title: Heat-generating iron oxide nanocubes: subtle "destructurators" of the tumoral microenvironment.
abstract: Several studies propose nanoparticles for tumor treatment, yet little is known about the fate of nanoparticles and intimate interactions with the heterogeneous and ever-evolving tumor environment. The latter, rich in extracellular matrix, is responsible for poor penetration of therapeutics and represents a paramount issue in cancer therapy. Hence new strategies start aiming to modulate the neoplastic stroma. From this perspective, we assessed the efficacy of 19 nm PEG-coated iron oxide nanocubes with optimized magnetic properties to mediate mild tumor magnetic hyperthermia treatment. After injection of a low dose of nanocubes (700 μg of iron) into epidermoid carcinoma xenografts in mice, we monitored the effect of heating nanocubes on tumor environment. In comparison with the long-term fate after intravenous administration, we investigated spatiotemporal patterns of nanocube distribution, evaluated the evolution of cubes magnetic properties, and examined nanoparticle clearance and degradation processes. While inside tumors nanocubes retained their magnetic properties and heating capacity throughout the treatment due to a mainly interstitial extracellular location, the particles became inefficient heaters after cell internalization and transfer to spleen and liver. Our multiscale analysis reveals that collagen-rich tumor extracellular matrix confines the majority of nanocubes. However, nanocube-mediated hyperthermia has the potential to "destructure" this matrix and improve nanoparticle and drug penetration into neoplastic tissue. This study provides insight into dynamic interactions between nanoparticles and tumor components under physical stimulation and suggests that nanoparticle-mediated hyperthermia could be used to locally modify tumor stroma and thus improve drug penetration.
authors.affiliation: Laboratoire Matière et Systèmes Complexes, UMR 7057 CNRS/ Université Paris Diderot , 10 rue Alice Domon et Léonie Duquet, F-75205 Paris Cedex 13, France.
authors.forename: Jelena
authors.initials: J
authors.lastname: Kolosnjaj-Tabi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Di Corato
authors.forename: Lénaic
authors.initials: L
authors.lastname: Lartigue
authors.forename: Iris
authors.initials: I
authors.lastname: Marangon
authors.forename: Pablo
authors.initials: P
authors.lastname: Guardia
authors.forename: Amanda K A
authors.initials: AK
authors.lastname: Silva
authors.forename: Nathalie
authors.initials: N
authors.lastname: Luciani
authors.forename: Olivier
authors.initials: O
authors.lastname: Clément
authors.forename: Patrice
authors.initials: P
authors.lastname: Flaud
authors.forename: Jaykrishna V
authors.initials: JV
authors.lastname: Singh
authors.forename: Paolo
authors.initials: P
authors.lastname: Decuzzi
authors.forename: Teresa
authors.initials: T
authors.lastname: Pellegrino
authors.forename: Claire
authors.initials: C
authors.lastname: Wilhelm
authors.forename: Florence
authors.initials: F
authors.lastname: Gazeau
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry*; D006358:Hot Temperature; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008280:Magnetics; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D011092:Polyethylene Glycols / Q000737:chemistry; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D005290:Ferric Compounds; C000499:ferric oxide; D011092:Polyethylene Glycols; D003094:Collagen