Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases

• Published in: Journal of controlled release Vol. 172; no. 3; pp. 812 - 822
• Main Authors: Thorsen, Frits, Fite, Brett, Mahakian, Lisa M., Seo, Jai W., Qin, Shengping, Harrison, Victoria, Johnson, Sarah, Ingham, Elizabeth, Caskey, Charles, Sundstrøm, Terje, Meade, Thomas J., Harter, Patrick N., Skaftnesmo, Kai Ove, Ferrara, Katherine W.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28-12-2013
• Subjects: Animals; Benzothiazoles; bioluminescence; Bioluminescence imaging; blood; brain; Brain - pathology; Brain metastasis; Brain Neoplasms - pathology; Brain Neoplasms - secondary; Contrast agents; Contrast Media; detection limit; Female; Gadolinium; histology; Humans; image analysis; Luminescence; Magnetic Resonance Imaging; melanoma; Melanoma - pathology; Melanoma - secondary; metastasis; Mice; Mice, SCID; molecular weight; MRI; Multimodal Imaging; neoplasm cells; Optical Imaging; patients; Permeability; PET; pharmacokinetics; Positron-Emission Tomography; therapeutics; tracer techniques; Contrast agents; Bioluminescence imaging; MRI; Brain metastasis; PET
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2013.10.019

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) 320D) 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 100μm sized lesions and leaky tumors with diameters down to 200μm after contrast injection at week 5. PET imaging showed that 18F-FLT (MW 244Da) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559Da and 2.066kDa) extravasated after 5weeks (tumor diameter 600μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27×10−5cm/s versus 1.12×10−5cm/s). PET imaging further demonstrated tumor permeability to 64Cu-BSA (MW 65.55kDa) at week 6 (tumor diameter 700μm). 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 18F-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.
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