imaging the intratumoral pH in relation to the peritumoral pH can provide a novel readout of therapeutic influence on the tumor microenvironment. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes chemical shifts of non-exchangeable protons from macrocyclic chelates (e.g., DOTP) complexed with paramagnetic thulium (Tm), to generate pH maps in rat brains bearing U251 tumors. Following TmDOTP infusion, T-weighted MRI provided delineation of the tumor boundary and BIRDS was used to image the pH gradient between intratumoral and peritumoral regions (ΔpH) in both untreated and temozolomide treated (40 mg/kg) rats bearing U251 tumors. Treated rats had reduced tumor volume (p < 0.01), reduced proliferation (Ki-67 staining; p < 0.03) and apoptosis induction (cleaved Caspase-3 staining; p < 0.001) when compared to untreated rats. The ΔpH was significantly higher in untreated compared to treated rats (p < 0.002), suggesting that temozolomide, which induces apoptosis and hinders proliferation, also normalizes intratumoral pH. Thus, BIRDS can be used to map the ΔpH in gliomas and provide a physiological readout of the therapeutic response on the tumor microenvironment.
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http://dx.doi.org/10.1038/s41598-017-07609-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554228PMC
August 2017

MicroRNA cluster miR-17-92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery After Stroke in Rats.

Stroke 2017 03;48(3):747-753

From the Department of Neurology, Henry Ford Hospital, Detroit, MI (H.X., M.K., F.W., J.-Y.Q., X.S.L., M.M.A., B.B., Z.G.Z., M.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).

Background And Purpose: Multipotent mesenchymal stromal cell (MSC) harvested exosomes are hypothesized as the major paracrine effectors of MSCs. In vitro, the miR-17-92 cluster promotes oligodendrogenesis, neurogenesis, and axonal outgrowth. We, therefore, investigated whether the miR-17-92 cluster-enriched exosomes harvested from MSCs transfected with an miR-17-92 cluster plasmid enhance neurological recovery compared with control MSC-derived exosomes.

Methods: Rats subjected to 2 hours of transient middle cerebral artery occlusion were intravenously administered miR-17-92 cluster-enriched exosomes, control MSC exosomes, or liposomes and were euthanized 28 days post-middle cerebral artery occlusion. Histochemistry, immunohistochemistry, and Golgi-Cox staining were used to assess dendritic, axonal, synaptic, and myelin remodeling. Expression of phosphatase and tensin homolog and activation of its downstream proteins, protein kinase B, mechanistic target of rapamycin, and glycogen synthase kinase 3β in the peri-infarct region were measured by means of Western blots.

Results: Compared with the liposome treatment, both exosome treatment groups exhibited significant improvement of functional recovery, but miR-17-92 cluster-enriched exosome treatment had significantly more robust effects on improvement of neurological function and enhancements of oligodendrogenesis, neurogenesis, and neurite remodeling/neuronal dendrite plasticity in the ischemic boundary zone (IBZ) than the control MSC exosome treatment. Moreover, miR-17-92 cluster-enriched exosome treatment substantially inhibited phosphatase and tensin homolog, a validated miR-17-92 cluster target gene, and subsequently increased the phosphorylation of phosphatase and tensin homolog downstream proteins, protein kinase B, mechanistic target of rapamycin, and glycogen synthase kinase 3β compared with control MSC exosome treatment.

Conclusions: Our data suggest that treatment of stroke with tailored exosomes enriched with the miR-17-92 cluster increases neural plasticity and functional recovery after stroke, possibly via targeting phosphatase and tensin homolog to activate the PI3K/protein kinase B/mechanistic target of rapamycin/glycogen synthase kinase 3β signaling pathway.
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http://dx.doi.org/10.1161/STROKEAHA.116.015204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330787PMC
March 2017

Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models.

Sci Rep 2017 01 31;7:41809. Epub 2017 Jan 31.

Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.

Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 is a selective CYP450 inhibitor, which has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route. IV treatment with HPßCD-HET0016 decreased tumor growth, and altered vascular kinetics in early and late treatment groups (p < 0.05). Similar growth inhibition was observed in syngeneic GL261 GBM (p < 0.05). Survival studies using patient derived xenografts of GBM811, showed prolonged survival to 26 weeks in animals treated with focal radiation, in combination with HET0016 and TMZ (p < 0.05). We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA), in addition to inflammation and angiogenesis markers in the treatment group (p < 0.05). Our results indicate that HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, and neovascularization. Furthermore, HPßCD-HET0016 significantly prolonged survival in PDX GBM811 model.
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http://dx.doi.org/10.1038/srep41809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282583PMC
January 2017

pH-Dependent Cellular Internalization of Paramagnetic Nanoparticle.

ACS Sens 2016 Aug 10;1(8):975-978. Epub 2016 Aug 10.

Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, United States.

A hallmark of the tumor microenvironment in malignant tumor is extracellular acidosis, which can be exploited for targeted delivery of drugs and imaging agents. A pH sensitive paramagnetic nanoaparticle (NP) is developed by incorporating GdDOTA-4AmP MRI contrast agent and pHLIP (pH Low Insertion Peptide) into the surface of a G5-PAMAM dendrimer. pHLIP showed pH-selective insertion and folding into cell membranes, but only in acidic conditions. We demonstrated that pHLIP-conjugated Gd-G5 paramagnetic nanoparticle binds and fuses with cellular membrane at low pH, but not at normal physiological pH, and that it promotes cellular uptake. Intracellular trafficking of NPs showed endosomal/lysosomal path ways.
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http://dx.doi.org/10.1021/acssensors.6b00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214587PMC
August 2016

Targeting Triple Negative Breast Cancer with a Small-sized Paramagnetic Nanoparticle.

J Nanomed Nanotechnol 2016 Oct 28;7(5). Epub 2016 Oct 28.

Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.

There is no available targeted therapy or imaging agent for triple negative breast cancer (TNBC). We developed a small-sized dendrimer-based nanoparticle containing a clinical relevant MRI contrast agent, GdDOTA and a NIR fluorescent dye, DL680. Systemic delivery of dual-modal nanoparticles led to accumulation of the agents in a flank mouse model of TNBC that were detected by both optical and MR imaging. fluorescence images, as well as fluorescence images of individual organs, demonstrated that nanoparticles accumulated into tumor selectively. A dual modal strategy resulted in a selective delivery of a small-sized (GdDOTA)42-G4-DL680 dendrimeric agent to TNBC tumors, avoiding other major organs.
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http://dx.doi.org/10.4172/2157-7439.1000404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5180609PMC
October 2016

Targeting Glioma with a Dual Mode Optical and Paramagnetic Nanoprobe across the Blood-brain Tumor Barrier.

J Nanomed Nanotechnol 2016 Aug 31;7(4). Epub 2016 Aug 31.

Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.

In brain tumors, delivering nanoparticles across the blood-tumor barrier presents major hurdles. A clinically relevant MRI contrast agent, GdDOTA and a near-infrared (NIR) fluorescent dye, DL680 were conjugated to a G5 PAMAM dendrimer, thus producing a dual-mode MRI and NIR imaging agent. Systemic delivery of the subsequent nano-sized agent demonstrated glioma-specific accumulation, probably due to the enhanced permeability and retention effect. MRI detected the agent in glioma tissue, but not in normal contralateral tissue; this observation was validated with and fluorescence imaging. A biodistribution study showed the agent to have accumulated in the glioma tumor and the liver, the latter being the excretion path for a G5 dendrimer-based agent.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042151PMC
http://dx.doi.org/10.4172/2157-7439.1000395DOI Listing
August 2016

Myelin-targeted, texaphyrin-based multimodal imaging agent for magnetic resonance and optical imaging.

Contrast Media Mol Imaging 2016 11 6;11(6):492-505. Epub 2016 Sep 6.

Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, 48202, MI, USA.

Reliable methods of imaging myelin are essential to investigate the causes of demyelination and to study drugs that promote remyelination. Myelin-specific compounds can be developed into imaging probes to detect myelin with various imaging techniques. The development of multimodal myelin-specific imaging probes enables the use of orthogonal imaging techniques to accurately visualize myelin content and validate experimental results. Here, we describe the synthesis and application of multimodal myelin-specific imaging agents for light microscopy and magnetic resonance imaging. The imaging agents were synthesized by incorporating the structural features of luxol fast blue MBS, a myelin-specific histological stain, into texaphyrins coordinated to Gd . These new complexes demonstrated absorption of visible light, emission of near-IR light, and relaxivity values greater than clinically approved contrast agents for magnetic resonance imaging. These properties enable the use of optical imaging and magnetic resonance imaging for visualization of myelin. We performed section- and en block-staining of ex vivo mouse brains to investigate the specificity for myelin of the new compounds. Images obtained from light microscopy and magnetic resonance imaging demonstrate that our complexes are retained in white matter structures and enable detection of myelin. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/cmmi.1711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247309PMC
November 2016

Spectroscopic Characterization of the 3+ and 2+ Oxidation States of Europium in a Macrocyclic Tetraglycinate Complex.

Inorg Chem 2016 Oct 31;55(20):9981-9988. Epub 2016 May 31.

Department of Chemistry, Wayne State University , 5101 Cass Avenue, Detroit, Michigan 48202, United States.

The 3+ and 2+ oxidation states of europium have drastically different magnetic and spectroscopic properties. Electrochemical measurements are often used to probe Eu oxidation state changes, but a full suite of spectroscopic characterization is necessary to demonstrate conversion between these two oxidation states in solution. Here, we report the facile conversion of an europium(III) tetraglycinate complex into its Eu analogue. We present electrochemical, luminescence, electron paramagnetic resonance, UV-visible, and NMR spectroscopic data demonstrating complete reversibility from the reduction and oxidation of the 3+ and 2+ oxidation states, respectively. The Eu-containing analogue has kinetic stability within the range of clinically approved Gd-containing complexes using an acid-catalyzed dissociation experiment. Additionally, we demonstrate that the 3+ and 2+ oxidation states provide redox-responsive behavior through chemical-exchange saturation transfer or proton relaxation, respectively. These results will be applicable to a wide range of redox-responsive contrast agents and Eu-containing complexes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067177PMC
http://dx.doi.org/10.1021/acs.inorgchem.6b00629DOI Listing
October 2016

Dendrimer-Based Responsive MRI Contrast Agents (G1-G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS).

Bioconjug Chem 2015 Dec 5;26(12):2315-23. Epub 2015 Nov 5.

Department of Neurology, Henry Ford Hospital , Detroit, Michigan 48202, United States.

Biosensor imaging of redundant deviation in shifts (BIRDS) is a molecular imaging platform for magnetic resonance that utilizes unique properties of low molecular weight paramagnetic monomers by detecting hyperfine-shifted nonexchangeable protons and transforming the chemical shift information to reflect its microenvironment (e.g., via temperature, pH, etc.). To optimize translational biosensing potential of BIRDS we examined if this detection scheme observed with monomers can be extended onto dendrimers, which are versatile and biocompatible macromolecules with modifiable surface for molecular imaging and drug delivery. Here we report on feasibility of paramagnetic dendrimers for BIRDS. The results show that BIRDS is resilient with paramagnetic dendrimers up to the fourth generation (i.e., G1-G4), where the model dendrimer and chelate were based on poly(amido amine) (PAMAM) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA(4-)) complexed with thulium ion (Tm(3+)). Temperature sensitivities of two prominent signals of Gn-PAMAM-(TmDOTA(-))x (where n = 1-4, x = 6-39) were comparable to that of prominent signals in TmDOTA(-). Transverse relaxation times of the coalesced nonexchangeable protons on Gn-PAMAM-(TmDOTA(-))x were relatively short to provide signal-to-noise ratio that was comparable to or better than that of TmDOTA(-). A fluorescent dye, rhodamine, was conjugated to a G2-PAMAM-(TmDOTA)12 to create a dual-modality nanosized contrast agent. BIRDS properties of the dendrimer were unaltered with rhodamine conjugation. Purposely designed paramagnetic dendrimers for BIRDS in conjunction with novel macromolecular surface modification for functional ligands/drugs could potentially be used for biologically compatible theranostic sensors.
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http://dx.doi.org/10.1021/acs.bioconjchem.5b00568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784965PMC
December 2015

Concentration-independent MRI of pH with a dendrimer-based pH-responsive nanoprobe.

Contrast Media Mol Imaging 2015 Nov-Dec;10(6):481-6. Epub 2015 Jul 14.

Henry Ford Hospital, Detroit, MI, USA.

The measurement of extracellular pH (pHe ) has significant clinical value for pathological diagnoses and for monitoring the effects of pH-altering therapies. One of the major problems of measuring pHe with a relaxation-based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH-unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation-based dendritic MRI contrast agent in a concentration-independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA-4AmP)44 -G5, a G5-PAMAM dendrimer-based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r1 ) increased from 7.91 to 9.65 mM(-1) s(-1) (on a per Gd(3+) basis) on changing pH from 8.84 to 6.35. At 7 T, r1 relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r2 ) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA-4AmP)44 -G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R2 /R1 also showed a linear relationship in a pH-responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA-4AmP)44 -G5 agent. Importantly, the nanoprobe (GdDOTA-4AmP)44 -G5 shows pH response in the range commonly found in the microenvironment of solid tumors.
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http://dx.doi.org/10.1002/cmmi.1651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713357PMC
October 2016

Effect of Curcumin on Pro-angiogenic Factors in the Xenograft Model of Breast Cancer.

Anticancer Agents Med Chem 2015 ;15(10):1285-96

Laboratorio de Investigacao Molecular no Cancer (LIMC), Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), Avenida Brigadeiro Faria Lima, 5416, Vila Sao Pedro, CEP 15090-000, Sao Jose do Rio Preto, SP, Brasil.

The formation of a new blood vessel is stimulated by angiogenic factors. Curcumin, which is the active ingredient of the spice plant Curcuma longa L and is used as food and traditional medicine, has shown anticancer effects against different types of cancers. We evaluated the effects of curcumin on angiogenesis/pro-angiogenic factors in a mouse model of human breast cancer. Cell viability was measured by the MTT assay after curcumin treatment in triple-negative breast cancer cells (MDA-MB-231). For the in vivo study, human breast cancer was induced in athymic mice and treated with 300 mg/kg/day of curcumin administered intraperitoneally. Tumor size was measured weekly, and the animals underwent single photon emission computed tomography (SPECT) scanning with Tc-99m tagged VEGF-c to detect the in vivo expression of VEGFR2/3. In addition, the expression of proangiogenic/ growth factors in the tumor extracts was evaluated by a membrane antibody array. Histological analysis was performed to confirm the effect of curcumin on neovascularization. The MTT assay showed that curcumin significantly reduced the cell viability of MDA-MB-231 cells. In breast cancer xenografts, curcumin treatment led to a decrease in tumor volume and cell proliferation (Ki-67) compared with the vehicle treated group. Tc-99m-HYNIC-VEGF-c-SPECT imaging showed decreased uptake to the tumor, which may indicate a lower expression of VEGFR2/3 in curcumin treated tumors; however, a statistically significant difference was not achieved (p>0.05). Additionally, curcumin treatment showed a significantly low level of expression of pro-angiogenic factors (p<0.05) and a decrease in micro-vessel density (vWF) in animals compared with that of vehicle treated tumors. In conclusion, curcumin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.
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http://dx.doi.org/10.2174/1871520615666150520093644DOI Listing
August 2016

Oxidation-responsive Eu(2+/3+)-liposomal contrast agent for dual-mode magnetic resonance imaging.

Chem Commun (Camb) 2014 Dec;50(94):14835-8

Department of Chemistry, Wayne State University, 5101 Cass Ave., Detroit, MI 48202, USA.

An oxidation-responsive contrast agent for magnetic resonance imaging was synthesized using Eu(2+) and liposomes. Positive contrast enhancement was observed with Eu(2+), and chemical exchange saturation transfer was observed before and after oxidation of Eu(2+). Orthogonal detection modes render the concentration of Eu inconsequential to molecular information provided through imaging.
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http://dx.doi.org/10.1039/c4cc07027eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214894PMC
December 2014

Monitoring adenoviral based gene delivery in rat glioma by molecular imaging.

World J Clin Oncol 2013 Nov;4(4):91-101

Nadimpalli Ravi S Varma, Branislava Janic, Adarsh Shankar, ASM Iskander, Meser M Ali, Ali S Arbab, Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, MI 48202, United States.

Aim: To determine whether endothelial progenitor cells (EPCs) can be used as delivery vehicle for adenoviral vectors and imaging probes for gene therapy in glioblastoma.

Methods: To use cord blood derived EPCs as delivery vehicle for adenoviral vectors and imaging probes for glioma gene therapy, a rat model of human glioma was made by implanting U251 cells orthotopically. EPCs were transfected with an adenovirus (AD5/carrying hNIS gene) and labeled with iron oxide and inoculated them directly into the tumor 14 d following implantation of U251 cells. Magnetic resonance imaging (MRI) was used to in vivo track the migration of EPCs in the tumor. The expression of gene products was determined by in vivo Tc-99m single photon emission computed tomography (SPECT). The findings were validated with immunohistochemistry (IHC).

Results: EPCs were successfully transfected with the adenoviral vectors carrying hNIS which was proved by significantly (P < 0.05) higher uptake of Tc-99m in transfected cells. Viability of EPCs following transfection and iron labeling was not altered. In vivo imaging showed the presence of iron positive cells and the expression of transgene (hNIS) product on MRI and SPECT, respectively, all over the tumors following administration of transfected and iron labeled EPCs in the tumors. IHC confirmed the distribution of EPC around the tumor away from the injection site and also showed transgene expression in the tumor. The results indicated the EPCs' ability to deliver adenoviral vectors into the glioma upon intratumor injection.

Conclusion: EPCs can be used as vehicle to deliver adenoviral vector to glioma and also act as imaging probe at the same time.
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http://dx.doi.org/10.5306/wjco.v4.i4.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053711PMC
November 2013

Lanthanide ion (III) complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate for dual biosensing of pH with chemical exchange saturation transfer (CEST) and biosensor imaging of redundant deviation in shifts (BIRDS).

Contrast Media Mol Imaging 2015 Jan-Feb;10(1):51-8. Epub 2014 May 6.

Department of Diagnostic Radiology, Yale University, New Haven, CT, 06520, USA; Magnetic Resonance Research Center, Yale University, New Haven, CT, 06520, USA.

Relaxivity-based magnetic resonance of phosphonated ligands chelated with gadolinium (Gd(3+)) shows promise for pH imaging. However instead of monitoring the paramagnetic effect of lanthanide complexes on the relaxivity of water protons, biosensor (or molecular) imaging with magnetic resonance is also possible by detecting either the nonexchangeable or the exchangeable protons on the lanthanide complexes themselves. The nonexchangeable protons (e.g. -CHx, where 3 ≥ x ≥ 1) are detected using a three-dimensional chemical shift imaging method called biosensor imaging of redundant deviation in shifts (BIRDS), whereas the exchangeable protons (e.g. -OH or -NHy , where 2 ≥ y ≥ 1) are measured with chemical exchange saturation transfer (CEST) contrast. Here we tested the feasibility of BIRDS and CEST for pH imaging of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate (DOTA-4AmP(8-)) chelated with thulium (Tm(3+) ) and ytterbium (Yb(3+)). BIRDS and CEST experiments show that both complexes are responsive to pH and temperature changes. Higher pH and temperature sensitivities are obtained with BIRDS for either complex when using the chemical shift difference between two proton resonances vs using the chemical shift of a single proton resonance, thereby eliminating the need to use water resonance as reference. While CEST contrast for both agents is linearly dependent on pH within a relatively large range (i.e. 6.3-7.9), much stronger CEST contrast is obtained with YbDOTA-4AmP(5-) than with TmDOTA-4AmP(5-). In addition, we demonstrate the prospect of using BIRDS to calibrate CEST as new platform for quantitative pH imaging.
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http://dx.doi.org/10.1002/cmmi.1604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222994PMC
November 2015

Effects of tyrosine kinase inhibitors and CXCR4 antagonist on tumor growth and angiogenesis in rat glioma model: MRI and protein analysis study.

Transl Oncol 2013 Dec 1;6(6):660-9. Epub 2013 Dec 1.

Cellular and Molecular Imaging Laboratory, Department of Radiology, Henry Ford Hospital, Detroit, MI ; Department of Radiology, Wayne State University School of Medicine, Detroit, MI.

The aim of the study was to determine the antiangiogenic efficacy of vatalanib, sunitinib, and AMD3100 in an animal model of human glioblastoma (GBM) by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and tumor protein expression analysis. Orthotopic GBM-bearing animals were randomly assigned either to control group or vatalanib, sunitinib, and AMD3100 treatment groups. Following 2 weeks of drug treatment, tumor growth and vascular parameters were measured using DCE-MRI. Expression of different angiogenic factors in tumor extracts was measured using a membrane-based human antibody array kit. Tumor angiogenesis and invasion were determined by immunohistochemistry. DCE-MRI showed a significant increase in tumor size after vatalanib treatment. AMD3100-treated group showed a significant decrease in a number of vascular parameters determined by DCE-MRI. AMD3100 significantly decreased the expression of different angiogenic factors compared to sunitinib or vatalanib; however, there were no significant changes in vascular density among the groups. Sunitinib-treated animals showed significantly higher migration of the invasive cells, whereas in both vatalanib- and AMD3100-treated animals the invasive cell migration distance was significantly lower compared to that of control. Vatalanib and sunitinib resulted in suboptimal therapeutic effect, but AMD3100 treatment resulted in a significant reduction in tumor growth, permeability, interstitial space volume, and invasion of tumor cells in an animal model of GBM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890700PMC
http://dx.doi.org/10.1593/tlo.13559DOI Listing
December 2013

Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.

PLoS One 2014 9;9(1):e85311. Epub 2014 Jan 9.

Laboratório de Investigação Molecular no Câncer, Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil ; Department of Molecular Biology, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil.

As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085311PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887041PMC
September 2014

Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo.

Chin J Cancer 2014 Mar 9;33(3):148-58. Epub 2013 Sep 9.

Department of Radiology, Henry Ford Hospital, Detroit, MI 48202, USA.

Tumor cell proliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme (GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77 (baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation (n = 8), or underwent no radiation (n = 8). Brain tissues were obtained on day 112 (nonirradiated) or day 133 (irradiated). Immunohistochemistry was performed to determine tumor cell proliferation (Ki-67) and to assess the expression of infiltration marker (matrix metalloproteinase-2, MMP-2) and cell migration marker (CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor (vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was (71 +/- 15)% compared with (25 +/- 12)% in the nonirradiated group (P = 0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance following radiation therapy for GBM.
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http://dx.doi.org/10.5732/cjc.013.10095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966215PMC
March 2014

Intravenous administration of human umbilical cord blood-derived AC133+ endothelial progenitor cells in rat stroke model reduces infarct volume: magnetic resonance imaging and histological findings.

Stem Cells Transl Med 2013 Sep 9;2(9):703-14. Epub 2013 Aug 9.

Department of Radiology, Henry Ford Hospital, Detroit, MI, USA.

Endothelial progenitor cells (EPCs) hold enormous therapeutic potential for ischemic vascular diseases. Previous studies have indicated that stem/progenitor cells derived from human umbilical cord blood (hUCB) improve functional recovery in stroke models. Here, we examined the effect of hUCB AC133+ EPCs on stroke development and resolution in a middle cerebral artery occlusion (MCAo) rat model. Since the success of cell therapies strongly depends on the ability to monitor in vivo the migration of transplanted cells, we also assessed the capacity of magnetic resonance imaging (MRI) to track in vivo the magnetically labeled cells that were administered. Animals were subjected to transient MCAo and 24 hours later injected intravenously with 10(7) hUCB AC133+ EPCs. MRI performed at days 1, 7, and 14 after the insult showed accumulation of transplanted cells in stroke-affected hemispheres and revealed that stroke volume decreased at a significantly higher rate in cell-treated animals. Immunohistochemistry analysis of brain tissues localized the administered cells in the stroke-affected hemispheres only and indicated that these cells may have significantly affected the magnitude of endogenous proliferation, angiogenesis, and neurogenesis. We conclude that transplanted cells selectively migrated to the ischemic brain parenchyma, where they exerted a therapeutic effect on the extent of tissue damage, regeneration, and time course of stroke resolution.
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http://dx.doi.org/10.5966/sctm.2013-0066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754470PMC
September 2013

Differential biodistribution of intravenously administered endothelial progenitor and cytotoxic T-cells in rat bearing orthotopic human glioma.

BMC Med Imaging 2013 Jun 10;13:17. Epub 2013 Jun 10.

Cellular and Molecular Imaging Laboratory, Radiology, Henry Ford Hospital, Detroit, MI, USA.

Background: A major challenge in the development of cell based therapies for glioma is to deliver optimal number of cells (therapeutic dose) to the tumor. Imaging tools such as magnetic resonance imaging (MRI), optical imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) has been used in cell tracking and/or biodistribution studies. In this study, we evaluate the dynamic biodistribution of systemic injected labeled cells [human cord blood derived endothelial progenitor cells (EPCs) and cytotoxic T-cells (CTLs)] in rat glioma model with in vivo SPECT imaging.

Methods: Human cord blood EPCs, T-cells and CD14⁺ cells (monocytes/dendritic cells) were isolated using the MidiMACS system. CD14⁺ cells were converted to dendritic cells (DC) and also primed with U251 tumor cell line lysate. T-cells were co-cultured with irradiated primed DCs at 10:1 ratio to make CTLs. Both EPCs and CTLs were labeled with In-111-oxine at 37°C in serum free DMEM media. Glioma bearing animals were randomly assigned into three groups. In-111 labeled cells or In-111 oxine alone were injected through tail vein and SPECT imaging was performed on day 0, 1, and 3. In-111 oxine activity in various organs and tumor area was determined. Histochemical analysis was performed to further confirm the migration and homing of injected cells at the tumor site.

Results: EPCs and CTLs showed an In-111 labeling efficiency of 87.06 ± 7.75% and 70.8 ± 12.9% respectively. Initially cell migration was observed in lung following inravenous administration of In-111 labeled cells and decreased on day 1 and 3, which indicate re-distribution of labeled cells from lung to other organs. Relatively higher In-111 oxine activity was observed in tumor areas at 24 hours in animals received In-111 labeled cells (EPCs or CTLs). Histiological analysis revealed iron positive cells in and around the tumor area in animals that received labeled cells (CTLs and EPCs).

Conclusion: We observed differential biodistribution of In-111-oxine labeled EPCs and CTLs in different organs and intracranial glioma. This study indicates In-111 oxine based SPECT imaging is an effective tool to study the biodistribution of therapeutically important cells.
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http://dx.doi.org/10.1186/1471-2342-13-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706264PMC
June 2013

A nano-sized PARACEST-fluorescence imaging contrast agent facilitates and validates in vivo CEST MRI detection of glioma.

Nanomedicine (Lond) 2012 Dec 14;7(12):1827-37. Epub 2012 Aug 14.

Henry Ford Hospital, Detroit, MI 48202, USA.

Aim: The authors have investigated the usefulness of in vivo chemical exchange saturation transfer MRI for detecting gliomas using a dual-modality imaging contrast agent.

Materials & Methods: A paramagnetic chemical exchange saturation transfer MRI contrast agent, Eu-1,4,7,10-tetraazacclododecane-1,4,7,10-tetraacetic acid-Gly(4) and a fluorescent agent, DyLight 680, were conjugated to a generation 5 polyamidoamine dendrimer to create the dual-modality, nano-sized imaging contrast agent.

Results: The agent was detected with in vivo chemical exchange saturation transfer MRI in an U87 glioma model. These results were validated using in vivo and ex vivo fluorescence imaging.

Conclusion: This study demonstrated the merits of using a nano-sized imaging contrast agent for detecting gliomas and using a dual-modality agent for detecting gliomas at different spatial scales.
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http://dx.doi.org/10.2217/nnm.12.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526688PMC
December 2012