1. Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas.
- Author
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Arrieta VA, Gould A, Kim KS, Habashy KJ, Dmello C, Vázquez-Cervantes GI, Palacín-Aliana I, McManus G, Amidei C, Gomez C, Dhiantravan S, Chen L, Zhang DY, Saganty R, Cholak ME, Pandey S, McCord M, McCortney K, Castro B, Ward R, Muzzio M, Bouchoux G, Desseaux C, Canney M, Carpentier A, Zhang B, Miska JM, Lesniak MS, Horbinski CM, Lukas RV, Stupp R, Lee-Chang C, and Sonabend AM
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Glioma drug therapy, Glioma immunology, Glioma pathology, Brain metabolism, Brain drug effects, Female, Drug Delivery Systems, Ultrasonic Waves, Glioblastoma drug therapy, Glioblastoma immunology, Glioblastoma pathology, Male, Microglia drug effects, Microglia metabolism, Mice, Inbred C57BL, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized pharmacology, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors administration & dosage, Polyethylene Glycols, Doxorubicin pharmacology, Doxorubicin administration & dosage, Doxorubicin therapeutic use, Doxorubicin analogs & derivatives, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Blood-Brain Barrier metabolism, Blood-Brain Barrier drug effects, Brain Neoplasms drug therapy, Brain Neoplasms immunology, Brain Neoplasms pathology, Microbubbles
- Abstract
Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM., (© 2024. The Author(s).)
- Published
- 2024
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