Abstract A39: Multimodal imaging of blood-brain barrier disruption during brain metastatic progression in a relevant experimental mouse model

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-02, Vol.73 (3_Supplement), p.A39-A39
• Main Authors: Thorsen, Frits, Fite, Brett, Mahakian, Lisa, Harrison, Victoria, Johnson, Sarah, Ingham, Elizabeth, Qin, Shengping, Seo, Jai W., Meade, Thomas, Sundstrøm, Terje, Ferrara, Katherine W.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.TIM2013-A39

Introduction: Efficient drug delivery to brain metastases is difficult due to an often intact blood-brain barrier (BBB) around smaller lesions, and very few therapeutic drugs penetrate an intact BBB. Relevant experimental brain metastatic models are needed to study biological mechanisms and therapeutic responses of early brain lesions in relation to the BBB. Previous studies injecting small molecules such as sodium fluorescein (MW 376D) have indicated that the BBB is disrupted in experimental brain metastasis larger than 0.25 mm (1). However, little is known regarding at which time point in experimental brain metastasis development the BBB is disrupted, and to what extent larger sized molecules at that time are able to penetrate tumor tissue. We addressed these issues by performing multimodal imaging studies, after injecting contrast agents of various sizes into an established melanoma brain metastasis model (2, 3). Materials and Methods: All studies were approved by the UCD Animal Care and Use Committee. As in (3), we injected 5X105 human melanoma brain metastasis cells harboring the Luciferase and GFP genes, intracardially into 32 NOD/SCID mice. All animals were followed by bioluminescence imaging (BLI) weekly for 6 weeks. MRI (Bruker Biospec 70/30, RARE sequence, RARE factor=2, TE/TR/ST=9 ms/750 ms/1mm, FOV=2x2 cm, Matrix=256x256, NA=4) was performed at weeks 3, 4, 5 and 6 after tumor cell inoculation, before and after i.v. injections of either Gd-HPDO3A (Prohance, MW 559D, 0.5 μmol/g, 20 mice) or a newly synthetized Gadolinium contrast agent with 3 Gd(III) chelates, termed C3, (MW 2kD, 0.167 μmol/g, 5 mice). 64Cu-Albumin (MW 66.5kD) and 18F-FLT (MW 244D) was also injected i.v. prior to PET imaging at weeks 4 and 6. Results and Discussion: BLI visualized tumor cell spread in all animal brains 15mins after injections, and a gradual increase in tumor burden between weeks 1 to 6. T1w MRI at week 3 did not show any tumors, however BLI confirmed presence of metastasis. MRI detected tumors at week 4, and the mean, total number of tumors increased from 26 tumors at week 4, to 89 tumors at week 6. There was an exponential increase in tumor burden from week 4 to 6. The number of leaky tumors also increased exponentially, with mean diameters increasing from around 600 μm to around 700 μm. The smallest leaky tumors detectable by MRI were ~200 μm (week 5). The number of non-leaky tumors peaked at 5 weeks, and their mean diameters increased from 260 μm to 450 μm. Me