Christian A Mason1, Lukas M Carter1, Komal Mandleywala1, Paula Demetrio de Souza Franca1,2, Jan-Philip Meyer1, Tanjeena Mamun1, Joseph M Backer3, Marina V Backer3, Thomas Reiner1,4,5, Jason S Lewis6,7,8. 1. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. 2. Department of Otorhinolaryngology and Head and Neck Surgery, Federal University of São Paulo, São Paulo, SP, 04023-062, Brazil. 3. SibTech Inc., Brookfield, CT, 06804, USA. 4. Department of Radiology, Weill Cornell Medical College, New York, NY, 10065, USA. 5. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. 6. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. Lewisj2@mskcc.org. 7. Department of Radiology, Weill Cornell Medical College, New York, NY, 10065, USA. Lewisj2@mskcc.org. 8. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. Lewisj2@mskcc.org.
Abstract
PURPOSE: Metastatic breast cancer is the second leading cause of cancer-related death in women. The 5-year survival rate for metastatic breast cancer has remained near 26.9 % for over a decade. The recruitment of hematopoietic stem cells with high expression of the vascular endothelial growth factor receptor 1 (VEGFR-1) has been implicated in early stages of metastasis formation. We propose the use of an 18F-labeled single-chain version of VEGF121, re-engineered to be selective for VEGFR-1 (scVR1), as a positron emission tomography (PET) imaging agent to non-invasively image early-stage metastases. PROCEDURES: scVR1 was 18F-labeled via a biorthogonal click reaction between site-specifically trans-cyclooctene functionalized scVR1 and an Al18F labeled tetrazine-NODA (1,4,7-triazacyclononane-1,4-diiacetic acid). The [18F]AlF-NODA-scVR1 was purified using a PD10 column and subsequently analyzed on HPLC to determine radiochemical purity. Animal experiments were performed in 6-8-week-old female BALB/c mice bearing orthotopic primary 4T1 breast tumors or 4T1 metastatic lesions. The [18F]AlF-NODA-scVR1 tracer was administered via tail vein injection; PET imaging and ex vivo analysis was performed 2 h post-injection. RESULTS: The [18F]AlF-NODA-scVR1 was prepared with a 98.2 ± 1.5 % radiochemical purity and an apparent molar activity of 7.5 ± 1.2 GBq/μmol. The specific binding of scVR1 to VEGFR-1 was confirmed via bead-based assay. The ex vivo biodistribution showed tumor uptake of 3.5 ± 0.5 % ID/g and was readily observable in PET images. Metastasis formation was detected with [18F]AlF-NODA-scVR1 tracer showing colocalization with bioluminescent imaging as well as ex vivo autoradiography and immunofluorescent staining of VEGFR-1. CONCLUSIONS: The diagnostic capabilities of the [18F]AlF-NODA-scVR1 PET tracer was confirmed in both orthotopic and metastatic murine cancer models. These results support the potential use of [18F]AlF-NODA-scVR1 as a PET tracer that could image metastases, providing clinicians with an additional tool to assess a patient's need for adjuvant therapies.
PURPOSE: Metastatic breast cancer is the second leading cause of cancer-related death in women. The 5-year survival rate for metastatic breast cancer has remained near 26.9 % for over a decade. The recruitment of hematopoietic stem cells with high expression of the vascular endothelial growth factor receptor 1 (VEGFR-1) has been implicated in early stages of metastasis formation. We propose the use of an 18F-labeled single-chain version of VEGF121, re-engineered to be selective for VEGFR-1 (scVR1), as a positron emission tomography (PET) imaging agent to non-invasively image early-stage metastases. PROCEDURES: scVR1 was 18F-labeled via a biorthogonal click reaction between site-specifically trans-cyclooctene functionalized scVR1 and an Al18F labeled tetrazine-NODA (1,4,7-triazacyclononane-1,4-diiacetic acid). The [18F]AlF-NODA-scVR1 was purified using a PD10 column and subsequently analyzed on HPLC to determine radiochemical purity. Animal experiments were performed in 6-8-week-old female BALB/c mice bearing orthotopic primary 4T1 breast tumors or 4T1 metastatic lesions. The [18F]AlF-NODA-scVR1 tracer was administered via tail vein injection; PET imaging and ex vivo analysis was performed 2 h post-injection. RESULTS: The [18F]AlF-NODA-scVR1 was prepared with a 98.2 ± 1.5 % radiochemical purity and an apparent molar activity of 7.5 ± 1.2 GBq/μmol. The specific binding of scVR1 to VEGFR-1 was confirmed via bead-based assay. The ex vivo biodistribution showed tumor uptake of 3.5 ± 0.5 % ID/g and was readily observable in PET images. Metastasis formation was detected with [18F]AlF-NODA-scVR1 tracer showing colocalization with bioluminescent imaging as well as ex vivo autoradiography and immunofluorescent staining of VEGFR-1. CONCLUSIONS: The diagnostic capabilities of the [18F]AlF-NODA-scVR1 PET tracer was confirmed in both orthotopic and metastatic murine cancer models. These results support the potential use of [18F]AlF-NODA-scVR1 as a PET tracer that could image metastases, providing clinicians with an additional tool to assess a patient's need for adjuvant therapies.
Entities:
Keywords:
Autoradiography; Immunofluorescence; Lung metastasis; Metastatic breast cancer; Metastatic niche; PET imaging; Radiochemistry; Tumor microenvironment; VEGFR-1
Authors: Jenny Yao; Xiumin Wu; Guanglei Zhuang; Ian M Kasman; Tobias Vogt; Vernon Phan; Masabumi Shibuya; Napoleone Ferrara; Carlos Bais Journal: Proc Natl Acad Sci U S A Date: 2011-06-27 Impact factor: 11.205
Authors: Sai Kiran Sharma; Serge K Lyashchenko; Hijin A Park; Nagavarakishore Pillarsetty; Yorann Roux; Jiong Wu; Sophie Poty; Kathryn M Tully; John T Poirier; Jason S Lewis Journal: Nucl Med Biol Date: 2019-05-03 Impact factor: 2.408