| Autor: |
Guo, Hua, Kommidi, Harikrishna, Vedvyas, Yogindra, McCloskey, Jaclyn E., Zhang, Weiqi, Chen, Nandi, Nurili, Fuad, Wu, Amy P., Sayman, Haluk B., Akin, Oguz, Rodriguez, Erik A., Aras, Omer, Jin, Moonsoo M., Ting, Richard |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Popis: |
Clinical trials that involve genome-edited-cells are growing in popularity, where CAR-T immunotherapy and CRISPR editing are more recognized strategies. Genetic reporters are needed to localize the molecular events that these cells cause in patients. Specifically, a non-immunogenic genetic reporter is urgently needed as current reporters are immunogenic due to derivation from non-human sources. Prostate-specific membrane antigen (PSMA) is potentially non-immunogenic due to its natural, low-level expression in select tissues (self-MHC display). PSMA overexpression on human prostate adenocarcinoma is also visible with certain contrast. We exploit these properties in a transduced, two-component, Human-Derived, Genetic, Positron-emitting and Fluorescent (HD-GPF) reporter system. Mechanistically analogous to the luciferase/luciferin reporter, PSMA is genetically encoded into non-PSMA expressing 8505C cells and tracked with ACUPA-Cy3-BF3, a single, systemically injected small-molecule that delivers both positron emitting fluoride ((18)F) and a fluorophore (Cy3) to report on PSMA expression. PSMA-lentivirus transduced tissues become visible by Cy3 fluorescence, [(18)F]-PET and ɣ-scintillated biodistribution. HD-GPF is visible at sub-cellular resolution, while a reduced PET background is achieved in vivo, due to rapid ACUPA-Cy3-BF3 renal excretion. Co-transduction with luciferase and GFP show specific advantages over popular genetic reporters in advanced murine models including: A ‘mosaic’ model of solid-tumor intratumoral heterogeneity, and a survival model for observing post-surgical recurrence. We report an advanced genetic reporter that is useful for tracking genetically modified cells from the deep tissue to the microscopic level by PET and fluorescence. This reporter system is potentially non-immunogenic and will therefore be useful in human studies. Due to derivation from prostate adenocarcinoma, translational ACUPA-Cy3-BF3 potential in radical prostatectomy is demonstrated. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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