Dataset Information

Comparison of the Effects of DOTA and NOTA Chelators on ⁶⁴Cu-Cudotadipep and ⁶⁴Cu-Cunotadipep for Prostate Cancer.

ABSTRACT:

Background

This study compared the effects of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) as ⁶⁴Cu-chelating agents in newly developed prostate-specific membrane antigen (PSMA) target compounds, ⁶⁴Cu-cudotadipep and ⁶⁴Cu-cunotadipep, on pharmacokinetics.

Methods

The in vitro stability of the chelators was evaluated using human and mouse serum. In vitro PSMA-binding affinity and cell uptake were compared using human 22Rv1 cells. To evaluate specific PSMA-expressing tumor-targeting efficiency, micro-positron emission tomography (mcroPET)/computed tomography (CT) and biodistribution analysis were performed using PSMA+ PC3-PIP and PSMA- PC3-flu tumor xenografts.

Results

The serum stability of DOTA- or NOTA-conjugated ⁶⁴Cu-cudotadipep and ⁶⁴Cu-cunotadipep was >97%. The Ki value of the NOTA derivative, cunotadipep, in the in vitro affinity binding analysis was higher (2.17 ± 0.25 nM) than that of the DOTA derivative, cudotadipep (6.75 ± 0.42 nM). The cunotadipep exhibited a higher cellular uptake (6.02 ± 0.05%/1 × 10⁶ cells) compared with the cudotadipep (2.93 ± 0.06%/1 × 10⁶ cells). In the biodistribution analysis and microPET/CT imaging, the ⁶⁴Cu-labeled NOTA derivative, ⁶⁴Cu-cunotadipep, demonstrated a greater tumor uptake and lower liver uptake than the DOTA derivative.

Conclusions

This study indicates that the PSMA-targeted ⁶⁴Cu-cunotadipep can be applied in clinical practice owing to its high diagnostic power for prostate cancer.

SUBMITTER: Lee I

PROVIDER: S-EPMC10453766 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Comparison of the Effects of DOTA and NOTA Chelators on <sup>64</sup>Cu-Cudotadipep and <sup>64</sup>Cu-Cunotadipep for Prostate Cancer.

Lee Inki I Kim Min Hwan MH Lee Kyongkyu K Oh Keumrok K Lim Hyunwoo H Ahn Jae Hun JH Lee Yong Jin YJ Cheon Gi Jeong GJ Chi Dae Yoon DY Lim Sang Moo SM

Diagnostics (Basel, Switzerland) 20230811 16

<h4>Background</h4>This study compared the effects of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) as <sup>64</sup>Cu-chelating agents in newly developed prostate-specific membrane antigen (PSMA) target compounds, <sup>64</sup>Cu-cudotadipep and <sup>64</sup>Cu-cunotadipep, on pharmacokinetics.<h4>Methods</h4>The in vitro stability of the chelators was evaluated using human and mouse serum. In vitro PSMA-binding affinity ...[more]

PMID: 37627908

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Project description:Background: The tumor-associated disialoganglioside GD2 is a bona fide immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma. GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)- expressing T cells as well as natural killer T cells (NKTs) are emerging. However, assessment of intra- and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease. Therefore, a non-invasive approach for the assessment and visualization of GD2 expression in-vivo is of upmost interest and might enable a more appropriate treatment stratification. Methods: Recently, [64Cu]Cu-NOTA-ch14.18/CHO (64Cu-GD2), a radiolabeled GD2-antibody for imaging with Positron-Emission-Tomography (PET) was developed. We here report our first clinical patients' series (n = 11) in different pediatric tumors assessed with 64Cu-GD2 PET/MRI. GD2-expression in tumors and tissue uptake in organs was evaluated by semiquantitative measurements of standardized uptake values (SUV) with PET/MRI on day 1 p.i. (n = 11) as well as on day 2 p.i. (n = 6). Results: In 8 of 9 patients with suspicious tumor lesions on PET/MRI at least one metastasis showed an increased 64Cu-GD2 uptake and a high tracer uptake (SUVmax > 10) was measured in 4 of those 8 patients. Of note, sufficient image quality with high tumor to background contrast was readily achieved on day 1. In case of 64Cu-GD2-positive lesions, an excellent tumor to background ratio (at least 6:1) was observed in bones, muscles or lungs, while lower tumor to background contrast was seen in the spleen, liver and kidneys. Furthermore, we demonstrated extensive tumor heterogeneity between patients as well as among different metastatic sites in individual patients. Dosimetry assessment revealed a whole-body dose of only 0.03 mGy/MBq (range 0.02-0.04). Conclusion: 64Cu-GD2 PET/MRI enables the non-invasive assessment of individual heterogeneity of GD2 expression, which challenges our current clinical practice of patient selection, stratification and immunotherapy application scheme for treatment with anti-GD2 directed therapies.

Project description:The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective small-animal models to test them. The purpose of this study was to evaluate 64Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTA-alendronate was synthesized, radiolabeled with 64Cu, and administered to normal or tumor-bearing aged, female, retired breeder Sprague-Dawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64Cu-DOTA-alendronate. Results:64Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion:64Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as well as the differentiation of malignant versus benign tumors based on absolute labeling uptake.

Dataset Information

Comparison of the Effects of DOTA and NOTA Chelators on ⁶⁴Cu-Cudotadipep and ⁶⁴Cu-Cunotadipep for Prostate Cancer.

Background

Methods

Results

Conclusions

Publications

Comparison of the Effects of DOTA and NOTA Chelators on <sup>64</sup>Cu-Cudotadipep and <sup>64</sup>Cu-Cunotadipep for Prostate Cancer.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Comparison of the Effects of DOTA and NOTA Chelators on 64Cu-Cudotadipep and 64Cu-Cunotadipep for Prostate Cancer.

Background

Methods

Results

Conclusions

Publications

Comparison of the Effects of DOTA and NOTA Chelators on <sup>64</sup>Cu-Cudotadipep and <sup>64</sup>Cu-Cunotadipep for Prostate Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Comparison of the Effects of DOTA and NOTA Chelators on ⁶⁴Cu-Cudotadipep and ⁶⁴Cu-Cunotadipep for Prostate Cancer.