title: An MRI Method To Map Tumor Hypoxia Using Red Blood Cells Loaded with a pO2-Responsive Gd-Agent.
abstract: Hypoxia is a typical hallmark of many solid tumors and often leads to therapy resistance and the development of a more aggressive cancer phenotype. Oxygen content in tissues has been evaluated using numerous different methods for several imaging modalities, but none has yet reached the required standard of spatial and temporal resolution. Magnetic Resonance Imaging (MRI) appears to be the technique of choice and several pO2-responsive probes have been designed for it over the years. In vivo translation is often hampered in Gd-relaxation agents as it is not possible to separate effects that arise from changes in local concentration from those associated with responsive properties. A novel procedure for the MRI based assessment of hypoxia is reported herein. The method relies on the combined use of Gd-DOTP- and Gd-HPDO3A-labeled red blood cells (RBCs) where the first probe acts as a vascular oxygenation-responsive agent, while the second reports the local labeled RBC concentration in a transplanted breast tumor mouse model. The MRI assessment of oxygenation state has been validated by photoacoustic imaging and ex vivo immunofluorescence. The method refines tumor staging in preclinical models and makes possible an accurate monitoring of the relationship between oxygenation and tumor growth.
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino , Torino 10126, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Di Gregorio
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino , Torino 10126, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ferrauto
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino , Torino 10126, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Gianolio
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino , Torino 10126, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Lanzardo
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino , Torino 10126, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Carrera
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino , Torino 10126, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Fedeli
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Torino , Torino 10126, Italy.|IBB-CNR-UOS at the University of Torino , Torino 10126, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Aime
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage; D004912:Erythrocytes / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D005682:Gadolinium / Q000008:administration & dosage; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000175:diagnosis* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D015674:Mammary Neoplasms, Animal / Q000097:blood / Q000098:blood supply / Q000175:diagnosis* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000008:administration & dosage; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D010100:Oxygen / Q000032:analysis* / Q000378:metabolism; D061088:Photoacoustic Techniques; D013194:Staining and Labeling / Q000379:methods; D014184:Transplantation, Homologous
chemical_list: D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; C062402:gadoteridol; C059412:gadolinium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetrakis(methylenephosphonic acid); D005682:Gadolinium; D010100:Oxygen
keywords: Gd-DOTP; contrast agents; magnetic resonance imaging; red blood cells; tumor hypoxia; vascular volume