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Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts

Miller, Miles A
Chandra, Ravi
Cuccarese, Michael F
Pfirschke, Christina
Engblom, Camilla
Stapleton, Shawn
Adhikary, Utsarga
Kohler, Rainer H
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Published in Science translational medicine. 2017, vol. 9, no. 392, eaal0225
Abstract Efficient delivery of therapeutic nanoparticles (TNPs) to tumors is critical in improving efficacy, yet strategies that universally maximize tumoral targeting by TNP modification have been difficult to achieve in the clinic. Instead of focusing on TNP optimization, we show that the tumor microenvironment itself can be therapeutically primed to facilitate accumulation of multiple clinically relevant TNPs. Building on the recent finding that tumor-associated macrophages (TAM) can serve as nanoparticle drug depots, we demonstrate that local tumor irradiation substantially increases TAM relative to tumor cells and, thus, TNP delivery. High-resolution intravital imaging reveals that after radiation, TAM primarily accumulate adjacent to microvasculature, elicit dynamic bursts of extravasation, and subsequently enhance drug uptake in neighboring tumor cells. TAM depletion eliminates otherwise beneficial radiation effects on TNP accumulation and efficacy, and controls with unencapsulated drug show that radiation effects are more pronounced with TNPs. Priming with combined radiation and cyclophosphamide enhances vascular bursting and tumoral TNP concentration, in some cases leading to a sixfold increase of TNP accumulation in the tumor, reaching 6% of the injected dose per gram of tissue. Radiation therapy alters tumors for enhanced TNP delivery in a TAM-dependent fashion, and these observations have implications for the design of next-generation tumor-targeted nanomaterials and clinical trials for adjuvant strategies.
Keywords AnimalsCell CountCell LineTumorChemistryPharmaceuticalCombined Modality TherapyCyclophosphamide/pharmacology/therapeutic useDrug Delivery SystemsExtravasation of Diagnostic and Therapeutic Materials/pathologyHumansIntravital MicroscopyMacrophages/drug effects/pathology/radiation effectsMiceNudeNanoparticles/chemistryNeoplasms/blood supply/drug therapy/radiotherapyPermeabilityPhagocytes/drug effects/pathology/radiation effectsTumor Microenvironment/drug effects/radiation effectsXenograft Model Antitumor Assays
PMID: 28566423
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Research group Comprendre et manipuler le système immunitaire pour lutter contre le cancer (1024)
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MILLER, Miles A et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. In: Science Translational Medicine, 2017, vol. 9, n° 392, p. eaal0225. doi: 10.1126/scitranslmed.aal0225

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Deposited on : 2021-08-24

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