Alpha particle enhanced permeabilization of the blood tumor barrier using alpha-v beta-3 (αvβ3) specific nanoparticles

633 Objectives Glioblastoma (GBM) is the most common primary malignant brain tumor characterized by extensive angiogenesis and micrometastasis. Despite the leaky nature of GBM blood vessels, effective delivery of therapeutics has been a major challenge due to the highly torturous nature of newly formed vasculature in the tumor microenvironment, especially in the non-enhancing regions seen on MRI. We previously showed the permeabilization of the blood brain barrier (BBB) using αVβ3-targeted nanoparticles radiolabeled with alpha particle emitting isotopes in normal brain. In this work, we examine the ability of our radiolabeled nanoparticles to enhance the permeability of blood tumor barrier (BTB) in an orthotopic GBM model, as has been reported to occur after external beam radiation. Methods Human GBM cells were implanted intracranially in nude mice and allowed to grow for ~14 days. 225Ac labeled nanoparticles were injected intracranially into mice (~1µCi/animal). Enhancement of BTB permeability was measured 2 and 5 days post 225Ac injection (n=3). Effect of dexamethasone administration (48 h) on 225Ac enhanced BTB opening was also examined. Inherent BTB permeability of tumors was measured and used as control. Evan’s blue dye and fluorescent PGLA nanoparticles were used to measure BTB permeability in all mice. Results When compared to control mice, 225Ac labeled nanoparticles caused significant enhancement of BTB permeability 2 and 5 days post injection. Administration of dexamethasone caused a modest decrease in 225Ac-induced enhanced BTB permeability. γ-H2A.X staining showed negligible double stranded DNA damage in sectioned brains away from the site of injection, indicating that the BTB permeability in the distal regions was not related to direct damage caused by alpha particle emission in these regions, in contrast to the direct tumor killing seen at the injection site. Conclusions Based on these results, our targeted nanoparticles radiolabeled with alpha particle emitters can potentially be exploited to enhance the permeability of BTB for systemically administered therapies in addition to their direct toxicity on their targets.