Imaging paclitaxel (chemotherapy)-induced tumor apoptosis with 99mTc C2A, a domain of synaptotagmin I: a preliminary study

Wang, Feng; Fang, Wei; Zhao, Ming; Wang, Zizheng; Ji, Shundong; Li, Yan; Zheng, Yuming

doi:10.1016/j.nucmedbio.2007.12.007

Cited by 41 publications

(33 citation statements)

References 24 publications

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“…Positron emission tomography (PET) has emerged as the leading modality for molecular imaging, enabling sensitive and quantitative assessment of cellular processes. Current approaches for in vivo detection of apoptosis are mostly based on large proteins or peptides, e.g., Annexin-V [1], C2A domain of synaptotagmin-I [2], or caspase substrates [3,4], which have limitations such as low clearance rate, suboptimal biodistribution or potential immunogenicity. No PET tracer for apoptosis is currently available for clinical use.…”

Section: Introductionmentioning

confidence: 99%

From the Gla domain to a novel small-molecule detector of apoptosis

Cohen¹,

Shirvan²,

Levin³

et al. 2009

Cell Res

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Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, targeting of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weight probes for apoptosis, we focused on the uncommon amino acid γ-carboxyglutamic acid (Gla), which plays a vital role in the binding of clotting factors to negatively charged phospholipid surfaces. Based on the alkyl-malonic acid motif of Gla, we have developed and now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid, MW=206 Da), the prototypical member of a novel family of small-molecule detectors of apoptosis. ML-10 was found to perform selective uptake and accumulation in apoptotic cells, while being excluded from either viable or necrotic cells. ML-10 uptake correlates with the apoptotic hallmarks of caspase activation, Annexin-V binding and disruption of mitochondrial membrane potential. The malonate moiety was found to be crucial for ML-10 function in apoptosis detection. ML-10 responds to a unique complex of features of the cell in early apoptosis, comprising irreversible loss of membrane potential, permanent acidification of cell membrane and cytoplasm, and preservation of membrane integrity. ML-10 is therefore the most compact apoptosis probe known to date. Due to its fluorine atom, ML-10 is amenable to radiolabeling with the 18 F isotope, towards its potential future use for clinical positron emission tomography imaging of apoptosis.

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Section: Introductionmentioning

confidence: 99%

From the Gla domain to a novel small-molecule detector of apoptosis

Cohen¹,

Shirvan²,

Levin³

et al. 2009

Cell Res

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“…This was first used, in animal models, in the form of a dimeric glutathione S-transferase-tagged construct (84 kDa) for imaging tumor cell death using MRI (11,12) as well as in 99m Tc-labeled form, for imaging tumor cell death (13) and cardiac ischemia using SPECT (14), and in 18 F-labeled form, for imaging cell death in a rabbit lung cancer model using PET (15).…”

mentioning

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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“…Both ex vivo and in vivo data indicate that both specific binding and passive leakage contribute to the accumulation of the radiotracer in the area at risk. 128 Annexin B1 (MW = 38 kDa) is a novel PS-binding protein with a slightly longer N-terminal domain compared with Annexin V. 129 99m Tc-Annexin B1 rapidly cleared from the blood and predominantly accumulated in the kidney. The marked increase in dexamethasone-treated murine thymus uptake and fas-mediated murine liver uptake correlated with histologic evidence of apoptosis.…”

Section: Imaging Apoptosis With Other Ps Binding Proteinsmentioning

confidence: 99%