Dataset Information

Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide.

ABSTRACT: Of the molecular biochemical alterations that occur during apoptosis, activation of caspases, notably caspase-3, is probably the most attractive for developing specific in vivo molecular imaging probes. We recently designed a library of isatin-5 sulfonamides and selected [18F]ICMT-11 for further evaluation on the basis of subnanomolar affinity for activated capsase-3, high metabolic stability, and facile radiolabeling. In this present study, we have demonstrated that [18F]ICMT-11 binds to a range of drug-induced apoptotic cancer cells in vitro and to 38C13 murine lymphoma xenografts in vivo by up to 2-fold at 24 h posttreatment compared to vehicle treatment. We further demonstrated that the increased signal intensity in tumors after drug treatment, detected by whole body in vivo microPET imaging, was associated with increased apoptosis. In summary, we have characterized [18F]ICMT-11 as a caspase-3/7 specific PET imaging radiotracer for the assessment of tumor apoptosis that could find utility in anticancer drug development and the monitoring of early responses to therapy.

SUBMITTER: Nguyen QD

PROVIDER: S-EPMC2752565 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Publications

Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide.

Nguyen Quang-Dé QD Smith Graham G Glaser Matthias M Perumal Meg M Arstad Erik E Aboagye Eric O EO

Proceedings of the National Academy of Sciences of the United States of America 20090903 38

Of the molecular biochemical alterations that occur during apoptosis, activation of caspases, notably caspase-3, is probably the most attractive for developing specific in vivo molecular imaging probes. We recently designed a library of isatin-5 sulfonamides and selected [18F]ICMT-11 for further evaluation on the basis of subnanomolar affinity for activated capsase-3, high metabolic stability, and facile radiolabeling. In this present study, we have demonstrated that [18F]ICMT-11 binds to a rang ...[more]

PMID: 19805307

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:Purpose: Positron emission tomography (PET) imaging of apoptosis is very important for early evaluation of tumor therapeutic efficacy. A stimuli-responsive probe based on the peptide sequence Asp-Glu-Val-Asp (DEVD), [18F]DEVD-Cys(StBu)-PPG(CBT)-AmBF3 ([18F]1), for PET imaging of tumor apoptosis was designed and prepared. This study aimed to develop a novel smart probe using a convenient radiosynthesis method and to fully examine the sensitivity and specificity of the probe response to the tumor treatment. Methods: The radiolabelling precursor DEVD-Cys(StBu)-PPG(CBT)-AmBF3 (1) was synthesized through multistep reactions. The reduction together with caspase-controlled macrocyclization and self-assembly of 1 was characterized and validated in vitro. After [18F]fluorination in the buffer (pH= 2.5), the radiolabelling yield (RLY), radiochemical purity (RCP) and stability of the probe [18F]1 in PBS and mouse serum were investigated by radio-HPLC. The sensitivity and specificity of [18F]1 for detecting the drug-induced apoptosis was fully evaluated in vitro and in vivo. The effect of cold precursor 1 on the cell uptake and tumor imaging of [18F]1 was also assessed. The level of activated caspase-3 in Hela cells and tumors with or without apoptosis induction was analyzed and compared by western blotting and histological staining. Results: The whole radiosynthesis process of [18F]1 was around 25 min with RLY of 50%, RCP of over 99% and specific activity of 1.45 ± 0.4 Ci/µmol. The probe was very stable in both PBS and mouse serum within 4 h. It can be activated by caspase-3 and then undergo an intermolecular cyclization to form nanosized particles. The retained [18F]1 in DOX-treated HeLa cells was 2.2 folds of that in untreated cells. Within 1 h microPET imaging of the untreated Hela-bearing mice, the injection of [18F]1 resulted in the increase of the uptake ratio of tumor to muscle (T/M) only from 1.74 to 2.18, while in the DOX-treated Hela-bearing mice T/M increased from 1.88 to 10.52 and the co-injection of [18F]1 and 1 even led to the increase of T/M from 3.08 to 14.81. Conclusions: A caspase-responsive smart PET probe [18F]1 was designed and prepared in a kit-like manner. Co-injection of [18F]1 and 1 generated remarkably enhanced tumor uptake and signal-to-noise ratio in the tumor-bearing mice with drug-induced apoptosis, which correlated well with the expression level of activated caspase-3. This early readout of treatment response ensured that the probe [18F]1 could serve as a promising PET imaging probe for timely and noninvasive evaluation of tumor therapy.

Dataset Information

Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide.

Publications

Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide.

Similar Datasets

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