Min Chen1, Zixin Chen2, Jessa B Castillo1, Liyang Cui1, Kaixiang Zhou1, Bin Shen1, Jinghang Xie1, Frederick T Chin1, Jianghong Rao3,4. 1. Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, 1201 Welch Rd., Rm.P078, Stanford, CA, 94305-5484, USA. 2. Department of Chemistry, Stanford University, Stanford, CA, 94305, USA. 3. Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, 1201 Welch Rd., Rm.P078, Stanford, CA, 94305-5484, USA. jrao@stanford.edu. 4. Department of Chemistry, Stanford University, Stanford, CA, 94305, USA. jrao@stanford.edu.
Abstract
Positron emission tomography (PET) imaging of apoptosis can noninvasively detect cell death in vivo and assist in monitoring tumor response to treatment in patients. While extensive efforts have been devoted to addressing this important need, no apoptosis PET imaging agents have yet been approved for clinical use. This study reports an improved 18F-labeled caspase-sensitive nanoaggregation tracer ([18F]-C-SNAT4) for PET imaging of tumor response to chemo- and immunotherapies in preclinical mouse models. METHODS: We rationally designed and synthesized a new PET tracer [18F]-C-SNAT4 to detect cell death both in vitro and in vivo. In vitro radiotracer uptake studies were performed on drug-sensitive and -resistant NSCLC cell lines (NCI-H460 and NCI-H1299, respectively) treated with cisplatin at different doses. In vivo therapy response monitoring by [18F]-C-SNAT4 PET imaging was evaluated with two treatment modalities-chemotherapy and immunotherapy in two tumor xenografts in mice. Radiotracer uptake in the tumors was validated ex vivo using γ-counting and cleaved caspase-3 immunofluorescence. RESULTS: This [18F]-C-SNAT4 PET tracer was facilely synthesized and displayed improved serum stability profiles. [18F]-C-SNAT4 cellular update was elevated in NCI-H460 cells in a time- and dose-dependent manner, which correlated well with cell death. A significant increase in [18F]-C-SNAT4 uptake was measured in NCI-H460 tumor xenografts in mice. In contrast, a rapid clearance of [18F]-C-SNAT4 was observed in drug-resistant NCI-H1299 in vitro and in tumor xenografts. Moreover, in BALB/C mice bearing murine colon cancer CT26 tumor xenografts receiving checkpoint inhibitors, [18F]-C-SNAT4 showed its ability for monitoring immunotherapy-induced apoptosis and reporting treatment-responding mice from non-responding. CONCLUSION: The uptake of [18F]-C-SNAT4 in tumors received chemotherapy and immunotherapy is positively correlated with the tumor apoptotic level and the treatment efficacy. [18F]-C-SNAT4 PET imaging can monitor tumor response to two different treatment modalities and predict the therapeutic efficacy in preclinical mouse models.
Positron emission tomography (PET) imaging of apoptosis can noninvasively detect cell death in vivo and assist in monitoring tumor response to treatment in patients. While extensive efforts have been devoted to addressing this important need, no apoptosis PET imaging agents have yet been approved for clinical use. This study reports an improved 18F-labeled caspase-sensitive nanoaggregation tracer ([18F]-C-SNAT4) for PET imaging of tumor response to chemo- and immunotherapies in preclinical mouse models. METHODS: We rationally designed and synthesized a new PET tracer [18F]-C-SNAT4 to detect cell death both in vitro and in vivo. In vitro radiotracer uptake studies were performed on drug-sensitive and -resistant NSCLC cell lines (NCI-H460 and NCI-H1299, respectively) treated with cisplatin at different doses. In vivo therapy response monitoring by [18F]-C-SNAT4 PET imaging was evaluated with two treatment modalities-chemotherapy and immunotherapy in two tumor xenografts in mice. Radiotracer uptake in the tumors was validated ex vivo using γ-counting and cleaved caspase-3 immunofluorescence. RESULTS: This [18F]-C-SNAT4 PET tracer was facilely synthesized and displayed improved serum stability profiles. [18F]-C-SNAT4 cellular update was elevated in NCI-H460 cells in a time- and dose-dependent manner, which correlated well with cell death. A significant increase in [18F]-C-SNAT4 uptake was measured in NCI-H460 tumor xenografts in mice. In contrast, a rapid clearance of [18F]-C-SNAT4 was observed in drug-resistant NCI-H1299 in vitro and in tumor xenografts. Moreover, in BALB/C mice bearing murinecolon cancerCT26tumor xenografts receiving checkpoint inhibitors, [18F]-C-SNAT4 showed its ability for monitoring immunotherapy-induced apoptosis and reporting treatment-responding mice from non-responding. CONCLUSION: The uptake of [18F]-C-SNAT4 in tumors received chemotherapy and immunotherapy is positively correlated with the tumor apoptotic level and the treatment efficacy. [18F]-C-SNAT4 PET imaging can monitor tumor response to two different treatment modalities and predict the therapeutic efficacy in preclinical mouse models.
Entities:
Keywords:
Apoptosis; Chemotherapy; Immunotherapy; Preclinical PET imaging; Tumor therapy response
Authors: Wolfgang A Weber; Volker Petersen; Burkhard Schmidt; Leishia Tyndale-Hines; Thomas Link; Christian Peschel; Markus Schwaiger Journal: J Clin Oncol Date: 2003-07-15 Impact factor: 44.544
Authors: Agnese Irkle; Alex T Vesey; David Y Lewis; Jeremy N Skepper; Joseph L E Bird; Marc R Dweck; Francis R Joshi; Ferdia A Gallagher; Elizabeth A Warburton; Martin R Bennett; Kevin M Brindle; David E Newby; James H Rudd; Anthony P Davenport Journal: Nat Commun Date: 2015-07-07 Impact factor: 14.919
Authors: Emily J Tonogai; Shan Huang; Rachel C Botham; Matthew R Berry; Stephen K Joslyn; Gregory B Daniel; Zixin Chen; Jianghong Rao; Xiang Zhang; Falguni Basuli; John H Rossmeisl; Gregory J Riggins; Amy K LeBlanc; Timothy M Fan; Paul J Hergenrother Journal: Neuro Oncol Date: 2021-10-01 Impact factor: 13.029