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; Mohan, James F; Pittet, Mikaël; Weissleder, Ralph

doi:10.1126/scitranslmed.aal0225

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Title		Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts
Authors		Miller, Miles A Chandra, Ravi Cuccarese, Michael F Pfirschke, Christina Engblom, Camilla Stapleton, Shawn Adhikary, Utsarga Kohler, Rainer H Mohan, James F Pittet, Mikaël Weissleder, Ralph show all authors [1 - 11]
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		Animals — Cell Count — Cell Line — Tumor — Chemistry — Pharmaceutical — Combined Modality Therapy — Cyclophosphamide/pharmacology/therapeutic use — Drug Delivery Systems — Extravasation of Diagnostic and Therapeutic Materials/pathology — Humans — Intravital Microscopy — Macrophages/drug effects/pathology/radiation effects — Mice — Nude — Nanoparticles/chemistry — Neoplasms/blood supply/drug therapy/radiotherapy — Permeability — Phagocytes/drug effects/pathology/radiation effects — Tumor Microenvironment/drug effects/radiation effects — Xenograft Model Antitumor Assays
Identifiers		DOI: 10.1126/scitranslmed.aal0225 PMID: 28566423
Full text		Article (Published version) (1.8 MB) - Limited access to UNIGE Other version: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681815/
Research group		Groupe Mikael Pittet (1024)
Citation (ISO format)		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 https://archive-ouverte.unige.ch/unige:154052