TY - JOUR T1 - Remodeling the Vascular Microenvironment of Glioblastoma with α-Particles JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1771 LP - 1777 DO - 10.2967/jnumed.116.173559 VL - 57 IS - 11 AU - Katja Behling AU - William F. Maguire AU - Valentina Di Gialleonardo AU - Lukas E.M. Heeb AU - Iman F. Hassan AU - Darren R. Veach AU - Kayvan R. Keshari AU - Philip H. Gutin AU - David A. Scheinberg AU - Michael R. McDevitt Y1 - 2016/11/01 UR - http://jnm.snmjournals.org/content/57/11/1771.abstract N2 - Tumors escape antiangiogenic therapy by activation of proangiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We previously investigated targeted α-particle therapy with 225Ac-E4G10 as an antivascular approach and showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here, we investigated changes in tumor vascular morphology and functionality caused by 225Ac-E4G10. Methods: We investigated remodeling of the tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4-kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphologic changes in the tumor blood–brain barrier microenvironment. Multicolor flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted MR imaged functional changes in the tumor vascular network. Results: The mechanism of drug action is a combination of remodeling of the glioblastoma vascular microenvironment, relief of edema, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis were lessened, resulting in increased perfusion and reduced diffusion. Pharmacologic uptake of dasatinib into tumor was enhanced after α-particle therapy. Conclusion: Targeted antivascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of platelet-derived growth factor–driven glioblastoma. ER -