Publications by authors named "Edwin Chang"

42 Publications

Tumor treating fields (TTFields) impairs aberrant glycolysis in glioblastoma as evaluated by [F]DASA-23, a non-invasive probe of pyruvate kinase M2 (PKM2) expression.

Neoplasia 2021 01 20;23(1):58-67. Epub 2020 Nov 20.

Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA; Departments of Bioengineering and Materials Science & Engineering, Stanford University, Stanford, CA, USA.

Despite the anti-proliferative and survival benefits from tumor treating fields (TTFields) in human glioblastoma (hGBM), little is known about the effects of this form of alternating electric fields therapy on the aberrant glycolysis of hGBM. [F]FDG is the most common radiotracer in cancer metabolic imaging, but its utility in hGBM is impaired due to high glucose uptake in normal brain tissue. With TTFields, radiochemistry, Western blot, and immunofluorescence microscopy, we identified pyruvate kinase M2 (PKM2) as a biomarker of hGBM response to therapeutic TTFields. We used [F]DASA-23, a novel radiotracer that measures PKM2 expression and which has been shown to be safe in humans, to detect a shift away from hGBM aberrant glycolysis in response to TTFields. Compared to unexposed hGBM, [F]DASA-23 uptake was reduced in hGBM exposed to TTFields (53%, P< 0.05) or temozolomide chemotherapy (33%, P > 0.05) for 3 d. A 6-d TTFields exposure resulted in a 31% reduction (P = 0.043) in 60-min uptake of [F]DASA-23. [F]DASA-23 was retained after a 10 but not 30-min wash-out period. Compared to [F]FDG, [F]DASA-23 demonstrated a 4- to 9-fold greater uptake, implying an improved tumor-to-background ratio. Furthermore, compared to no-TTFields exposure, a 6-d TTFields exposure caused a 35% reduction in [F]DASA-23 30-min uptake compared to only an 8% reduction in [F]FDG 30-min uptake. Quantitative Western blot analysis and qualitative immunofluorescence for PKM2 confirmed the TTFields-induced reduction in PKM2 expression. This is the first study to demonstrate that TTFields impairs hGBM aberrant glycolytic metabolism through reduced PKM2 expression, which can be non-invasively detected by the [F]DASA-23 radiotracer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neo.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689378PMC
January 2021

Molecular Imaging of Infective Endocarditis With 6''-[F]Fluoromaltotriose Positron Emission Tomography-Computed Tomography.

Circulation 2020 May 26;141(21):1729-1731. Epub 2020 May 26.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Bio-X Program (M.W., G.G., E.C., M.N., T.H., M.T.G., J.C.W., S.S.G.), Stanford University School of Medicine, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043924DOI Listing
May 2020

Reconstructed Apoptotic Bodies as Targeted "Nano Decoys" to Treat Intracellular Bacterial Infections within Macrophages and Cancer Cells.

ACS Nano 2020 05 4;14(5):5818-5835. Epub 2020 May 4.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, California 94305, United States.

() is a highly pathogenic facultative anaerobe that in some instances resides as an intracellular bacterium within macrophages and cancer cells. This pathogen can establish secondary infection foci, resulting in recurrent systemic infections that are difficult to treat using systemic antibiotics. Here, we use reconstructed apoptotic bodies (ReApoBds) derived from cancer cells as "nano decoys" to deliver vancomycin intracellularly to kill by targeting inherent "eat me" signaling of ApoBds. We prepared ReApoBds from different cancer cells (SKBR3, MDA-MB-231, HepG2, U87-MG, and LN229) and used them for vancomycin delivery. Physicochemical characterization showed ReApoBds size ranges from 80 to 150 nm and vancomycin encapsulation efficiency of 60 ± 2.56%. We demonstrate that the loaded vancomycin was able to kill intracellular efficiently in an model of infected RAW-264.7 macrophage cells, and U87-MG (p53-wt) and LN229 (p53-mt) cancer cells, compared to free-vancomycin treatment ( < 0.001). The vancomycin loaded ReApoBds treatment in infected macrophages showed a two-log-order higher CFU reduction than the free-vancomycin treatment group. studies revealed that ReApoBds can specifically target macrophages and cancer cells. Vancomycin loaded ReApoBds have the potential to kill intracellular infection in macrophages and cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.0c00921DOI Listing
May 2020

A sensitive LC-MS assay using derivatization with boron trifluoride to quantify curcuminoids in biological samples.

Anal Biochem 2020 05 17;596:113636. Epub 2020 Feb 17.

Pasarow Mass Spectrometry Laboratory, Jane and Terry Semel Institute for Neuroscience and Human Behavior and Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

A procedure is described to measure curcumin (C), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumim (TC) and their glucuronidated metabolites (CG, DMCG, and BDMCG) in plasma, brain, liver and tumor samples. The procedure involves converting the analytes to their boron difluoride derivatives and analyzing them by combined liquid chromatography coupled to an ion trap mass spectrometer operating in the negative ion MS scan mode. The method has superb limits of detection of 0.01 nM for all curcuminoids and 0.5 nM for TC and the glucuroniated metabolites, and several representative chromatograms of biological samples containing these analytes are provided. In addition, the pharmacokinetic profile of these compounds in one human who daily consumed an over-the-counter curcuminoid product shows the peak and changes in circulating concentrations achieved by this mode of administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ab.2020.113636DOI Listing
May 2020

Amyloid protein aggregates: new clients for mitochondrial energy production in the brain?

FEBS J 2020 08 13;287(16):3386-3395. Epub 2020 Feb 13.

Biomaterials and Advanced Drug Delivery Laboratory, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.

Mitochondria are key organelles, which maintain energy metabolism and cellular homeostasis. Mitochondria support transcriptional regulation and proteostatic signaling mechanisms through crosstalk between the mitochondria itself, the nucleus, and the cytoplasm. Mitochondrial dysfunction leads to impaired proteostasis, and both are key pathological features of age-related neurological disorders. For example, Alzheimer's and Parkinson's diseases feature mitochondrial-targeted protein aggregates and impaired mitochondrial function, although the mechanistic causes are poorly understood. Vascular abnormalities and hypometabolism in such neurological diseases are reported several years before key clinical disease symptoms even become apparent. Recent investigations suggest that processing of such aggregates within mitochondria can offer protective functions, specifically by restoring energy (ATP) in starving cells. We hypothesize that the accumulation of protein aggregates in mitochondria can not only disrupt its functions, but also render a protective role to fulfill energy demands in hypometabolic conditions. Growing evidence favors mitochondrial defense to toxic amyloid aggregates/oligomers as a protective response. In this viewpoint article, we will present several publications (in addition to our own) that serve to connect the possible role of protein aggregates in mitochondrial energy production for degenerative conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/febs.15225DOI Listing
August 2020

Intranasal delivery of targeted polyfunctional gold-iron oxide nanoparticles loaded with therapeutic microRNAs for combined theranostic multimodality imaging and presensitization of glioblastoma to temozolomide.

Biomaterials 2019 10 12;218:119342. Epub 2019 Jul 12.

Cellular Pathway Imaging Laboratory (CPIL), Molecular Imaging Program at Stanford, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94305, USA. Electronic address:

The prognosis for glioblastoma (GBM) remains depressingly low. The biological barriers of the brain present a major challenge to achieving adequate drug concentrations for GBM therapy. To address this, we explore the potential of the nose-to-brain direct transport pathway to bypass the blood-brain barrier, and to enable targeted delivery of theranostic polyfunctional gold-iron oxide nanoparticles (polyGIONs) surface loaded with therapeutic miRNAs (miR-100 and antimiR-21) to GBMs in mice. These nanoformulations would thus allow presensitization of GBM cells to the systemically delivered chemotherapy drug temozolomide (TMZ), as well as in vivo multimodality molecular and anatomic imaging of nanoparticle delivery, trafficking, and treatment effects. First, we synthesized GIONs coated with β-cyclodextrin-chitosan (CD-CS) hybrid polymer, and co-loaded with miR-100 and antimiR-21. Then we decorated their surface with PEG-T7 peptide using CD-adamantane host-guest chemistry. The resultant polyGIONs showed efficient miRNA loading with enhanced serum stability. We characterized them for particle size, PDI, polymer functionalization, charge and release using dynamic light scattering analysis, TEM and qRT-PCR. For in vivo intranasal delivery, we used U87-MG GBM cell-derived orthotopic xenograft models in mice. Intranasal delivery resulted in efficient accumulation of Cy5-miRNAs in mice treated with T7-targeted polyGIONs, as demonstrated by in vivo optical fluorescence and MR imaging. We measured the therapeutic response of these FLUC-EGFP labelled U87-MG GBMs using bioluminescence imaging. Overall, there was a significant increase in survival of mice co-treated with T7-polyGIONs loaded with miR-100/antimiR-21 plus systemic TMZ, compared to the untreated control group, or the animals receiving non-targeted polyGIONs-miR-100/antimiR-21, or TMZ alone. Once translated clinically, this novel theranostic nanoformulation and its associated intranasal delivery strategy will have a strong potential to potentiate the effects of TMZ treatment in GBM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2019.119342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663564PMC
October 2019

Management of Thoracic and Lumbar Spine Fractures: Is MRI Necessary in Patients without Neurological Deficits?

Am Surg 2019 Mar;85(3):306-311

MRI after a CT scan for thoracolumbar spine (TLS) trauma has become commonplace because of the concerns for detection of posterior ligamentous complex injuries in the absence of substantial scientific evidence to support its use. We hypothesized that MRI scans were not necessary in the clinical management of TLS fractures. A prospective study was conducted at our Level I trauma center. A total of 39 neurologically intact patients with TLS fracture on CT were enrolled. The patients' CT scan and neurological examination were reviewed by a senior neurosurgeon, who determined clinical management based on these data. Assessment was repeated after an MRI of the spine was performed, and a second clinical plan was devised. The two treatment schemes were then compared. MRI resulted in a change in clinical management in 15 per cent of patients. Ten per cent of patients changed from requiring a brace to no brace and merely observation alone. In no patient planned for nonoperative care was surgery deemed necessary after completion of MRI. Among five patients with initial plans for operative intervention, two avoided surgery after the MRI. MRI has little impact on the management of patients with CT-proven thoracic and lumbar spine fractures. Only when surgery is planned based on CT studies does an MRI seem to assist with determining optimal care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/000313481908500338DOI Listing
March 2019

Tumor treating fields increases membrane permeability in glioblastoma cells.

Cell Death Discov 2018 5;4:113. Epub 2018 Dec 5.

1Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Room E150, 318 Campus Drive West, Stanford, CA 94305 USA.

Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41420-018-0130-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281619PMC
December 2018

A blood biomarker for monitoring response to anti-EGFR therapy.

Cancer Biomark 2018 ;22(2):333-344

Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.

Background And Objective: To monitor therapies targeted to epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC), we investigated Peroxiredoxin 6 (PRDX6) as a biomarker of response to anti-EGFR agents.

Methods: We studied cells that are sensitive (H3255, HCC827) or resistant (H1975, H460) to gefitinib. PRDX6 was examined with either gefitinib or vehicle treatment using enzyme-linked immunosorbent assays. We created xenograft models from one sensitive (HCC827) and one resistant cell line (H1975) and monitored serum PRDX6 levels during treatment.

Results: PRDX6 levels in cell media from sensitive cell lines increased significantly after gefitinib treatment vs. vehicle, whereas there was no significant difference for resistant lines. PRDX6 accumulation over time correlated positively with gefitinib sensitivity. Serum PRDX6 levels in gefitinib-sensitive xenograft models increased markedly during the first 24 hours of treatment and then decreased dramatically during the following 48 hours. Differences in serum PRDX6 levels between vehicle and gefitinib-treated animals could not be explained by differences in tumor burden.

Conclusions: Our results show that changes in serum PRDX6 during the course of gefitinib treatment of xenograft models provide insight into tumor response and such an approach offers several advantages over imaging-based strategies for monitoring response to anti-EGFR agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/CBM-171149DOI Listing
October 2018

The Exosome Total Isolation Chip.

ACS Nano 2017 11 1;11(11):10712-10723. Epub 2017 Nov 1.

Stanford PULSE Institute, SLAC National Accelerator Lab, Menlo Park, California 94025, United States.

Circulating tumor-derived extracellular vesicles (EVs) have emerged as a promising source for identifying cancer biomarkers for early cancer detection. However, the clinical utility of EVs has thus far been limited by the fact that most EV isolation methods are tedious, nonstandardized, and require bulky instrumentation such as ultracentrifugation (UC). Here, we report a size-based EV isolation tool called ExoTIC (exosome total isolation chip), which is simple, easy-to-use, modular, and facilitates high-yield and high-purity EV isolation from biofluids. ExoTIC achieves an EV yield ∼4-1000-fold higher than that with UC, and EV-derived protein and microRNA levels are well-correlated between the two methods. Moreover, we demonstrate that ExoTIC is a modular platform that can sort a heterogeneous population of cancer cell line EVs based on size. Further, we utilize ExoTIC to isolate EVs from cancer patient clinical samples, including plasma, urine, and lavage, demonstrating the device's broad applicability to cancers and other diseases. Finally, the ability of ExoTIC to efficiently isolate EVs from small sample volumes opens up avenues for preclinical studies in small animal tumor models and for point-of-care EV-based clinical testing from fingerprick quantities (10-100 μL) of blood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.7b04878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983373PMC
November 2017

Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields.

J Neurooncol 2017 Sep 5;134(2):259-268. Epub 2017 Jul 5.

Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, CA, USA.

Glioblastoma (GBM) is the most aggressive and lethal form of brain cancer. Standard therapies are non-specific and often of limited effectiveness; thus, efforts are underway to uncover novel, unorthodox therapies against GBM. In previous studies, we investigated Withaferin A, a steroidal lactone from Ayurvedic medicine that inhibits proliferation in cancers including GBM. Another novel approach, tumor treating fields (TTFields), is thought to disrupt mitotic spindle formation and stymie proliferation of actively dividing cells. We hypothesized that combining TTFields with Withaferin A would synergistically inhibit proliferation in glioblastoma. Human glioblastoma cells (GBM2, GBM39, U87-MG) and human breast adenocarcinoma cells (MDA-MB-231) were isolated from primary tumors. The glioma cell lines were genetically engineered to express firefly luciferase. Proliferative potential was assessed either by bioluminescence imaging or cell counting via hemocytometer. TTFields (4 V/cm) significantly inhibited growth of the four cancer cell lines tested (n = 3 experiments per time point, four measurements per sample, p < 0.02 at least; 2-way ANOVA, control vs. treatment). The combination of Withaferin A (10-100 nM) with TTFields significantly inhibited the growth of the glioma cells to a degree beyond that of Withaferin A or TTFields alone. The interaction of the Withaferin A and TTFields on glioma cells was found to be synergistic in nature (p < 0.01, n = 3 experiments). These findings were validated by both bioluminescence and hemocytometric measurements. The combination of Withaferin A with TTFields represents a novel approach to treat GBM in a manner that is likely better than either treatment alone and that is synergistic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-017-2534-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711586PMC
September 2017

A Novel Theranostic Strategy for -Expressing Glioblastomas Impacts Survival.

Mol Cancer Ther 2017 09 28;16(9):1909-1921. Epub 2017 Jun 28.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California.

Glioblastoma (GBM) has a dismal prognosis. Evidence from preclinical tumor models and human trials indicates the role of GBM-initiating cells (GIC) in GBM drug resistance. Here, we propose a new treatment option with tumor enzyme-activatable, combined therapeutic and diagnostic (theranostic) nanoparticles, which caused specific toxicity against GBM tumor cells and GICs. The theranostic cross-linked iron oxide nanoparticles (CLIO) were conjugated to a highly potent vascular disrupting agent (ICT) and secured with a matrix-metalloproteinase (MMP-14) cleavable peptide. Treatment with CLIO-ICT disrupted tumor vasculature of -expressing GBM, induced GIC apoptosis, and significantly impaired tumor growth. In addition, the iron core of CLIO-ICT enabled drug tracking with MR imaging. Treatment with CLIO-ICT plus temozolomide achieved tumor remission and significantly increased survival of human GBM-bearing mice by more than 2-fold compared with treatment with temozolomide alone. Thus, we present a novel therapeutic strategy with significant impact on survival and great potential for clinical translation. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-17-0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587386PMC
September 2017

Withaferin A and its potential role in glioblastoma (GBM).

J Neurooncol 2017 01 11;131(2):201-211. Epub 2016 Nov 11.

Department of Radiology, Molecular Imaging Program at Stanford and Canary Center at Stanford for Early Cancer Detection, Stanford University, Palo Alto, CA, USA.

Within the Ayurvedic medical tradition of India, Ashwagandha (Withania somnifera) is a well-known herb. A large number of withanolides have been isolated from both its roots and its leaves and many have been assessed for their pharmacological activities. Amongst them, Withaferin A is one of its most bioactive phytoconstituents. Due to the lactonal steroid's potential to modulate multiple oncogenic pathways, Withaferin A has gained much attention as a possible anti-neoplastic agent. This review focuses on the use of Withaferin A alone, or in combination with other treatments, as a newer option for therapy against the most aggressive variant of brain tumors, Glioblastoma. We survey the various studies that delineate Withaferin A's anticancer mechanisms, its toxicity profiles, its pharmacokinetics and pharmacodynamics and its immuno-modulating properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-016-2303-xDOI Listing
January 2017

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models.

J Neurooncol 2016 Jan 9;126(2):253-64. Epub 2015 Dec 9.

Departments of Radiology and Bioengineering, Stanford University, Palo Alto, CA, USA.

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O'Neill (J Neurooncol 107: 359-364, 2012). An extract from the winter cherry plant (Withania somnifera ), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985-1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3-5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 µM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 µM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-015-1972-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597337PMC
January 2016

Cone-beam Computed Tomography for Detecting Vertical Root Fractures in Endodontically Treated Teeth: A Systematic Review.

J Endod 2016 Feb 26;42(2):177-85. Epub 2015 Nov 26.

Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Discipline of Dental Public Health, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; Discipline of Endodontics, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Introduction: A vertical root fracture (VRF), commonly found in teeth with endodontic treatment, is challenging to diagnose and has poor treatment outcomes. Cone-beam computed tomography (CBCT) has become an increasingly popular imaging modality in endodontics, but image artifacts arising from root-filling materials may hinder VRF detection. The aim of this investigation was to conduct a systematic review to assess the diagnostic ability of CBCT for detecting VRFs in endodontically treated teeth.

Methods: A systematic review of in vivo clinical diagnostic literature (initial search December 2014, updated August 2015) was conducted. Assessment of methodological quality was performed by using the modified Quality Assessment of Diagnostic Accuracy Studies tool.

Results: Four studies with a total of 130 patients were included. The reported ranges of values were 40%-90% for VRF prevalence, 84% (0.64-0.95) to 100% (0.83-1.00) for sensitivity, 64% (0.35-0.87) to 100% (0.03-1.00) for specificity, 71% (0.51-0.87) to 100% (0.63-1.00) for positive predictive value, and 50% (0.01-0.99) to 100% (0.84-1.00) for negative predictive value. All 4 studies revealed multiple items at high risk or unclear risk of bias.

Conclusions: Because of the significant imprecision in the range of reported estimates and the biases observed in the included studies, there is currently insufficient evidence to suggest that CBCT is a reliable test in detecting VRFs in endodontically treated teeth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.joen.2015.10.005DOI Listing
February 2016

PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2.

Sci Transl Med 2015 Oct;7(310):310ra169

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 943065, USA. Departments of Bioengineering and Materials Science & Engineering, Bio-X, Stanford University, Stanford, CA 943065, USA.

Cancer cells reprogram their metabolism to meet increased biosynthetic demands, commensurate with elevated rates of replication. Pyruvate kinase M2 (PKM2) catalyzes the final and rate-limiting step in tumor glycolysis, controlling the balance between energy production and the synthesis of metabolic precursors. We report here the synthesis and evaluation of a positron emission tomography (PET) radiotracer, [(11)C]DASA-23, that provides a direct noninvasive measure of PKM2 expression in preclinical models of glioblastoma multiforme (GBM). In vivo, orthotopic U87 and GBM39 patient-derived tumors were clearly delineated from the surrounding normal brain tissue by PET imaging, corresponding to exclusive tumor-associated PKM2 expression. In addition, systemic treatment of mice with the PKM2 activator TEPP-46 resulted in complete abrogation of the PET signal in intracranial GBM39 tumors. Together, these data provide the basis for the clinical evaluation of imaging agents that target this important gatekeeper of tumor glycolysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aac6117DOI Listing
October 2015

A Magnetic Bead-Based Sensor for the Quantification of Multiple Prostate Cancer Biomarkers.

PLoS One 2015 30;10(9):e0139484. Epub 2015 Sep 30.

Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, United States of America; Bioengineering, Materials Science & Engineering, Bio-X, Stanford University, Stanford, California, United States of America.

Novel biomarker assays and upgraded analytical tools are urgently needed to accurately discriminate benign prostatic hypertrophy (BPH) from prostate cancer (CaP). To address this unmet clinical need, we report a piezeoelectric/magnetic bead-based assay to quantitate prostate specific antigen (PSA; free and total), prostatic acid phosphatase, carbonic anhydrase 1 (CA1), osteonectin, IL-6 soluble receptor (IL-6sr), and spondin-2. We used the sensor to measure these seven proteins in serum samples from 120 benign prostate hypertrophy patients and 100 Gleason score 6 and 7 CaP using serum samples previously collected and banked. The results were analyzed with receiver operator characteristic curve analysis. There were significant differences between BPH and CaP patients in the PSA, CA1, and spondin-2 assays. The highest AUC discrimination was achieved with a spondin-2 OR free/total PSA operation--the area under the curve was 0.84 with a p value below 10(-6). Some of these data seem to contradict previous reports and highlight the importance of sample selection and proper assay building in the development of biomarker measurement schemes. This bead-based system offers important advantages in assay building including low cost, high throughput, and rapid identification of an optimal matched antibody pair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139484PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589536PMC
March 2016

Exercise induces stromal cell-derived factor-1α-mediated release of endothelial progenitor cells with increased vasculogenic function.

Plast Reconstr Surg 2015 Feb;135(2):340e-350e

Stanford, Calif. From the Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine.

Background: Endothelial progenitor cells have been shown to traffic to and incorporate into ischemic tissues, where they participate in new blood vessel formation, a process termed vasculogenesis. Previous investigation has demonstrated that endothelial progenitor cells appear to mobilize from bone marrow to the peripheral circulation after exercise. In this study, the authors investigate potential etiologic factors driving this mobilization and investigate whether the mobilized endothelial progenitor cells are the same as those present at baseline.

Methods: Healthy volunteers (n = 5) performed a monitored 30-minute run to maintain a heart rate greater than 140 beats/min. Venous blood samples were collected before, 10 minutes after, and 24 hours after exercise. Endothelial progenitor cells were isolated and evaluated.

Results: Plasma levels of stromal cell-derived factor-1α significantly increased nearly two-fold immediately after exercise, with a nearly four-fold increase in circulating endothelial progenitor cells 24 hours later. The endothelial progenitor cells isolated following exercise demonstrated increased colony formation, proliferation, differentiation, and secretion of angiogenic cytokines. Postexercise endothelial progenitor cells also exhibited a more robust response to hypoxic stimulation.

Conclusions: Exercise appears to mobilize endothelial progenitor cells and augment their function by means of stromal cell-derived factor 1α-dependent signaling. The population of endothelial progenitor cells mobilized following exercise is primed for vasculogenesis with increased capacity for proliferation, differentiation, secretion of cytokines, and responsiveness to hypoxia. Given the evidence demonstrating positive regenerative effects of exercise, this may be one possible mechanism for its benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PRS.0000000000000917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311572PMC
February 2015

18F-FAZA PET imaging response tracks the reoxygenation of tumors in mice upon treatment with the mitochondrial complex I inhibitor BAY 87-2243.

Clin Cancer Res 2015 Jan 7;21(2):335-46. Epub 2014 Nov 7.

Department of Radiology, Molecular Imaging Program at Stanford, Canary Center for Early Cancer Detection, Stanford University, Palo Alto, California.

Purpose: We describe a noninvasive PET imaging method that monitors early therapeutic efficacy of BAY 87-2243, a novel small-molecule inhibitor of mitochondrial complex I as a function of hypoxia-inducible factor-1α (HIF1α) activity.

Experimental Design: Four PET tracers [(18)F-FDG, (18)F-Fpp(RGD)2, (18)F-FLT, and (18)F-FAZA] were assessed for uptake into tumor xenografts of drug-responsive (H460, PC3) or drug-resistant (786-0) carcinoma cells. Mice were treated with BAY 87-2243 or vehicle. At each point, RNA from treated and vehicle H460 tumor xenografts (n = 3 each) was isolated and analyzed for target genes.

Results: Significant changes in uptake of (18)F-FAZA, (18)F-FLT, and (18)F-Fpp(RGD)2 (P < 0.01) occurred with BAY 87-2243 treatment with (18)F-FAZA being the most prominent. (18)F-FDG uptake was unaffected. (18)F-FAZA tumor uptake declined by 55% to 70% (1.21% ± 0.10%ID/g to 0.35 ± 0.1%ID/g; n = 6, vehicle vs. treatment) in both H460 (P < 0.001) and PC3 (P < 0.05) xenografts 1 to 3 days after drug administration. (18)F-FAZA uptake in 786-0 xenografts was unaffected. Decline occurred before significant differences in tumor volume, thus suggesting (18)F-FAZA decrease reflected early changes in tumor metabolism. BAY 87-2243 reduced expression of hypoxia-regulated genes CA IX, ANGPTL4, and EGLN-3 by 99%, 93%, and 83%, respectively (P < 0.001 for all), which corresponds with reduced (18)F-FAZA uptake upon drug treatment. Heterogeneous expression of genes associated with glucose metabolism, vessel density, and proliferation was observed.

Conclusions: Our studies suggest suitability of (18)F-FAZA-PET as an early pharmacodynamic monitor on the efficacy of anticancer agents that target the mitochondrial complex I and intratumor oxygen levels (e.g., BAY 87-2243).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-14-0217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297600PMC
January 2015

A fracture-resistant high-entropy alloy for cryogenic applications.

Science 2014 Sep;345(6201):1153-8

Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Department of Materials Science and Engineering, University of California, Berkeley, CA 94720, USA.

High-entropy alloys are equiatomic, multi-element systems that can crystallize as a single phase, despite containing multiple elements with different crystal structures. A rationale for this is that the configurational entropy contribution to the total free energy in alloys with five or more major elements may stabilize the solid-solution state relative to multiphase microstructures. We examined a five-element high-entropy alloy, CrMnFeCoNi, which forms a single-phase face-centered cubic solid solution, and found it to have exceptional damage tolerance with tensile strengths above 1 GPa and fracture toughness values exceeding 200 MPa·m(1/2). Furthermore, its mechanical properties actually improve at cryogenic temperatures; we attribute this to a transition from planar-slip dislocation activity at room temperature to deformation by mechanical nanotwinning with decreasing temperature, which results in continuous steady strain hardening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1254581DOI Listing
September 2014

Protective role of Arapaima gigas fish scales: structure and mechanical behavior.

Acta Biomater 2014 Aug 9;10(8):3599-614. Epub 2014 May 9.

Materials Science & Engineering Program, University of California, San Diego, La Jolla, CA 92093, USA; Department of Mechanical & Aerospace Engineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The scales of the arapaima (Arapaima gigas), one of the largest freshwater fish in the world, can serve as inspiration for the design of flexible dermal armor. Each scale is composed of two layers: a laminate composite of parallel collagen fibrils and a hard, highly mineralized surface layer. We review the structure of the arapaima scales and examine the functions of the different layers, focusing on the mechanical behavior, including tension and penetration of the scales, with and without the highly mineralized outer layer. We show that the fracture of the mineral and the stretching, rotation and delamination of collagen fibrils dissipate a significant amount of energy prior to catastrophic failure, providing high toughness and resistance to penetration by predator teeth. We show that the arapaima's scale has evolved to minimize damage from penetration by predator teeth through a Bouligand-like arrangement of successive layers, each consisting of parallel collagen fibrils with different orientations. This inhibits crack propagation and restricts damage to an area adjoining the penetration. The flexibility of the lamellae is instrumental to the redistribution of the compressive stresses in the underlying tissue, decreasing the severity of the concentrated load produced by the action of a tooth. The experimental results, combined with small-angle X-ray scattering characterization and molecular dynamics simulations, provide a complete picture of the mechanisms of deformation, delamination and rotation of the lamellae during tensile extension of the scale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2014.04.009DOI Listing
August 2014

ROS and brain diseases: the good, the bad, and the ugly.

Oxid Med Cell Longev 2013 5;2013:963520. Epub 2013 Dec 5.

Department of Psychiatry, Rostock University Medical School, Gehlsheimer Straße 20, 18147 Rostock, Germany ; Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy, 200349 Craiova, Romania.

The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms. This paper reviews the Janus-faced properties of reactive oxygen species. It will describe the positive aspects of moderately induced ROS but it will also outline recent research findings concerning the impact of oxidative and nitrooxidative stress on neuronal structure and function in neuropsychiatric diseases, including major depression. A common denominator of all neuropsychiatric diseases including schizophrenia and ADHD is an increased inflammatory response of the brain caused either by an exposure to proinflammatory agents during development or an accumulation of degenerated neurons, oxidized proteins, glycated products, or lipid peroxidation in the adult brain. Therefore, modulation of the prooxidant-antioxidant balance provides a therapeutic option which can be used to improve neuroprotection in response to oxidative stress. We also discuss the neuroprotective role of the nuclear factor erythroid 2-related factor (Nrf2) in the aged brain in response to oxidative stressors and nanoparticle-mediated delivery of ROS-scavenging drugs. The antioxidant therapy is a novel therapeutic strategy. However, the available drugs have pleiotropic actions and are not fully characterized in the clinic. Additional clinical trials are needed to assess the risks and benefits of antioxidant therapies for neuropsychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2013/963520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871919PMC
July 2014

Integrin-targeted molecular imaging of experimental abdominal aortic aneurysms by (18)F-labeled Arg-Gly-Asp positron-emission tomography.

Circ Cardiovasc Imaging 2013 Nov 30;6(6):950-6. Epub 2013 Aug 30.

Division of Cardiovascular Medicine.

Background: Both inflammation and neoangiogenesis contribute to abdominal aortic aneurysm (AAA) disease. Arg-Gly-Asp-based molecular imaging has been shown to detect the integrin αvβ3. We studied a clinical dimeric (18)F-labeled Arg-Gly-Asp positron-emission tomography (PET) agent ((18)F-FPPRGD2) for molecular imaging of experimental AAAs.

Methods And Results: Murine AAAs were induced in Apo-E-deficient mice by angiotensin II infusion, with monitoring of aortic diameter on ultrasound. AAA (n=10) and saline-infused control mice (n=7) were injected intravenously with (18)F-FPPRGD2, as well as an intravascular computed tomography contrast agent, then scanned using a small-animal PET/computed tomography scanner. Aortic uptake of (18)F-FPPRGD2 was quantified by percentage-injected dose per gram and target-to-

Background: =0.003; median target-to-

Background: =0.0008). Ex vivo autoradiography demonstrated high uptake of (18)F-FPPRGD2 into the AAA wall, with immunohistochemistry showing substantial cluster of differentiation (CD)-11b(+) macrophages and CD-31(+) neovessels. Target-to-

Background: =-0.29, P=0.41) but did strongly correlate with both mural macrophage density (r=0.79, P=0.007) and neovessel counts (r=0.87, P=0.001) on immunohistochemistry.

Conclusions: PET imaging of experimental AAAs using (18)F-FPPRGD2 detects biologically active disease, correlating to the degree of vascular inflammation and neoangiogenesis. This may provide a clinically translatable molecular imaging approach to characterize AAA biology to predict risk beyond size alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCIMAGING.113.000234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909706PMC
November 2013

Cerenkov Luminescence Imaging (CLI) for cancer therapy monitoring.

J Vis Exp 2012 Nov 13(69):e4341. Epub 2012 Nov 13.

Department of Radiology and Bio-X Program Canary Cancer at Stanford for Cancer Early Detection, Stanford University, USA.

In molecular imaging, positron emission tomography (PET) and optical imaging (OI) are two of the most important and thus most widely used modalities. PET is characterized by its excellent sensitivity and quantification ability while OI is notable for non-radiation, relative low cost, short scanning time, high throughput, and wide availability to basic researchers. However, both modalities have their shortcomings as well. PET suffers from poor spatial resolution and high cost, while OI is mostly limited to preclinical applications because of its limited tissue penetration along with prominent scattering optical signals through the thickness of living tissues. Recently a bridge between PET and OI has emerged with the discovery of Cerenkov Luminescence Imaging (CLI). CLI is a new imaging modality that harnesses Cerenkov Radiation (CR) to image radionuclides with OI instruments. Russian Nobel laureate Alekseyevich Cerenkov and his colleagues originally discovered CR in 1934. It is a form of electromagnetic radiation emitted when a charged particle travels at a superluminal speed in a dielectric medium. The charged particle, whether positron or electron, perturbs the electromagnetic field of the medium by displacing the electrons in its atoms. After passing of the disruption photons are emitted as the displaced electrons return to the ground state. For instance, one (18)F decay was estimated to produce an average of 3 photons in water. Since its emergence, CLI has been investigated for its use in a variety of preclinical applications including in vivo tumor imaging, reporter gene imaging, radiotracer development, multimodality imaging, among others. The most important reason why CLI has enjoyed much success so far is that this new technology takes advantage of the low cost and wide availability of OI to image radionuclides, which used to be imaged only by more expensive and less available nuclear imaging modalities such as PET. Here, we present the method of using CLI to monitor cancer drug therapy. Our group has recently investigated this new application and validated its feasibility by a proof-of-concept study. We demonstrated that CLI and PET exhibited excellent correlations across different tumor xenografts and imaging probes. This is consistent with the overarching principle of CR that CLI essentially visualizes the same radionuclides as PET. We selected Bevacizumab (Avastin; Genentech/Roche) as our therapeutic agent because it is a well-known angiogenesis inhibitor. Maturation of this technology in the near future can be envisioned to have a significant impact on preclinical drug development, screening, as well as therapy monitoring of patients receiving treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/4341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916946PMC
November 2012

Proof-of-concept study of monitoring cancer drug therapy with cerenkov luminescence imaging.

J Nucl Med 2012 Feb 12;53(2):312-317. Epub 2012 Jan 12.

Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, California.

Unlabelled: Cerenkov luminescence imaging (CLI) has emerged as a less expensive, easier-to-use, and higher-throughput alternative to other nuclear imaging modalities such as PET. It is expected that CLI will find many applications in biomedical research such as cancer detection, probe development, drug screening, and therapy monitoring. In this study, we explored the possibility of using CLI to monitor drug efficacy by comparisons against PET. To assess the performance of both modalities in therapy monitoring, 2 murine tumor models (large cell lung cancer cell line H460 and prostate cancer cell line PC3) were given bevacizumab versus vehicle treatments. Two common radiotracers, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and (18)F-FDG, were used to monitor bevacizumab treatment efficacy.

Methods: One group of mice (n = 6) was implanted with H460 xenografts bilaterally in the shoulder region, divided into treatment and control groups (n = 3 each), injected with (18)F-FLT, and imaged with PET immediately followed by CLI. The other group of mice (n = 6) was implanted with PC3 xenografts in the same locations, divided into treatment and control groups (n = 3 each), injected with (18)F-FDG, and imaged by the same modalities. Bevacizumab treatment was performed by 2 injections of 20 mg/kg at days 0 and 2.

Results: On (18)F-FLT scans, both CLI and PET revealed significantly decreased signals from H460 xenografts in treated mice from pretreatment to day 3. Moderately increased to unchanged signals were observed in untreated mice. On (18)F-FDG scans, both CLI and PET showed relatively unchanged signals from PC3 tumors in both treated and control groups. Quantifications of tumor signals of Cerenkov luminescence and PET images showed that the 2 modalities had excellent correlations (R(2) > 0.88 across all study groups).

Conclusion: CLI and PET exhibit excellent correlations across different tumor xenografts and radiotracers. This is the first study, to our knowledge, demonstrating the use of CLI for monitoring cancer treatment. The findings warrant further exploration and optimization of CLI as an alternative to PET in preclinical therapeutic monitoring and drug screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.111.094623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143153PMC
February 2012

Diffuse Idiopathic Skeletal Hyperostosis (DISH)-A Rare Etiology of Dysphagia.

Clin Med Insights Arthritis Musculoskelet Disord 2011 20;4:71-5. Epub 2011 Sep 20.

Staten Island University Hospital, Staten Island, NY, USA.

A 72-year-old gentleman presented to the hospital with progressively worsening dysphagia to soft foods and liquids. He was diagnosed with severe pharyngeal dysphagia by modified barium swallow. A CT scan of the neck with IV contrast showed anterior flowing of bridging osteophytes from C3-C6, indicative of DISH, resulting in esophageal impingement. He underwent resection of the DISH segments. Following the surgery, a PEG tube for nutrition supplementation was placed. However, the PEG tube was removed after five months when the speech and swallow evaluation showed no residual dysphagia. DISH is a rare non-inflammatory condition that results in pathological ossification and calcification of the anterolateral spinal ligaments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4137/CMAMD.S6949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201108PMC
November 2011

Adipose tissue-derived stem cells display a proangiogenic phenotype on 3D scaffolds.

J Biomed Mater Res A 2011 Sep 31;98(3):383-93. Epub 2011 May 31.

Department of Cardiothoracic Surgery, Stanford University School of Medicine, California, USA.

Ischemic heart disease is the leading cause of death worldwide. Recent studies suggest that adipose tissue-derived stem cells (ASCs) can be used as a potential source for cardiovascular tissue engineering due to their ability to differentiate along the cardiovascular lineage and to adopt a proangiogenic phenotype. To understand better ASCs' biology, we used a novel 3D culture device. ASCs' and b.END-3 endothelial cell proliferation, migration, and vessel morphogenesis were significantly enhanced compared to 2D culturing techniques. ASCs were isolated from inguinal fat pads of 6-week-old GFP+/BLI+ mice. Early passage ASCs cells (P3-P4), PKH26-labeled murine b.END-3 cells or a co-culture of ASCs and b.END-3 cells were seeded at a density of 1 × 10(5) on three different surface configurations: (a) a 2D surface of tissue culture plastic, (b) Matrigel, and (c) a highly porous 3D scaffold fabricated from inert polystyrene. VEGF expression, cell proliferation, and tubulization, were assessed using optical microscopy, fluorescence microscopy, 3D confocal microscopy, and SEM imaging (n = 6). Increased VEGF levels were seen in conditioned media harvested from co-cultures of ASCs and b.END-3 on either Matrigel or a 3D matrix. Fluorescence, confocal, SEM, bioluminescence revealed improved cell, proliferation, and tubule formation for cells seeded on the 3D polystyrene matrix. Collectively, these data demonstrate that co-culturing ASCs with endothelial cells in a 3D matrix environment enable us to generate prevascularized tissue-engineered constructs. This can potentially help us to surpass the tissue thickness limitations faced by the tissue engineering community today.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbm.a.33113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161132PMC
September 2011

Pilot pharmacokinetic and dosimetric studies of (18)F-FPPRGD2: a PET radiopharmaceutical agent for imaging α(v)β(3) integrin levels.

Radiology 2011 Jul 18;260(1):182-91. Epub 2011 Apr 18.

Molecular Imaging Program, Department of Radiology, Division of Nuclear Medicine, Stanford Hospital and Clinics, 300 Pasteur Dr, Room H2200, Stanford, CA 94305-5281, USA.

Purpose: To assess the safety, biodistribution, and dosimetric properties of the positron emission tomography (PET) radiopharmaceutical agent fluorine 18 ((18)F) FPPRGD2 (2-fluoropropionyl labeled PEGylated dimeric RGD peptide [PEG3-E{c(RGDyk)}2]), which is based on the dimeric arginine-glycine-aspartic acid (RGD) peptide sequence and targets α(v)β(3) integrin, in the first volunteers imaged with this tracer.

Materials And Methods: The protocol was approved by the institutional review board, and written informed consent was obtained from all participants. Five healthy volunteers underwent whole-body combined PET-computed tomography 0.5, 1.0, 2.0, and 3.0 hours after tracer injection (mean dose, 9.5 mCi ± 3.4 [standard deviation] [351.5 MBq ± 125.8]; mean specific radioactivity, 1200 mCi/mmol ± 714 [44.4 GBq/mmol ± 26.4]). During this time, standard vital signs, electrocardiographic (ECG) readings, and blood sample values (for chemistry, hematologic, and liver function tests) were checked at regular intervals and 1 and 7 days after the injection. These data were used to evaluate tracer biodistribution and dosimetric properties, time-activity curves, and the stability of laboratory values. Significant changes in vital signs and laboratory values were evaluated by using a combination of population-averaged generalized estimating equation regression and exact paired Wilcoxon tests.

Results: The administration of (18)F-FPPRGD2 was well tolerated, with no marked effects on vital signs, ECG readings, or laboratory values. The tracer showed the same pattern of biodistribution in all volunteers: primary clearance through the kidneys (0.360 rem/mCi ± 0.185 [0.098 mSv/MBq ± 0.050]) and bladder (0.862 rem/mCi ± 0.436 [0.233 mSv/MBq ± 0.118], voiding model) and uptake in the spleen (0.250 rem/mCi ± 0.168 [0.068 mSv/MBq ± 0.046]) and large intestine (0.529 rem/mCi ± 0.236 [0.143 mSv/MBq ± 0.064]). The mean effective dose of (18)F-FPPRGD2 was 0.1462 rem/mCi ± 0.0669 (0.0396 mSv/MBq ± 0.0181). With an injected dose of 10 mCi (370 MBq) and a 1-hour voiding interval, a patient would be exposed to an effective radiation dose of 1.5 rem (15 mSv). Above the diaphragm, there was minimal uptake in the brain ventricles, salivary glands, and thyroid gland. Time-activity curves showed rapid clearance from the vasculature, with a mean 26% ± 17 of the tracer remaining in the circulation at 30 minutes and most of the activity occurring in the plasma relative to cells (mean whole blood-plasma ratio, 0.799 ± 0.096).

Conclusion: (18)F-FPPRGD2 has desirable pharmacokinetic and biodistribution properties. The primary application is likely to be PET evaluation of oncologic patients-especially those with brain, breast, or lung cancer. Specific indications may include tumor staging, identifying patients who would benefit from antiangiogenesis therapy, and separating treatment responders from nonresponders early.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.11101139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121013PMC
July 2011

First experience with clinical-grade ([18F]FPP(RGD₂): an automated multi-step radiosynthesis for clinical PET studies.

Mol Imaging Biol 2012 Feb;14(1):88-95

Molecular Imaging Program at Stanford (MIPS), Departments of Radiology and Bioengineering, Bio-X Program, Stanford University School of Medicine, Stanford, CA 94305, USA.

Purpose: A reliable and routine process to introduce a new ¹⁸F-labeled dimeric RGD-peptide tracer ([¹⁸F]FPP(RGD₂) for noninvasive imaging of α(v)β₃ expression in tumors needed to be developed so the tracer could be evaluated for the first time in man. Clinical-grade [¹⁸F]FPP(RGD)₂ was screened in mouse prior to our first pilot study in human.

Procedures: [¹⁸F]FPP(RGD)₂ was synthesized by coupling 4-nitrophenyl-2-[¹⁸F]fluoropropionate ([¹⁸F]NPE) with the dimeric RGD-peptide (PEG₃-c(RGDyK)₂). Imaging studies with [¹⁸F]FPP(RGD)₂ in normal mice and a healthy human volunteer were carried out using small animal and clinical PET scanners, respectively.

Results: Through optimization of each radiosynthetic step, [¹⁸F]FPP(RGD)₂ was obtained with RCYs of 16.9 ± 2.7% (n = 8, EOB) and specific radioactivity of 114 ± 72 GBq/μmol (3.08 ± 1.95 Ci/μmol; n = 8, EOB) after 170 min of radiosynthesis. In our mouse studies, high radioactivity uptake was only observed in the kidneys and bladder with the clinical-grade tracer. Favorable [¹⁸F]FPP(RGD)₂ biodistribution in human studies, with low background signal in the head, neck, and thorax, showed the potential applications of this RGD-peptide tracer for detecting and monitoring tumor growth and metastasis.

Conclusions: A reliable, routine, and automated radiosynthesis of clinical-grade [¹⁸F]FPP(RGD)₂ was established. PET imaging in a healthy human volunteer illustrates that [¹⁸F]FPP(RGD)₂ possesses desirable pharmacokinetic properties for clinical noninvasive imaging of α(v)β₃ expression. Further imaging studies using [¹⁸F]FPP(RGD)₂ in patient volunteers are now under active investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11307-011-0477-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617483PMC
February 2012

Reproducibility study of [(18)F]FPP(RGD)2 uptake in murine models of human tumor xenografts.

Eur J Nucl Med Mol Imaging 2011 Apr 2;38(4):722-30. Epub 2010 Dec 2.

Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford University, 1201 Welch Road, Lucas Center, P020A, Stanford, CA 94305-5484, USA.

Purpose: An (18)F-labeled PEGylated arginine-glycine-aspartic acid (RGD) dimer {[(18)F]FPP(RGD)(2)} has been used to image tumor α(v)β(3) integrin levels in preclinical and clinical studies. Serial positron emission tomography (PET) studies may be useful for monitoring antiangiogenic therapy response or for drug screening; however, the reproducibility of serial scans has not been determined for this PET probe. The purpose of this study was to determine the reproducibility of the integrin α(v)β(3)-targeted PET probe, [(18)F]FPP(RGD)(2,) using small animal PET.

Methods: Human HCT116 colon cancer xenografts were implanted into nude mice (n = 12) in the breast and scapular region and grown to mean diameters of 5-15 mm for approximately 2.5 weeks. A 3-min acquisition was performed on a small animal PET scanner approximately 1 h after administration of [(18)F]FPP(RGD)(2) (1.9-3.8 MBq, 50-100 μCi) via the tail vein. A second small animal PET scan was performed approximately 6 h later after reinjection of the probe to assess for reproducibility. Images were analyzed by drawing an ellipsoidal region of interest (ROI) around the tumor xenograft activity. Percentage injected dose per gram (%ID/g) values were calculated from the mean or maximum activity in the ROIs. Coefficients of variation and differences in %ID/g values between studies from the same day were calculated to determine the reproducibility.

Results: The coefficient of variation (mean±SD) for %ID(mean)/g and %ID(max)/g values between [(18)F]FPP(RGD)(2) small animal PET scans performed 6 h apart on the same day were 11.1 ± 7.6% and 10.4 ± 9.3%, respectively. The corresponding differences in %ID(mean)/g and %ID(max)/g values between scans were -0.025 ± 0.067 and -0.039 ± 0.426. Immunofluorescence studies revealed a direct relationship between extent of α(ν)β(3) integrin expression in tumors and tumor vasculature with level of tracer uptake. Mouse body weight, injected dose, and fasting state did not contribute to the variability of the scans; however, consistent scanning parameters were necessary to ensure accurate studies, in particular, noting tumor volume, as well as making uniform: the time of imaging after injection and the ROI size. Reanalysis of ROI placement displayed variability for %ID(mean)/g of 6.6 ± 3.9% and 0.28 ± 0.12% for %ID(max)/g.

Conclusion: [(18)F]FPP(RGD)(2) small animal PET mouse tumor xenograft studies are reproducible with relatively low variability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-010-1672-1DOI Listing
April 2011