Somit Pandey, Gurvinder Kaur, Nivedita Rana, Sejal Chopra, Imran Rather, Rajender Kumar, Ishita Laroiya, Vijayta D Chadha, Stanley Satz, Micheal G Stabin, Bhagwant Rai Mittal, Jaya Shukla
{"title":"通过整合素αVβ3靶向拟肽IAC推进癌症治疗:从工作台到病床。","authors":"Somit Pandey, Gurvinder Kaur, Nivedita Rana, Sejal Chopra, Imran Rather, Rajender Kumar, Ishita Laroiya, Vijayta D Chadha, Stanley Satz, Micheal G Stabin, Bhagwant Rai Mittal, Jaya Shukla","doi":"10.1089/cbr.2023.0140","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Introduction:</i></b> The expression of alpha-five beta-three (αVβ3) integrins is upregulated in various malignancies undergoing angiogenesis. The development of integrin antagonists as diagnostic probes makes the αVβ3 integrin a suitable candidate for targeting tumor angiogenesis. The goal of this study was to optimize the radiolabeling and evaluate the potential of conjugated integrin antagonist carbamate (IAC), a peptidomimetic, as a theranostic radiopharmaceutical for targeting tumor angiogenesis. <b><i>Methodology:</i></b> Radiolabeling of DOTAGA [2,2',2\"-{10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl} triacetic-acid]-IAC with [<sup>68</sup>Ga]Ga, [<sup>177</sup>Lu]Lu, and [<sup>225</sup>Ac]Ac was optimized. The binding affinity (K<sub>d</sub>) of DOTAGA-IAC for the αVβ3 receptor and cancer cell lines was quantified. The biodistribution studies were conducted in healthy Wistar rats. Dosimetry analysis was performed on [<sup>177</sup>Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [<sup>68</sup>Ga]Ga-DOTAGA-IAC and [<sup>18</sup>F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [<sup>68</sup>Ga]Ga-DOTAGA-IAC and [<sup>18</sup>F]FDG in these patients. <b><i>Results:</i></b> Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). K<sub>d</sub> and B<sub>max</sub> measurements were 15.02 nM and 417 fmol for αVβ3 receptor protein: 115.7 nM and 295.3 fmol for C6 glioma cells. Biodistribution studies in rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [<sup>177</sup>Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq. The dynamic study in patients revealed the optimal imaging time to be 30-35 mins postadministration. Out of the cohort, [<sup>68</sup>Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUV<sub>max</sub>) of 3.94 ± 0.58 compared with [<sup>18</sup>F]FDG (SUV<sub>max</sub> 13.8 ± 6.53). <b><i>Conclusion:</i></b> The study demonstrates that DOTAGA-IAC exhibits strong binding to αVβ3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The outcomes from the pilot study suggest the potential of [<sup>68</sup>Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. While recognizing the theranostic potential of DOTAGA-IAC for αVβ3 integrin-expressing tumors, further clinical investigations are warranted to comprehensively assess therapeutic efficacy.</p>","PeriodicalId":55277,"journal":{"name":"Cancer Biotherapy and Radiopharmaceuticals","volume":" ","pages":"632-643"},"PeriodicalIF":2.4000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Advancing Cancer Theranostics Through Integrin αVβ3-Targeted Peptidomimetic IAC: From Bench to Bedside.\",\"authors\":\"Somit Pandey, Gurvinder Kaur, Nivedita Rana, Sejal Chopra, Imran Rather, Rajender Kumar, Ishita Laroiya, Vijayta D Chadha, Stanley Satz, Micheal G Stabin, Bhagwant Rai Mittal, Jaya Shukla\",\"doi\":\"10.1089/cbr.2023.0140\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b><i>Introduction:</i></b> The expression of alpha-five beta-three (αVβ3) integrins is upregulated in various malignancies undergoing angiogenesis. The development of integrin antagonists as diagnostic probes makes the αVβ3 integrin a suitable candidate for targeting tumor angiogenesis. The goal of this study was to optimize the radiolabeling and evaluate the potential of conjugated integrin antagonist carbamate (IAC), a peptidomimetic, as a theranostic radiopharmaceutical for targeting tumor angiogenesis. <b><i>Methodology:</i></b> Radiolabeling of DOTAGA [2,2',2\\\"-{10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl} triacetic-acid]-IAC with [<sup>68</sup>Ga]Ga, [<sup>177</sup>Lu]Lu, and [<sup>225</sup>Ac]Ac was optimized. The binding affinity (K<sub>d</sub>) of DOTAGA-IAC for the αVβ3 receptor and cancer cell lines was quantified. The biodistribution studies were conducted in healthy Wistar rats. Dosimetry analysis was performed on [<sup>177</sup>Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [<sup>68</sup>Ga]Ga-DOTAGA-IAC and [<sup>18</sup>F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [<sup>68</sup>Ga]Ga-DOTAGA-IAC and [<sup>18</sup>F]FDG in these patients. <b><i>Results:</i></b> Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). K<sub>d</sub> and B<sub>max</sub> measurements were 15.02 nM and 417 fmol for αVβ3 receptor protein: 115.7 nM and 295.3 fmol for C6 glioma cells. Biodistribution studies in rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [<sup>177</sup>Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq. The dynamic study in patients revealed the optimal imaging time to be 30-35 mins postadministration. Out of the cohort, [<sup>68</sup>Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUV<sub>max</sub>) of 3.94 ± 0.58 compared with [<sup>18</sup>F]FDG (SUV<sub>max</sub> 13.8 ± 6.53). <b><i>Conclusion:</i></b> The study demonstrates that DOTAGA-IAC exhibits strong binding to αVβ3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The outcomes from the pilot study suggest the potential of [<sup>68</sup>Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. While recognizing the theranostic potential of DOTAGA-IAC for αVβ3 integrin-expressing tumors, further clinical investigations are warranted to comprehensively assess therapeutic efficacy.</p>\",\"PeriodicalId\":55277,\"journal\":{\"name\":\"Cancer Biotherapy and Radiopharmaceuticals\",\"volume\":\" \",\"pages\":\"632-643\"},\"PeriodicalIF\":2.4000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Biotherapy and Radiopharmaceuticals\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1089/cbr.2023.0140\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Biotherapy and Radiopharmaceuticals","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/cbr.2023.0140","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/8 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Advancing Cancer Theranostics Through Integrin αVβ3-Targeted Peptidomimetic IAC: From Bench to Bedside.
Introduction: The expression of alpha-five beta-three (αVβ3) integrins is upregulated in various malignancies undergoing angiogenesis. The development of integrin antagonists as diagnostic probes makes the αVβ3 integrin a suitable candidate for targeting tumor angiogenesis. The goal of this study was to optimize the radiolabeling and evaluate the potential of conjugated integrin antagonist carbamate (IAC), a peptidomimetic, as a theranostic radiopharmaceutical for targeting tumor angiogenesis. Methodology: Radiolabeling of DOTAGA [2,2',2"-{10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl} triacetic-acid]-IAC with [68Ga]Ga, [177Lu]Lu, and [225Ac]Ac was optimized. The binding affinity (Kd) of DOTAGA-IAC for the αVβ3 receptor and cancer cell lines was quantified. The biodistribution studies were conducted in healthy Wistar rats. Dosimetry analysis was performed on [177Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [68Ga]Ga-DOTAGA-IAC and [18F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [68Ga]Ga-DOTAGA-IAC and [18F]FDG in these patients. Results: Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). Kd and Bmax measurements were 15.02 nM and 417 fmol for αVβ3 receptor protein: 115.7 nM and 295.3 fmol for C6 glioma cells. Biodistribution studies in rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [177Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq. The dynamic study in patients revealed the optimal imaging time to be 30-35 mins postadministration. Out of the cohort, [68Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUVmax) of 3.94 ± 0.58 compared with [18F]FDG (SUVmax 13.8 ± 6.53). Conclusion: The study demonstrates that DOTAGA-IAC exhibits strong binding to αVβ3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The outcomes from the pilot study suggest the potential of [68Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. While recognizing the theranostic potential of DOTAGA-IAC for αVβ3 integrin-expressing tumors, further clinical investigations are warranted to comprehensively assess therapeutic efficacy.
期刊介绍:
Cancer Biotherapy and Radiopharmaceuticals is the established peer-reviewed journal, with over 25 years of cutting-edge content on innovative therapeutic investigations to ultimately improve cancer management. It is the only journal with the specific focus of cancer biotherapy and is inclusive of monoclonal antibodies, cytokine therapy, cancer gene therapy, cell-based therapies, and other forms of immunotherapies.
The Journal includes extensive reporting on advancements in radioimmunotherapy, and the use of radiopharmaceuticals and radiolabeled peptides for the development of new cancer treatments.