Three-dimensional MR mapping of angiogenesis with α₅β ₁(α_νβ₃)-targeted theranostic nanoparticles in the MDA-MB-435 xenograft mouse model

Our objectives were 1) to characterize angiogenesis in the MDA-MB-435 xenograft mouse model with three-dimensional (3D) MR molecular imaging using α₅β₁(RGD)- or irrelevant RGS-targeted paramagnetic nanoparticles and 2) to use MR molecular imaging to assess the antiangiogenic effectiveness of α₅β₁(α _νβ₃)- vs. α_νβ ₃-targeted fumagillin (50 μg/kg) nanoparticles. Tumor-bearing mice were imaged with MR before and after administration of either α₅β₁(RGD) or irrelevant RGS-paramagnetic nanoparticles. In experiment 2, mice received saline or α ₅β₁(α_νβ₃)- or α_νβ₃-targeted fumagillin nanoparticles on days 7, 11, 15, and 19 posttumor implant. On day 22, MRI was performed using α₅β₁(α_νβ₃)- targeted paramagnetic nanoparticles to monitor the antiangiogenic response. 3D reconstructions of α₅β₁(RGD)-signal enhancement revealed a sparse, asymmetrical pattern of angiogenesis along the tumor periphery, which occupied <2.0% tumor surface area. α₅β ₁-targeted rhodamine nanoparticles colocalized with FITC-lectin corroborated the peripheral neovascular signal. α₅β ₁(α_νβ₃)-fumagillin nanoparticles decreased neovasculature to negligible levels relative to control; α_νβ₃-targeted fumagillin nanoparticles were less effective (P>0.05). Reduction of angiogenesis in MDA-MB-435 tumors from low to negligible levels did not decrease tumor volume. MR molecular imaging may be useful for characterizing tumors with sparse neovasculature that are unlikely to have a reduced growth response to targeted antiangiogenic therapy.