Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas

• DOI: 10.1038/s41467-024-48326-w
• Publication Date: 2024-06-06T10:03:47Z
• Authors: Víctor A. Arrieta; Andrew Gould; Kwang-Soo Kim; Karl J. Habashy; Crismita Dmello; Gustavo I. Vázque...; Irina Palacín-Aliana; Graysen McManus; Christina Amidei; Cristal Gomez; Silpol Dhiantravan; Li Chen; Daniel Y. Zhang; Ruth Saganty; Meghan E. Cholak; Surya Pandey; Matthew McCord; Kathleen McCortney; Brandyn Castro; Rachel Ward; Miguel Muzzio; Guillaume Bouchoux; Carole Desseaux; Michael Canney; Alexandre Carpentier; Bin Zhang; Jason M. Miska; Maciej S. Lesniak; Craig M. Horbinski; Rimas V. Lukas; Roger Stupp; Catalina Lee-Chang; Adam M. Sonabend
• Keywords: Male; 0301 basic medicine; Science; Programmed Cell Death 1 Receptor; Antibodies, Monoclonal, Humanized; Article; Mice; 03 medical and health sciences; Drug Delivery Systems; Cell Line, Tumor; Animals; Humans; Immune Checkpoint Inhibitors; Microbubbles; Brain Neoplasms; Q; Brain; Glioma; Mice, Inbred C57BL; Ultrasonic Waves; Doxorubicin; Blood-Brain Barrier; Female; Microglia; Glioblastoma

Abstract Given the marginal penetration of most drugs across blood-brain barrier, efficacy various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open barrier increase concentration liposomal doxorubicin PD-1 blocking antibodies (aPD-1). We report results on a cohort 4 GBM patients preclinical models treated with this approach. LIPU/MB increases by 2-fold 3.9-fold in human murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated disruption leads 6-fold aPD-1 concentrations peritumoral brain regions from pembrolizumab, Doxorubicin delivered upregulate major histocompatibility complex (MHC) class I II tumor cells. Increased achieved elicit IFN-γ MHC expression microglia macrophages. long-term survival glioma-bearing mice, which rely myeloid cells lymphocytes their efficacy. Overall, translational study supports utility potentiate antitumoral activities GBM.