Radiolabelled 177 Lu-Bispidine-Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers
Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid-selective nonadentate bispidine ligand suitable for Lu ion complexation. The ligand (bisp,1) was derivat...
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| Published in | Chemistry : a European journal Vol. 30; no. 14; p. e202303805 |
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| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
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07.03.2024
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| Abstract | Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid-selective nonadentate bispidine ligand suitable for
Lu
ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN
) group as a bioconjugation handle for light-induced labelling of proteins. Quantitative radiosynthesis of [
Lu]Lu-1
was accomplished in 10 minutes at 40 °C. Subsequent incubation of [
Lu]Lu-1
with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0-8.3, gave the radiolabelled mAb, [
Lu]Lu-1-azepin-trastuzumab ([
Lu]Lu-1-mAb) in a decay-corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK-OV-3 human ovarian cancer cells confirmed that [
Lu]Lu-1-mAb remained biological active and displayed specific binding to HER2/neu. Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK-OV-3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g
vs. 14.8±6.1 %ID g
, respectively; P-value=0.037). The data indicate that bispidine-based ligand systems are suitable starting points for constructing novel, high-denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides. |
|---|---|
| AbstractList | Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid-selective nonadentate bispidine ligand suitable for
Lu
ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN
) group as a bioconjugation handle for light-induced labelling of proteins. Quantitative radiosynthesis of [
Lu]Lu-1
was accomplished in 10 minutes at 40 °C. Subsequent incubation of [
Lu]Lu-1
with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0-8.3, gave the radiolabelled mAb, [
Lu]Lu-1-azepin-trastuzumab ([
Lu]Lu-1-mAb) in a decay-corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK-OV-3 human ovarian cancer cells confirmed that [
Lu]Lu-1-mAb remained biological active and displayed specific binding to HER2/neu. Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK-OV-3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g
vs. 14.8±6.1 %ID g
, respectively; P-value=0.037). The data indicate that bispidine-based ligand systems are suitable starting points for constructing novel, high-denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides. Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid-selective nonadentate bispidine ligand suitable for 177 Lu3+ ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN3 ) group as a bioconjugation handle for light-induced labelling of proteins. Quantitative radiosynthesis of [177 Lu]Lu-1+ was accomplished in 10 minutes at 40 °C. Subsequent incubation of [177 Lu]Lu-1+ with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0-8.3, gave the radiolabelled mAb, [177 Lu]Lu-1-azepin-trastuzumab ([177 Lu]Lu-1-mAb) in a decay-corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK-OV-3 human ovarian cancer cells confirmed that [177 Lu]Lu-1-mAb remained biological active and displayed specific binding to HER2/neu. Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK-OV-3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g-1 vs. 14.8±6.1 %ID g-1 , respectively; P-value=0.037). The data indicate that bispidine-based ligand systems are suitable starting points for constructing novel, high-denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides. Abstract Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid‐selective nonadentate bispidine ligand suitable for 177 Lu 3+ ion complexation. The ligand (bisp, 1 ) was derivatised with a photoactivatable aryl azide (ArN 3 ) group as a bioconjugation handle for light‐induced labelling of proteins. Quantitative radiosynthesis of [ 177 Lu]Lu‐ 1 + was accomplished in 10 minutes at 40 °C. Subsequent incubation of [ 177 Lu]Lu‐ 1 + with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0–8.3, gave the radiolabelled mAb, [ 177 Lu]Lu‐ 1 ‐azepin‐trastuzumab ([ 177 Lu]Lu‐ 1 ‐mAb) in a decay‐corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK‐OV‐3 human ovarian cancer cells confirmed that [ 177 Lu]Lu‐ 1 ‐mAb remained biological active and displayed specific binding to HER2/ neu . Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK‐OV‐3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g −1 vs. 14.8±6.1 %ID g −1 , respectively; P ‐value=0.037). The data indicate that bispidine‐based ligand systems are suitable starting points for constructing novel, high‐denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides. |
| Author | Nolff, Mirja Klingler, Simon Cieslik, Patrick A Holland, Jason P |
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| Keywords | photoconjugation Bispidines lanthanoids cancer imaging radiotheranostics |
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| Snippet | Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and... Abstract Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis,... |
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| SubjectTerms | Animals Bridged Bicyclo Compounds, Heterocyclic Cell Line, Tumor Female Humans Ligands Lutetium Mice Mice, Nude Neoplasms - diagnostic imaging Neoplasms - drug therapy Radioisotopes Receptor, ErbB-2 Trastuzumab |
| Title | Radiolabelled 177 Lu-Bispidine-Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers |
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