Bone marrow-derived macrophages loaded with boron carbide nanoparticles as selective boron carriers for crossing the blood-brain barrier toward the glioma microenvironment for boron neutron capture therapy

Abstract

BackgroundBoron neutron capture therapy (BNCT) is a type of targeted radiotherapy that destroys boron-containing cancer cells using a neutron beam. It is intended for the treatment of patients with tumors that are resistant to conventional treatment, inoperable and recurrent. Therefore, it represents a promising therapy for the treatment of glioblastoma multiforme, the most aggressive stage IV cancer. To ensure high efficacy of BNCT, it is necessary to use selective boron carriers that deliver therapeutic doses of the boron-10 isotope to the tumor site, demonstrate a lack of systemic toxicity, and, most importantly, cross the blood-brain barrier. In our studies, we propose using bone marrow-derived macrophages as cellular carriers of boron carbide nanoparticles to selectively deliver boron-10 to the tumor microenvironment. Macrophages can efficiently engulf foreign particles, migrate and accumulate at the tumor site, as well as cross the blood-brain barrier, making them extremely promising boron carriers for BNCT. ResultsBone marrow-derived macrophages in three polarization states (M0, M1, and M2) demonstrated a high uptake ability of boron carbide nanoparticles at a concentration of 100 {micro}g/ml during 24-hour incubation. The highest boron concentration was detected in M1 macrophages, resulting in the greatest inhibition of viability and slower spontaneous migration of this population compared to other types of macrophages. Nevertheless, all macrophage populations (M0, M1, and M2) loaded with boron carbide nanoparticles migrated comparably through the brain endothelial cell layer, mimicking the blood-brain barrier, toward the CCL2-rich supernatant of GL-261 glioma cells. Furthermore, macrophages with nanoparticles did not affect the viability of glioma spheroids after 6 days of co-culture, in contrast to macrophages without nanoparticles, which increased the survival of tumor cells. Importantly, M1 macrophages did not repolarize toward the M2 phenotype during co-culture, as evidenced by the stable expression of CD206 in these cells. In addition, M2 macrophages loaded with B4C nanoparticles showed lower CD206 expression after contact with spheroids compared to this macrophage population without nanoparticles. ConclusionsBone marrow-derived macrophages loaded with boron carbide nanoparticles showed great potential for use in BNCT as boron carriers crossing the blood-brain barrier toward the glioma microenvironment.