Optical imaging of cell death in traumatic brain injury using a heat shock protein-90 alkylator

Xie, Bangwen; Park, Danielle; Beek, Ermond R. van; Blankevoort, Vicky; Orabi, Y.; Que, Ivo; Kaijzel, Eric L.; Chan, Alan; Hogg, Philip J.; Löwik, Clemens W.G.M.

doi:10.1038/cddis.2012.207

Cited by 20 publications

(33 citation statements)

References 36 publications

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“…Rationale for the platelet necrosis marker GSAO is a tripeptide trivalent arsenical that has recently been characterized as an imaging agent for necrotic and late apoptotic nucleated cells [15][16][17] ( Figure 1A). When tagged with a reporter compound at the g-glutamyl residue of the glutathione moiety, the compound is unable to cross the plasma membrane of viable cells.…”

Section: Resultsmentioning

confidence: 99%

“…[15][16][17] We employed conjugates of GSAO with AF647, AF546, or Oregon Green in this study. A GSAO control compound, GSCA [4-…”

Section: Resultsmentioning

confidence: 99%

“…Traditional markers of loss of membrane integrity that bind to nuclear material such as propidium iodide or Sytox dyes cannot be used in the anucleate platelet. Thus, we investigated the use of a cell death imaging agent that complexes with cytoplasmic ligands, 4-[N-(S-glutathionylacetyl) amino] phenylarsonous acid (GSAO), [15][16][17] to determine whether we could identify the procoagulant platelet in vitro and in vivo. Using GSAO, we show that necrotic platelets are generated within a few seconds of agonist stimulation in vitro and are procoagulant.…”

Section: Introductionmentioning

confidence: 99%

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Necrotic platelets provide a procoagulant surface during thrombosis

Hua

Abeynaike

Glaros

et al. 2015

Blood

111

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Key Points• The major subpopulation of platelets involved in thrombus development form via regulated necrosis involving cyclophilin D.• Necrotic platelets may be targeted independent of platelet activation.A subpopulation of platelets fulfills a procoagulant role in hemostasis and thrombosis by enabling the thrombin burst required for fibrin formation and clot stability at the site of vascular injury. Excess procoagulant activity is linked with pathological thrombosis. The identity of the procoagulant platelet has been elusive. The cell death marker 4-[N-(S-glutathionylacetyl)amino]phenylarsonous acid (GSAO) rapidly enters a subpopulation of agonist-stimulated platelets via an organic anion-transporting polypeptide and is retained in the cytosol through covalent reaction with protein dithiols. Labeling with GSAO, together with exposure of P-selectin, distinguishes necrotic from apoptotic platelets and correlates with procoagulant potential. GSAO 1 platelets form in occluding murine thrombi after ferric chloride injury and are attenuated with megakaryocyte-directed deletion of the cyclophilin D gene. These platelets form a procoagulant surface, supporting fibrin formation, and reduction in GSAO 1 platelets is associated with reduction in platelet thrombus size and fibrin formation. Analysis of platelets from human subjects receiving aspirin therapy indicates that these procoagulant platelets form despite aspirin therapy, but are attenuated by inhibition of the necrosis pathway. These findings indicate that the major subpopulation of platelets involved in fibrin formation are formed via regulated necrosis involving cyclophilin D, and that they may be targeted independent of platelet activation. (Blood. 2015;126(26):2852-2862

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Section: Resultsmentioning

confidence: 99%

“…[15][16][17] We employed conjugates of GSAO with AF647, AF546, or Oregon Green in this study. A GSAO control compound, GSCA [4-…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Necrotic platelets provide a procoagulant surface during thrombosis

Hua

Abeynaike

Glaros

et al. 2015

Blood

111

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“…There was a significant increase in the GSAO fluorescence signal in the treated tumours measured in vivo and ex vivo and the signal co-localized with apoptotic cells in sectioned tumours [22]. In another study, fluorophore-labelled conjugates of GSAO localized to murine cerebral cryolesions and the areas of fluorescence corresponded with areas of TUNEL staining ex vivo [23].…”

Section: Discussionmentioning

confidence: 90%

Biodistribution and imaging of an hsp90 ligand labelled with 111In and 67Ga for imaging of cell death

et al. 2020

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Background: 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated at the γ-glutamyl residue with fluorophores and radio-isotopes is able to image dead and dying cells in vitro and in vivo by binding to intracellular 90-kDa heat shock proteins (hsp90) when cell membrane integrity is compromised. The ability to image cell death has potential clinical impact especially for early treatment response assessment in oncology. This work aims to assess the biodistribution and tumour uptake of diethylene triamine pentaacetic acid GSAO labelled with 111 In ([ 111 In]In-DTPA-GSAO) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid GSAO labelled with 67 Ga ([ 67 Ga]Ga-DOTA-GSAO) in a murine subcutaneous tumour xenograft model and estimate dosimetry of [ 67 Ga]Ga-DOTA-GSAO. Results: There was good tumour uptake of both [ 111 In]In-DTPA-GSAO and [ 67 Ga]Ga-DOTA-GSAO (2.44 ± 0.26% injected activity per gramme of tissue (%IA/g) and 2.75 ± 0.34 %IA/g, respectively) in Balb c nu/nu mice bearing subcutaneous tumour xenografts of a human metastatic prostate cancer cell line (PC3M-luc-c6). Peak tumour uptake occurred at 2.7 h post injection. [ 111 In]In-DTPA-GSAO and [ 67 Ga]Ga-DOTA-GSAO demonstrated increased uptake in the liver (4.40 ± 0.86 %IA/g and 1.72 ± 0.27 %IA/g, respectively), kidneys (16.54 ± 3.86 %IA/g and 8.16 ± 1.33 %IA/g) and spleen (6.44 ± 1.24 %IA/g and 1.85 ± 0.44 %IA/g); however, uptake in these organs was significantly lower with [ 67 Ga]Ga-DOTA-GSAO (p = 0.006, p = 0.017 and p = 0.003, respectively). Uptake of [ 67 Ga]Ga-DOTA-GSAO into tumour was higher than all organs except the kidneys. There was negligible uptake in the other organs. Excretion of [ 67 Ga]Ga-DOTA-GSAO was more rapid than [ 111 In]In-DTPA-GSAO. Estimated effective dose of [ 67 Ga]Ga-DOTA-GSAO for an adult male human was 1.54 × 10 − 2 mSv/MBq. Conclusions: [ 67 Ga]Ga-DOTA-GSAO demonstrates higher specific uptake in dead and dying cells within tumours and lower uptake in normal organs than [ 111 In]In-DTPA-GSAO. [ 67 Ga]Ga-DOTA-GSAO may be potentially useful for imaging cell death in vivo. Dosimetry estimates for [ 67 Ga]Ga-DOTA-GSAO are acceptable for future human studies. This work also prepares for development of 68 Ga GSAO radiopharmaceuticals.

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“…In vitro , cell death was studied using a cryo-induced cell death assay as previously described [40]. In short, 4T1-luc2 cells were seeded onto 24-well tissue culture plates (Sigma-Aldrich) and grown until confluent.…”

Section: Methodsmentioning

confidence: 99%

Pre-clinical Evaluation of a Cyanine-Based SPECT Probe for Multimodal Tumor Necrosis Imaging

et al. 2016

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PurposeRecently we showed that a number of carboxylated near-infrared fluorescent (NIRF) cyanine dyes possess strong necrosis avid properties in vitro as well as in different mouse models of spontaneous and therapy-induced tumor necrosis, indicating their potential use for cancer diagnostic- and prognostic purposes. In the previous study, the detection of the cyanines was achieved by whole body optical imaging, a technique that, due to the limited penetration of near-infrared light, is not suitable for investigations deeper than 1 cm within the human body. Therefore, in order to facilitate clinical translation, the purpose of the present study was to generate a necrosis avid cyanine-based NIRF probe that could also be used for single photon emission computed tomography (SPECT). For this, the necrosis avid NIRF cyanine HQ4 was radiolabeled with 111indium, via the chelate diethylene triamine pentaacetic acid (DTPA).ProceduresThe necrosis avid properties of the radiotracer [111In]DTPA-HQ4 were examined in vitro and in vivo in different breast tumor models in mice using SPECT and optical imaging. Moreover, biodistribution studies were performed to examine the pharmacokinetics of the probe in vivo.ResultsUsing optical imaging and radioactivity measurements, in vitro, we showed selective accumulation of [111In]DTPA-HQ4 in dead cells. Using SPECT and in biodistribution studies, the necrosis avidity of the radiotracer was confirmed in a 4T1 mouse breast cancer model of spontaneous tumor necrosis and in a MCF-7 human breast cancer model of chemotherapy-induced tumor necrosis.ConclusionsThe radiotracer [111In]DTPA-HQ4 possessed strong and selective necrosis avidity in vitro and in various mouse models of tumor necrosis in vivo, indicating its potential to be clinically applied for diagnostic purposes and to monitor anti-cancer treatment efficacy.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-0972-7) contains supplementary material, which is available to authorized users.

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Optical imaging of cell death in traumatic brain injury using a heat shock protein-90 alkylator

Cited by 20 publications

References 36 publications

Necrotic platelets provide a procoagulant surface during thrombosis

Necrotic platelets provide a procoagulant surface during thrombosis

Biodistribution and imaging of an hsp90 ligand labelled with 111In and 67Ga for imaging of cell death

Pre-clinical Evaluation of a Cyanine-Based SPECT Probe for Multimodal Tumor Necrosis Imaging

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