title: Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases.
abstract: Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting d-luciferin (molecular weight (MW) 320 D) suggested that tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200 μm after contrast injection at week 5. PET imaging showed that (18)F-FLT (MW 244 Da) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559 Da and 2.066 kDa) extravasated after 5 weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27 × 10(-5)cm/s versus 1.12 × 10(-5)cm/s). PET imaging further demonstrated tumor permeability to (64)Cu-BSA (MW 65.55 kDa) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to d-luciferin and the amphipathic small molecule (18)F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway. Electronic address: frits.thorsen@biomed.uib.no.
authors.forename: Frits
authors.initials: F
authors.lastname: Thorsen
authors.forename: Brett
authors.initials: B
authors.lastname: Fite
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.forename: Jai W
authors.initials: JW
authors.lastname: Seo
authors.forename: Shengping
authors.initials: S
authors.lastname: Qin
authors.forename: Victoria
authors.initials: V
authors.lastname: Harrison
authors.forename: Sarah
authors.initials: S
authors.lastname: Johnson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ingham
authors.forename: Charles
authors.initials: C
authors.lastname: Caskey
authors.forename: Terje
authors.initials: T
authors.lastname: Sundstrøm
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Meade
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.forename: Kai Ove
authors.initials: KO
authors.lastname: Skaftnesmo
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D001921:Brain / Q000473:pathology*; D001932:Brain Neoplasms / Q000473:pathology* / Q000556:secondary*; D003287:Contrast Media; D005260:Female; D005682:Gadolinium; D006801:Humans; D049449:Luminescence; D008279:Magnetic Resonance Imaging; D008545:Melanoma / Q000473:pathology* / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D064847:Multimodal Imaging; D061848:Optical Imaging; D010539:Permeability; D049268:Positron-Emission Tomography
chemical_list: D052160:Benzothiazoles; D003287:Contrast Media; C532924:D-luciferin; D005682:Gadolinium
keywords: Bioluminescence imaging; Brain metastasis; Contrast agents; MRI; PET