Detection of Cell Death in Tumors by Using MR Imaging and a Gadolinium-based Targeted Contrast Agent

Krishnan, Anant; Neves, André; Backer, Maaike M. de; Hu, De‐En; Davletov, Bazbek; Kettunen, Mikko I.; Brindle, Kevin M.

doi:10.1148/radiol.2463070471

Cited by 70 publications

(71 citation statements)

References 22 publications

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“…In vivo any primary signal changes associated with apoptotic cells in tissue parenchyma would be potentially convoluted with signal changes caused by differences in vascular permeability to gadolinium that may occur with vascular cell death. Specific approaches have relied on gadolinium chelates of the C2A domain of synaptotagmin-I that binds to phosphatidyl serine exposed on apoptotic and apo-necrotic cell membranes (29). Other new approaches rely on measurements of intracellular sodium with MRI and have found this to correlate to taxotere chemosensitivity-induced regions of apoptosis (30).…”

Section: Discussionmentioning

confidence: 99%

Ultrasound Imaging of Apoptosis in Tumor Response: Novel Preclinical Monitoring of Photodynamic Therapy Effects

Banihashemi

Vlad²,

Debeljevic³

et al. 2008

Cancer Research

136

157

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High-frequency ultrasound is a novel method to detect apoptotic cell death based on changes in cell morphology that cause alterations in the viscoelastic and, consequently, the acoustic properties of cell ensembles and tissues. In this study, we evaluated the first preclinical tumor-based use of highfrequency ultrasound spectroscopy to noninvasively monitor tumor treatment by following xenograft malignant melanoma tumor responses to photodynamic therapy (PDT) in vivo. We observed a time-dependant increase in ultrasound backscatter variables after treatment. The observed increases in spectroscopic variables correlated with morphologic findings, indicating increases in apoptotic cell death, which peaked at 24 hours after PDT. We analyzed the changes in spectral slope and backscatter in relation to apoptosis and histologic variations in cell nuclear size. Changes in spectral slope strongly correlated with the changes in mean nuclear size over time, associated with apoptosis, after PDT (P < 0.05). At 48 hours, a decrease in ultrasound backscatter was observed, which could be explained by an increase in cell nuclear degradation. In summary, we show that high-frequency ultrasound spectroscopic variables can be used noninvasively to monitor response after treatment in a preclinical tumor cancer model. These findings provide a foundation for future investigations regarding the use of ultrasound to monitor and aid the customization of treatments noninvasively based on responses to specific interventions. [Cancer Res 2008;68(20):8590-6]

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Section: Discussionmentioning

confidence: 99%

Ultrasound Imaging of Apoptosis in Tumor Response: Novel Preclinical Monitoring of Photodynamic Therapy Effects

Banihashemi

Vlad²,

Debeljevic³

et al. 2008

Cancer Research

136

157

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“…Among these, the characterization and utilities of annexin V and the C2A domain of synaptotagmin I have been reported in various applications (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Both annexin V and C2A are calcium-dependent phospholipidbinding proteins, in which calcium ions in the binding pocket mediate the binding between the protein and the lipid membrane in the form of calcium bridges (42,43).…”

Section: Discussionmentioning

confidence: 99%

^99mTc-Labeled Duramycin as a Novel Phosphatidylethanolamine-Binding Molecular Probe

Zhao¹,

Li²,

Bugenhagen³

2008

J Nucl Med

120

121

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With only 19 amino acids, duramycin is the smallest known polypeptide that has a defined 3-dimensional binding structure. Duramycin binds phosphatidylethanolamine (PtdE) at a 1:1 ratio with high affinity and exclusive specificity. As an abundant binding target, PtdE is a major phospholipid and accounts for about 20% of the phospholipid content in mammalian cellular membranes. PtdE is externalized to the surface of apoptotic cells and also becomes accessible in necrotic cells because of compromised plasma membrane integrity. Given the unique physicochemical properties of duramycin and the availability of PtdE in acute cell death, the goal of this study was to develop and evaluate 99m Tc-duramycin as a novel molecular probe for imaging PtdE. Methods: Duramycin is covalently modified with succinimidyl 6-hydrazinonicotinate acetone hydrazone (HYNIC) and labeled with 99m Tc using a coordination chemistry involving tricine-phosphine coligands. The retention of PtdE-binding activities was confirmed using competition assays with PtdEcontaining liposomes. The blood clearance, pharmacokinetics, and biodistribution of 99m Tc-duramycin were measured in rats. Finally, 99m Tc-duramycin binding to acute cell death in vivo was demonstrated using a rat model of acute myocardial infarction induced by ischemia and reperfusion and confirmed using autoradiography and histology. Results: HYNIC-derivatized duramycin with 1:1 stoicheometry was synthesized and confirmed by mass spectrometry. The radiolabeling efficiency was 80%-85%, radiochemical purity was 78%-89%, and specific activity was 54 GBq. The radiotracer was purified with high-performance liquid chromatography radiodetection before use. The specific uptake of 99m Tc-duramycin in apoptotic cells, compared with that in viable control cells, was enhanced by more than 30-fold. This binding was competitively diminished in the presence of PtdE-containing liposomes but not by liposomes consisting of other phospholipid species. Intravenously injected 99m Tc-duramycin has favorable pharmacokinetic and biodistribution profiles: it quickly clears from the circulation via the renal system, with a blood half-life of less than 4 min in rats. The hepatic and gastrointestinal uptake were very low. 99m Tc-duramycin is completely unmetabolized in vivo, and the intact agent is recovered from the urine. Combined with a fast clearance and low hepatic background, the avid binding of 99m Tc-duramycin to the infarcted myocardium quickly becomes conspicuous shortly after injection. The uptake of radioactivity in infarcted tissues was confirmed by autoradiography and histology. Conclusion: 99m Tc-duramycin is a stable, low-molecular-weight PtdE-binding radiopharmaceutical, with favorable in vivo imaging profiles. It is a strong candidate as a molecular probe for PtdE imaging and warrants further development and characterization.

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“…This problem is illustrated by our experience with a PS-targeted agent based on the C2A domain of the protein synaptotagmin. The protein has been labelled with superparamagnetic iron oxide nanoparticles and with Gd 3+ chelates and has been shown to detect dead or dying tumour cells in vivo in T 2 and T 1 weighted images, respectively [42,43], as illustrated for the Gd 3+ chelate-labelled agent in Figure 5. Although the accumulation of the agent in the tumour at 24 h after drug treatment is clear in these false colour images, the concentration of the agent in treated tumours was only twice that in the untreated controls.…”

Section: C]fumaratementioning

confidence: 99%

Watching tumours gasp and die with MRI: the promise of hyperpolarised¹³C MR spectroscopic imaging

Brindle

2012

BJR

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Detection of Cell Death in Tumors by Using MR Imaging and a Gadolinium-based Targeted Contrast Agent

Abstract: A relatively small (approximately 100 kDa) Gd(3+)-based contrast agent, which gives positive contrast on MR images, can be used to detect tumor cell death in vivo, and future derivatives of it may be used to assess early tumor responses to treatment.

Cited by 70 publications

References 22 publications

Ultrasound Imaging of Apoptosis in Tumor Response: Novel Preclinical Monitoring of Photodynamic Therapy Effects

Ultrasound Imaging of Apoptosis in Tumor Response: Novel Preclinical Monitoring of Photodynamic Therapy Effects

^99mTc-Labeled Duramycin as a Novel Phosphatidylethanolamine-Binding Molecular Probe

Watching tumours gasp and die with MRI: the promise of hyperpolarised¹³C MR spectroscopic imaging

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Detection of Cell Death in Tumors by Using MR Imaging and a Gadolinium-based Targeted Contrast Agent

Abstract: A relatively small (approximately 100 kDa) Gd(3+)-based contrast agent, which gives positive contrast on MR images, can be used to detect tumor cell death in vivo, and future derivatives of it may be used to assess early tumor responses to treatment.

Cited by 70 publications

References 22 publications

Ultrasound Imaging of Apoptosis in Tumor Response: Novel Preclinical Monitoring of Photodynamic Therapy Effects

Ultrasound Imaging of Apoptosis in Tumor Response: Novel Preclinical Monitoring of Photodynamic Therapy Effects

99mTc-Labeled Duramycin as a Novel Phosphatidylethanolamine-Binding Molecular Probe

Watching tumours gasp and die with MRI: the promise of hyperpolarised13C MR spectroscopic imaging

Contact Info

Product

Resources

About

^99mTc-Labeled Duramycin as a Novel Phosphatidylethanolamine-Binding Molecular Probe

Watching tumours gasp and die with MRI: the promise of hyperpolarised¹³C MR spectroscopic imaging