title: Covalent assembly of nanoparticles as a peptidase-degradable platform for molecular MRI.
abstract: Ligand-conjugated microparticles of iron oxide (MPIO) have the potential to provide high sensitivity contrast for molecular magnetic resonance imaging (MRI). However, the accumulation and persistence of non-biodegradable micron-sized particles in liver and spleen precludes their clinical use and limits the translational potential of MPIO-based contrast agents. Here we show that ligand-targeted MPIO derived from multiple iron oxide nanoparticles may be coupled covalently through peptide linkers that are designed to be cleaved by intracellular macrophage proteases. The synthesized particles possess potential characteristics for targeted MRI contrast agents, including high relaxivity, unappreciable sedimentation, clearance from circulation and no overt toxicity. Importantly, we demonstrate that these particles are rapidly degraded both in vitro and in vivo, and that the targeted probes can be used for detection of inflammation in vivo using MRI. This approach provides a platform for molecular MRI contrast agents that is potentially more suitable for translation to humans.
authors.affiliation: Department of Oncology, Cancer Research UK &Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.|Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Francisco
authors.initials: F
authors.lastname: Perez-Balderas
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Sander I
authors.initials: SI
authors.lastname: van Kasteren
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.|Department of Cardiovascular Medicine and Oxford Acute Vascular Imaging Centre, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Alaa A A
authors.initials: AA
authors.lastname: Aljabali
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.|Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Wals
authors.affiliation: Department of Oncology, Cancer Research UK &Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Serres
authors.affiliation: Department of Cardiovascular Medicine and Oxford Acute Vascular Imaging Centre, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jefferson
authors.affiliation: Department of Oncology, Cancer Research UK &Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sarmiento Soto
authors.affiliation: Department of Oncology, Cancer Research UK &Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Khrapitchev
authors.affiliation: Department of Oncology, Cancer Research UK &Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: James R
authors.identifier: 0000-0002-4169-8447
authors.initials: JR
authors.lastname: Larkin
authors.affiliation: Department of Oncology, Cancer Research UK &Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Bristow
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Seung Seo
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bort
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Filippo
authors.initials: F
authors.lastname: De Simone
authors.affiliation: Department of Oncology, Cancer Research UK &Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Campbell
authors.affiliation: Department of Cardiovascular Medicine and Oxford Acute Vascular Imaging Centre, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
authors.forename: Daniel C
authors.identifier: 0000-0003-1380-6655
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Department of Oncology, Cancer Research UK &Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Davis
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D003287:Contrast Media / Q000737:chemistry; D005290:Ferric Compounds / Q000737:chemistry; D006801:Humans; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D010316:Particle Size; D010447:Peptide Hydrolases / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000906:Antibodies; D003287:Contrast Media; D005290:Ferric Compounds; D058185:Magnetite Nanoparticles; D019010:Vascular Cell Adhesion Molecule-1; C000499:ferric oxide; D010447:Peptide Hydrolases