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

Frits Thorsen, Brett Fite, Lisa M. Mahakian, Jai Seo, Shengping Qin, Victoria Harrison, Sarah Johnson, Elizabeth Ingham, Charles Caskey, Terje Sundstrøm, Thomas J. Meade, Patrick N. Harter, Kai Ove Skaftnesmo, Katherine W. Ferrara

Research output: Contribution to journalArticle

32 Scopus citations

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. 7 T 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 18F-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 64Cu-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 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.

Original languageEnglish (US)
Pages (from-to)812-822
Number of pages11
JournalJournal of Controlled Release
Volume172
Issue number3
DOIs
StatePublished - 2013

Keywords

  • Bioluminescence imaging
  • Brain metastasis
  • Contrast agents
  • MRI
  • PET

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Thorsen, F., Fite, B., Mahakian, L. M., Seo, J., Qin, S., Harrison, V., Johnson, S., Ingham, E., Caskey, C., Sundstrøm, T., Meade, T. J., Harter, P. N., Skaftnesmo, K. O., & Ferrara, K. W. (2013). Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases. Journal of Controlled Release, 172(3), 812-822. https://doi.org/10.1016/j.jconrel.2013.10.019