Objective: Epidermal growth factor receptor(EGFR) is overexpressed in a wide variety of solid tumors, serving as a well-characterized target for cancer imaging or therapy. In this study, we aimed to design and synthes...Objective: Epidermal growth factor receptor(EGFR) is overexpressed in a wide variety of solid tumors, serving as a well-characterized target for cancer imaging or therapy. In this study, we aimed to design and synthesize a radiotracer, ^(64) Cu-NOTA-C225, targeting EGFR for tumor positron emission tomography(PET) imaging.Methods: Cetuximab(C225) was conjugated to a bifunctional chelator, p-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid(NOTA), and further radiolabeled with copper-^(64) for PET imaging. ^(64) CuNOTA-IgG and Cy5.5-C225 were also synthesized as control probes. A431 and A549 mouse models were established for micro-PET and/or near-infrared fluorescence(NIRF) imaging.Results: ^(64) Cu-NOTA-C225 exhibited stability in vivo and in vitro up to 24 h and 50 h post-injection,respectively. A431 tumors with average standard uptake values(SUVs) of 5.61±0.69, 6.68±1.14, 7.80±1.51 at 6, 18 and 36 h post-injection, respectively, which were significantly higher than that of moderate EGFR expressing tumors(A549), with SUVs of 0.89±0.16, 4.70±0.81, 2.01±0.50 at 6, 18 and 36 h post-injection, respectively. The expression levels of A431 and A549 were confirmed by western blotting. Additionally, the tracer uptake in A431 tumors can be blocked by unlabeled cetuximab, suggesting that tracer uptake by tumors was receptor-mediated.Furthermore, NIRF imaging using Cy5.5-C225 showed that the fluorescence intensity in tumors increased with time, with a maximal intensity of 8.17 E+10(p/s/cm^2/sr)/(μW/cm^2) at 48 h post-injection, which is consistent with the paradigm from micro-PET imaging in A431 tumor-bearing mice.Conclusions: The ^(64) Cu-NOTA-C225 PET imaging may be able to specifically and sensitively differentiate tumor models with different EGFR expression levels. It offers potentials as a PET radiotracer for imaging of tracer EGFR-positive tumors.展开更多
Copper-64 is a radioisotope of medical interest that could be used for positron emission tomography imaging and targeted radiotherapy of cancer. In this work,we investigated the possibility of producing the^(64)Cu iso...Copper-64 is a radioisotope of medical interest that could be used for positron emission tomography imaging and targeted radiotherapy of cancer. In this work,we investigated the possibility of producing the^(64)Cu isotope through a^(65)Cu(γ,n) reaction using high-intensity γ-beams produced at the Extreme Light InfrastructureNuclear Physics facility(ELI-NP). The specific activity for^(64)Cu was obtained as a function of target geometry, irradiation time, and electron beam energy, which translates into γ-beam energy. Optimized conditions for the generation of^(64)Cu isotopes at the ELI-NP were discussed. We estimated that an achievable saturation specific activity is of the order of 1–2 m Ci/g for thin targets(radius 1–2 mm,thickness 1 cm) and for a γ-beam flux of 10^(11) s ~1. Based on these results, the ELI-NP could provide great potential for the production of some innovative radioisotopes of medical interest in sufficient quantities suitable for nuclear medicine research.展开更多
基金supported by Natural Science Foundation of Beijing Municipality (No. 7162041)Beijing Nova program (No. Z171100001117020)+1 种基金Beijing Municipal Commission of Health and Family Planning (215 backbone program No. 2015-3-072)Beijing talent project (No. 2017000021223ZK33)
文摘Objective: Epidermal growth factor receptor(EGFR) is overexpressed in a wide variety of solid tumors, serving as a well-characterized target for cancer imaging or therapy. In this study, we aimed to design and synthesize a radiotracer, ^(64) Cu-NOTA-C225, targeting EGFR for tumor positron emission tomography(PET) imaging.Methods: Cetuximab(C225) was conjugated to a bifunctional chelator, p-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid(NOTA), and further radiolabeled with copper-^(64) for PET imaging. ^(64) CuNOTA-IgG and Cy5.5-C225 were also synthesized as control probes. A431 and A549 mouse models were established for micro-PET and/or near-infrared fluorescence(NIRF) imaging.Results: ^(64) Cu-NOTA-C225 exhibited stability in vivo and in vitro up to 24 h and 50 h post-injection,respectively. A431 tumors with average standard uptake values(SUVs) of 5.61±0.69, 6.68±1.14, 7.80±1.51 at 6, 18 and 36 h post-injection, respectively, which were significantly higher than that of moderate EGFR expressing tumors(A549), with SUVs of 0.89±0.16, 4.70±0.81, 2.01±0.50 at 6, 18 and 36 h post-injection, respectively. The expression levels of A431 and A549 were confirmed by western blotting. Additionally, the tracer uptake in A431 tumors can be blocked by unlabeled cetuximab, suggesting that tracer uptake by tumors was receptor-mediated.Furthermore, NIRF imaging using Cy5.5-C225 showed that the fluorescence intensity in tumors increased with time, with a maximal intensity of 8.17 E+10(p/s/cm^2/sr)/(μW/cm^2) at 48 h post-injection, which is consistent with the paradigm from micro-PET imaging in A431 tumor-bearing mice.Conclusions: The ^(64) Cu-NOTA-C225 PET imaging may be able to specifically and sensitively differentiate tumor models with different EGFR expression levels. It offers potentials as a PET radiotracer for imaging of tracer EGFR-positive tumors.
基金supported by Extreme Light Infrastructure-Nuclear Physics(ELI-NP)-Phase Ia project co-financed by the European Union through the European Regional Development Fund+1 种基金the National Natural Science Foundation of China(No.11405083)the Young Talent Project of the University of South China
文摘Copper-64 is a radioisotope of medical interest that could be used for positron emission tomography imaging and targeted radiotherapy of cancer. In this work,we investigated the possibility of producing the^(64)Cu isotope through a^(65)Cu(γ,n) reaction using high-intensity γ-beams produced at the Extreme Light InfrastructureNuclear Physics facility(ELI-NP). The specific activity for^(64)Cu was obtained as a function of target geometry, irradiation time, and electron beam energy, which translates into γ-beam energy. Optimized conditions for the generation of^(64)Cu isotopes at the ELI-NP were discussed. We estimated that an achievable saturation specific activity is of the order of 1–2 m Ci/g for thin targets(radius 1–2 mm,thickness 1 cm) and for a γ-beam flux of 10^(11) s ~1. Based on these results, the ELI-NP could provide great potential for the production of some innovative radioisotopes of medical interest in sufficient quantities suitable for nuclear medicine research.
