PO-312 Molecular imaging of integrin αVβ3 upregulation in a mouse model of brain metastasis

Abstract

IntroductionAngiogenesis is an important marker of tumour stage and aggressiveness. Many anti-angiogenic therapies exist, although clinical success remains poor partly due to difficulties in patient selection. Molecular magnetic resonance imaging (MRI) using targeted microparticles of iron oxide (MPIO) has been used to image angiogenic vessels in solid tumours by targeting integrin αvβ3 with the peptide RGD. The aim of this study was to determine whether RGD conjugated MPIO can be used to detect angiogenic vessels in a mouse model of brain metastasis.Material and methodsMice (n=34) were injected intracerebrally with 4 T1 murine metastatic mammary carcinoma cells. Mice underwent MRI following intravenous injection of either RGD-MPIO or control scrambled RDG-MPIO, at days 7, 14, 21, 28 or 35 using a T2* weighted sequence to detect MPIO-induced hypointensities. Following imaging, brains were perfusion-fixed for histology.Results and discussionsIn mice receiving RGD-MPIO, post-contrast hypointensities were evident at most time-points, and were significantly increased in tumour-bearing vs. contralateral striatum at day 35 (p<0.05). At days 7 and 14, a trend towards increased hypointensities was observed in RGD-MPIO injected mice compared to both the control hemisphere and mice injected with RDG-MPIO. No significant differences were found between the tumour-bearing and contralateral striatum in RDG-MPIO injected mice. Thus, hypointensities observed in mice injected with RGD-MPIO likely reflect specific binding to endothelial αvβ3.At later stages, however, hypointensities were also observed in gadolinium-enhancing tumours in mice receiving RDG-MPIO and unconjugated MPIO. Histological analysis indicated that MPIO of both types were largely present in macrophages associated with tumour blood vessels, suggesting that perivascular macrophages may actively phagocytose MPIO once the BBB is no longer intact. Nevertheless, endothelium-specific binding was also evident histologically in mice imaged with RGD-MPIO, but not with RDG-MPIO.ConclusionRGD-MPIO appear to detect integrin αvβ3 positive blood vessels in a mouse model of brain metastasis. However, molecularly targeted MRI using MPIO may be precluded once tumours reach later stages with overt BBB breakdown, since retention is no longer target-specific.