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Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas.
- Source :
-
Nature communications [Nat Commun] 2024 Jun 06; Vol. 15 (1), pp. 4698. Date of Electronic Publication: 2024 Jun 06. - Publication Year :
- 2024
-
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.<br /> (© 2024. The Author(s).)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 38844770
- Full Text :
- https://doi.org/10.1038/s41467-024-48326-w