Characterization of [99mTc]Duramycin as a SPECT Imaging Agent for Early Assessment of Tumor Apoptosis

Elvas, Filipe; Vangestel, Christel; Rapic, Sara; Verhaeghe, Jeroen; Gray, Brian; Pak, Koon Y.; Stroobants, Sigrid; Staelens, Steven; wyffels, Leonie

doi:10.1007/s11307-015-0852-6

Cited by 45 publications

(49 citation statements)

References 34 publications

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“…We recently demonstrated the usefulness of 99m Tc-duramycin in an oncology setting showing ability to detect irinotecan-induced tumor apoptosis early (11). In the same study, we showed that the administration of 99m Tc-duramycin is safe from a dosimetry perspective and compatible with SPECT imaging in humans (11). The goal of the current study was to further validate its potential for early monitoring of treatment response, using a human colorectal cancer xenograft treated with chemotherapy and radiotherapy.…”

Section: Discussionmentioning

confidence: 69%

“…The obtained 99m Tc-duramycin was purified using highperformance liquid chromatography as previously described (11).…”

Section: Radiolabeling Of Duramycinmentioning

confidence: 99%

“…Static whole-body SPECT images were acquired 4 h after radiotracer injection using a micro-SPECT/CT scanner (VECTor/CT; MILabs) equipped with a rat multipinhole SPECT collimator, followed by CT acquisition (45 kV and 615 mA), as described previously (11). Mice were kept under approximately 2% isoflurane anesthesia and a constant body temperature during SPECT/CT imaging.…”

Section: Treatment Regimensmentioning

confidence: 99%

“…In this context, the phosphatidylethanolamine-binding radiotracer 99m Tcduramycin has recently gained attention for detecting cell death in animal models of disease (8)(9)(10), exploiting its high affinity and selectivity for phosphatidylethanolamine and its optimal biodistribution profile for in vivo SPECT imaging of cell death. Recently, we demonstrated favorable dosimetry estimates together with the usefulness of 99m Tc-duramycin for the early detection of irinotecaninduced tumor cell death in a proof-of-concept study (11).…”

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confidence: 99%

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Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin

et al. 2016

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Noninvasive imaging of cell death can provide an early indication of the efficacy of tumor treatment, aiding clinicians in distinguishing responding patients from nonresponding patients early on. 99m Tcduramycin is a SPECT tracer for cell death imaging. In this study, our aim was to validate the use of 99m Tc-duramycin for imaging the early response of tumors to treatment. Methods: An in vitro binding assay was performed on COLO205 cells treated with 5-fluorouracil (3.1, 31, or 310 μM) and oxaliplatin (0.7 or 7 μM) or radiation (2 or 4.5 Gy). 99m Tc-duramycin cell binding and the levels of cell death were evaluated after treatment. In vivo imaging was performed on 4 groups of CD1-deficient mice bearing COLO205 human colorectal cancer tumors. Each group included 6 tumors. The first group was given irinotecan (100 mg/kg), the second oxaliplatin (5 mg/kg), the third irinotecan (80 mg/kg) plus oxaliplatin (5 mg/kg), and the fourth vehicle (0.9% NaCl and 5% glucose). For radiotherapy studies, COLO205 tumors received 4.5 Gy, 2 fractions of 4.5 Gy in a 24-h interval, pretreatment with an 80 mg/kg dose of irinotecan combined with 2 fractions of 4.5 Gy in a 24-h interval, or no treatment (n 5 5-6/group). Therapy response was evaluated by 99m Tc-duramycin SPECT 24 h after the last dose of therapy. Blocking was used to confirm tracer specificity. Radiotracer uptake in the tumors was validated ex vivo using γ-counting, cleaved caspase-3, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) histology. Results: Chemotherapy and radiotherapy increased 99m Tc-duramycin binding to COLO205 cells in a concentration/ dose-and time-dependent manner, which correlated well with cell death levels (P , 0.05) as analyzed by annexin V and caspase 3/7 activity. In vivo, 99m Tc-duramycin uptake in COLO205 xenografts was increased 2.3-and 2.8-fold (P , 0.001) in mice treated with irinotecan and combination therapy, respectively. Blocking with unlabeled duramycin demonstrated specific binding of the radiotracer. After tumor irradiation with 4.5 Gy, 99m Tc-duramycin uptake in tumors increased significantly (1.24 ± 0.07 vs. 0.57 ± 0.08 percentage injected dose per gram in the unirradiated tumors; P , 0.001). γ-counting of radioactivity in the tumors positively correlated with cleaved caspase-3 (r 5 0.85, P , 0.001) and TUNEL (r 5 0.81, P , 0.001) staining. Conclusion: We demonstrated that 99m Tc-duramycin can be used to image induction of cell death early after chemotherapy and radiotherapy. It holds potential to be translated into clinical use for early assessment of treatment response.

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Section: Discussionmentioning

confidence: 69%

“…The obtained 99m Tc-duramycin was purified using highperformance liquid chromatography as previously described (11).…”

Section: Radiolabeling Of Duramycinmentioning

confidence: 99%

Section: Treatment Regimensmentioning

confidence: 99%

mentioning

confidence: 99%

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Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin

et al. 2016

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“…Duramycin is a 19-amino-acid peptide that binds with high affinity and specificity to the phosphatidylethanolamine externalized by dying cells (30). 99m Tc-labeled duramycin has been used recently to detect response to chemotherapy in a mouse model of colorectal cancer, in which accumulation of the agent was found to correlate with markers of cell death (31). However, the clinical utility of duramycin has yet to be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I

et al. 2017

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Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of a phosphatidylserine-binding agent for detecting tumor cell death in vivo based on the C2A domain of synaptotagmin-I. Methods: The capability of nearinfrared fluorophore-labeled and 99m In-labeled derivatives of C2Am for imaging tumor cell death, using planar near-infrared fluorescence imaging and SPECT, respectively, was evaluated in implanted and genetically engineered mouse models of lymphoma and in a human colorectal xenograft. Results: The fluorophorelabeled C2Am derivative showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (2%-5%). There was a significant correlation (R . 0.9, P , 0.05) between fluorescently labeled C2Am binding and histologic markers of cell death, including cleaved caspase-3, whereas there was no such correlation with a site-directed mutant of C2Am (iC2Am) that does not bind phosphatidylserine. 99m In-C2Am also showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the liver and spleen at 24 h after probe administration. 99m In-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3· and 2.2·, respectively, at 2 h and 7.3· and 4.1·, respectively, at 24 h after administration. Conclusion: Given the favorable biodistribution profile of 99m In-labeled C2Am, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation.

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Exploring the potential of radiolabeled duramycin as an infection imaging probe

Kumar,

Mitra,

Khatoon

et al. 2023

Drug Development Research

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The continuous pursuit of designing an ideal infection imaging agent is a crucial and ongoing endeavor in the field of biomedical research. Duramycin, an antimicrobial peptide exerts its antimicrobial action on bacteria by specific recognition of phosphatidylethanolamine (PE) moiety present on most bacterial membranes, particularly Escherichia coli (E. coli). E. coli membranes contain more than 60% PE. Therefore, duramycin is an attractive candidate for the formulation of probes for in situ visualization of E. coli driven focal infections. The aim of the present study is to develop 99mTc labeled duramycin as a single‐photon emission computed tomography (SPECT)‐based agent to image such infections. Duramycin was successfully conjugated with a bifunctional chelator, hydrazinonicotinamide (HYNIC). PE specificity of HYNIC‐duramycin was confirmed by a dye release assay on PE‐containing model membranes. Radiolabeling of HYNIC–duramycin with 99mTc was performed with consistently high radiochemical yield (>90%) and radiochemical purity (>90%). [99mTc]Tc‐HYNIC‐duramycin retained its specificity for E. coli, in vitro. SPECT and biodistribution studies showed that the tracer could specifically identify E. coli driven infection at 3 h post injection. While 99mTc‐labeled duramycin is employed for monitoring early response to cancer therapy and cardiotoxicity, the current studies have confirmed, for the first time, the potential of utilizing 99mTc labeled duramycin as an imaging agent for detecting bacteria. Its application in imaging PE‐positive bacteria represents a novel and promising advancement.

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Characterization of [99mTc]Duramycin as a SPECT Imaging Agent for Early Assessment of Tumor Apoptosis

Cited by 45 publications

References 34 publications

Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin

Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin

Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I

Exploring the potential of radiolabeled duramycin as an infection imaging probe

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Characterization of [99mTc]Duramycin as a SPECT Imaging Agent for Early Assessment of Tumor Apoptosis

Cited by 45 publications

References 34 publications

Early Prediction of Tumor Response to Treatment: Preclinical Validation of 99mTc-Duramycin

Early Prediction of Tumor Response to Treatment: Preclinical Validation of 99mTc-Duramycin

Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I

Exploring the potential of radiolabeled duramycin as an infection imaging probe

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Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin

Early Prediction of Tumor Response to Treatment: Preclinical Validation of ^99mTc-Duramycin