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Noninvasive imaging of cell death using an Hsp90 ligand.

ABSTRACT: Cell death plays a central role in normal physiology and in disease. Common to apoptotic and necrotic cell death is the eventual loss of plasma membrane integrity. We have produced a small organoarsenical compound, 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid, that rapidly accumulates in the cytosol of dying cells coincident with loss of plasma membrane integrity. The compound is retained in the cytosol predominantly by covalent reaction with the 90 kDa heat shock protein (Hsp90), the most abundant molecular chaperone of the eukaryotic cytoplasm. The organoarsenical was tagged with either optical or radioisotope reporting groups to image cell death in cultured cells and in murine tumors ex vivo and in situ. Tumor cell death in mice was noninvasively imaged by SPECT/CT using an (111)In-tagged compound. This versatile compound should enable the imaging of cell death in most experimental settings.

SUBMITTER: Park D

PROVIDER: S-EPMC7371243 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Noninvasive imaging of cell death using an Hsp90 ligand.

Park Danielle D Don Anthony S AS Massamiri Tania T Karwa Amol A Warner Beth B MacDonald Jan J Hemenway Christine C Naik Arati A Kuan Kah-Tiong KT Dilda Pierre J PJ Wong Jason W H JW Camphausen Kevin K Chinen Lori L Dyszlewski Mary M Hogg Philip J PJ

Journal of the American Chemical Society 20110215 9

Cell death plays a central role in normal physiology and in disease. Common to apoptotic and necrotic cell death is the eventual loss of plasma membrane integrity. We have produced a small organoarsenical compound, 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid, that rapidly accumulates in the cytosol of dying cells coincident with loss of plasma membrane integrity. The compound is retained in the cytosol predominantly by covalent reaction with the 90 kDa heat shock protein (Hsp90), the mo ...[more]

PMID: 21322555

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Project description:BACKGROUND:4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated at the ?-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 111In ([111In]In-DTPA-GSAO) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid GSAO labelled with 67Ga ([67Ga]Ga-DOTA-GSAO) in a murine subcutaneous tumour xenograft model and estimate dosimetry of [67Ga]Ga-DOTA-GSAO. RESULTS:There was good tumour uptake of both [111In]In-DTPA-GSAO and [67Ga]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. [111In]In-DTPA-GSAO and [67Ga]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 [67Ga]Ga-DOTA-GSAO (p?=?0.006, p?=?0.017 and p?=?0.003, respectively). Uptake of [67Ga]Ga-DOTA-GSAO into tumour was higher than all organs except the kidneys. There was negligible uptake in the other organs. Excretion of [67Ga]Ga-DOTA-GSAO was more rapid than [111In]In-DTPA-GSAO. Estimated effective dose of [67Ga]Ga-DOTA-GSAO for an adult male human was 1.54?×?10-?2?mSv/MBq. CONCLUSIONS:[67Ga]Ga-DOTA-GSAO demonstrates higher specific uptake in dead and dying cells within tumours and lower uptake in normal organs than [111In]In-DTPA-GSAO. [67Ga]Ga-DOTA-GSAO may be potentially useful for imaging cell death in vivo. Dosimetry estimates for [67Ga]Ga-DOTA-GSAO are acceptable for future human studies. This work also prepares for development of 68Ga GSAO radiopharmaceuticals.

Project description:ObjectivesThe aim of this study was to investigate the potential of coronary ultrafast Doppler angiography (CUDA), a novel vascular imaging technique based on ultrafast ultrasound, to image noninvasively with high sensitivity the intramyocardial coronary vasculature and quantify the coronary blood flow dynamics.BackgroundNoninvasive coronary imaging techniques are currently limited to the observation of the epicardial coronary arteries. However, many studies have highlighted the importance of the coronary microcirculation and microvascular disease.MethodsCUDA was performed in vivo in open-chest procedures in 9 swine. Ultrafast plane-wave imaging at 2,000 frames/s was combined to an adaptive spatiotemporal filtering to achieve ultrahigh-sensitive imaging of the coronary blood flows. Quantification of the flow change was performed during hyperemia after a 30-s left anterior descending (LAD) artery occlusion followed by reperfusion and was compared to gold standard measurements provided by a flowmeter probe placed at a proximal location on the LAD (n = 5). Coronary flow reserve was assessed during intravenous perfusion of adenosine. Vascular damages were evaluated during a second set of experiments in which the LAD was occluded for 90 min, followed by 150 min of reperfusion to induce myocardial infarction (n = 3). Finally, the transthoracic feasibility of CUDA was assessed on 2 adult and 2 pediatric volunteers.ResultsUltrahigh-sensitive cine loops of venous and arterial intramyocardial blood flows were obtained within 1 cardiac cycle. Quantification of the coronary flow changes during hyperemia was in good agreement with gold standard measurements (r2 = 0.89), as well as the assessment of coronary flow reserve (2.35 ± 0.65 vs. 2.28 ± 0.84; p = NS). On the infarcted animals, CUDA images revealed the presence of strong hyperemia and the appearance of abnormal coronary vessel structures in the reperfused LAD territory. Finally, the feasibility of transthoracic coronary vasculature imaging was shown on 4 human volunteers.ConclusionsUltrafast Doppler imaging can map the coronary vasculature with high sensitivity and quantify intramural coronary blood flow changes.

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Noninvasive imaging of cell death using an Hsp90 ligand.

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Noninvasive imaging of cell death using an Hsp90 ligand.

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