Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas.
Víctor A ArrietaAndrew GouldKwang-Soo KimKarl J HabashyCrismita DmelloGustavo I Vázquez-CervantesIrina Palacín-AlianaGraysen McManusChristina AmideiCristal GomezSilpol DhiantravanLi ChenDaniel Y ZhangRuth SagantyMeghan E CholakSurya PandeyMatthew McCordKathleen McCortneyBrandyn CastroRachel WardMiguel MuzzioGuillaume BouchouxCarole DesseauxMichael CanneyAlexandre CarpentierBin ZhangJason M MiskaMaciej S LesniakCraig M HorbinskiRimas V LukasRoger StuppCatalina Lee-ChangAdam M SonabendPublished in: Nature communications (2024)
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.
Keyphrases
- drug delivery
- blood brain barrier
- cancer therapy
- end stage renal disease
- cerebral ischemia
- resting state
- white matter
- magnetic resonance imaging
- newly diagnosed
- poor prognosis
- endothelial cells
- ejection fraction
- inflammatory response
- induced apoptosis
- multiple sclerosis
- chronic kidney disease
- prognostic factors
- stem cells
- cell proliferation
- mesenchymal stem cells
- peritoneal dialysis
- advanced non small cell lung cancer
- cell therapy
- minimally invasive
- functional connectivity
- high grade
- spinal cord
- spinal cord injury
- neuropathic pain
- contrast enhanced ultrasound