title: PEGylated Anionic Magnetofluorescent Nanoassemblies: Impact of Their Interface Structure on Magnetic Resonance Imaging Contrast and Cellular Uptake.
abstract: Controlling the interactions of functional nanostructures with water and biological media represents high challenges in the field of bioimaging applications. Large contrast at low doses, high colloidal stability in physiological conditions, the absence of cell cytotoxicity, and efficient cell internalization represent strong additional needs. To achieve such requirements, we report on high-payload magnetofluorescent architectures made of a shell of superparamagnetic iron oxide nanoparticles tightly anchored around fluorescent organic nanoparticles. Their external coating is simply modulated using anionic polyelectrolytes in a final step to provide efficient magnetic resonance imaging (MRI) and fluorescence imaging of live cells. Various structures of PEGylated polyelectrolytes have been synthesized and investigated, differing from their iron oxide complexing units (carboxylic vs phosphonic acid), their structure (block- or comblike), their hydrophobicity, and their fabrication process [conventional or reversible addition-fragmentation chain transfer (RAFT)-controlled radical polymerization] while keeping the central magnetofluorescent platforms the same. Combined photophysical, magnetic, NMRD, and structural investigations proved the superiority of RAFT polymer coatings containing carboxylate units and a hydrophobic tail to impart the magnetic nanoassemblies (NAs) with enhanced-MRI negative contrast, characterized by a high r2/r1ratio and a transverse relaxation r2equal to 21 and 125 s-1mmol-1L, respectively, at 60 MHz clinical frequency (∼1.5 T). Thanks to their dual modality, cell internalization of the NAs in mesothelioma cancer cells could be evidenced by both confocal fluorescence microscopy and magnetophoresis. A 72 h follow-up showed efficient uptake after 24 h with no notable cell mortality. These studies again pointed out the distinct behavior of RAFT polyelectrolyte-coated bimodal NAs that internalize at a slower rate with no adverse cytotoxicity. Extension to multicellular tumor cell spheroids that mimic solid tumors revealed the successful internalization of the NAs in the periphery cells, which provides efficient deep-imaging labels thanks to their induced T2* contrast, large emission Stokes shift, and bright dotlike signal, popping out of the strong spheroid autofluorescence.
authors.affiliation: IRS UN, INSERM-UMR 1232, CRCINA, 8 quai Monconsu, 44007 Nantes, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Linot
authors.affiliation: IS2M, UMR, CNRS 7361, Université de Haute-Alsace , 15 rue Jean Starcky, 68057 Mulhouse, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Poly
authors.affiliation: CEISAM, UMR, CNRS 6230, Université de Nantes , 2 rue de la Houssinière, 44322 Nantes, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Boucard
authors.affiliation: IRS UN, INSERM-UMR 1232, CRCINA, 8 quai Monconsu, 44007 Nantes, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pouliquen
authors.affiliation: INSERM, UMS 016, UMS, CNRS 3556, Université de Nantes , 8 quai Moncousu, 44007 Nantes, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Nedellec
authors.affiliation: INSERM, UMS 016, UMS, CNRS 3556, Université de Nantes , 8 quai Moncousu, 44007 Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hulin
authors.affiliation: Plateforme CytoCell, INSERM, UMR 1232, Université de Nantes , 44007 Nantes, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Marec
authors.affiliation: Department of Physics, Università di Pavia , via Bassi, 27100 Pavia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.affiliation: Department of Physics, Università di Pavia , via Bassi, 27100 Pavia, Italy.|Department of Physics, Università degli Studi di Milano and INSTM , via Celoria 16, 20133 Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lascialfari
authors.affiliation: ICCOM-CNR via Madonna del Piano 10, 50019 Sesto Fiorentino, Fiorentino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Guerrini
authors.affiliation: ICCOM-CNR via Madonna del Piano 10, 50019 Sesto Fiorentino, Fiorentino, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sangregorio
authors.affiliation: Department of Physics, Università di Pavia , via Bassi, 27100 Pavia, Italy.|CSPBAT-UMR CNRS 7244, Université de Villetaneuse-Paris 13 , 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lecouvey
authors.affiliation: CEISAM, UMR, CNRS 6230, Université de Nantes , 2 rue de la Houssinière, 44322 Nantes, France.
authors.forename: Lénaïc
authors.initials: L
authors.lastname: Lartigue
authors.affiliation: IRS UN, INSERM-UMR 1232, CRCINA, 8 quai Monconsu, 44007 Nantes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanquart
authors.affiliation: CEISAM, UMR, CNRS 6230, Université de Nantes , 2 rue de la Houssinière, 44322 Nantes, France.
authors.forename: Eléna
authors.identifier: http://orcid.org/0000-0002-2965-1224
authors.initials: E
authors.lastname: Ishow
mesh_terms: D000838:Anions; D003287:Contrast Media / Q000737:chemistry*; D006801:Humans; D008279:Magnetic Resonance Imaging; D053758:Nanoparticles; D009369:Neoplasms; D011092:Polyethylene Glycols
chemical_list: D000838:Anions; D003287:Contrast Media; D011092:Polyethylene Glycols
keywords: MRI; fluorescence; iron oxide nanoparticles water-soluble RAFT polymers; live cells; multimodal nanoassemblies; organic nanoparticles; spheroids