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- Title
Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas.
- Authors
Arrieta, Víctor A.; Gould, Andrew; Kim, Kwang-Soo; Habashy, Karl J.; Dmello, Crismita; Vázquez-Cervantes, Gustavo I.; Palacín-Aliana, Irina; McManus, Graysen; Amidei, Christina; Gomez, Cristal; Dhiantravan, Silpol; Chen, Li; Zhang, Daniel Y.; Saganty, Ruth; Cholak, Meghan E.; Pandey, Surya; McCord, Matthew; McCortney, Kathleen; Castro, Brandyn; Ward, Rachel
- 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. Ultrasound-mediated blood-brain barrier opening has been exploited to improve drug delivery in the brain. Here the authors show that low-intensity pulsed ultrasound in combination with intravenous injection of microbubbles enhances the delivery of doxorubicin and anti-PD1 in gliomas, improving anti-tumor immune responses.
- Subjects
DOXORUBICIN; IMMUNOREGULATION; BLOOD-brain barrier; GLIOMAS; PROGRAMMED cell death 1 receptors; MAJOR histocompatibility complex; MYELOID cells
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-48326-w