title: A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy.
abstract: Engineered nanoparticles that respond to pathophysiological parameters, such as pH or redox potential, have been developed as contrast agents for the magnetic resonance imaging (MRI) of tumours. However, beyond anatomic assessment, contrast agents that can sense these pathological parameters and rapidly amplify their magnetic resonance signals are desirable because they could potentially be used to monitor the biological processes of tumours and improve cancer diagnosis. Here, we report an MRI contrast agent that rapidly amplifies magnetic resonance signals in response to pH. We confined Mn(2+) within pH-sensitive calcium phosphate (CaP) nanoparticles comprising a poly(ethylene glycol) shell. At a low pH, such as in solid tumours, the CaP disintegrates and releases Mn(2+) ions. Binding to proteins increases the relaxivity of Mn(2+) and enhances the contrast. We show that these nanoparticles could rapidly and selectively brighten solid tumours, identify hypoxic regions within the tumour mass and detect invisible millimetre-sized metastatic tumours in the liver.
authors.affiliation: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan.|Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.|Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industry Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors.forename: Peng
authors.initials: P
authors.lastname: Mi
authors.affiliation: National Institute of Radiological Sciences, Japan Agency for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba 263-8555, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kokuryo
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Wu
authors.affiliation: SPring 8, JASRI, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5198, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Terada
authors.affiliation: National Institute of Radiological Sciences, Japan Agency for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba 263-8555, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
authors.affiliation: National Institute of Radiological Sciences, Japan Agency for Quantum and Radiological Science and Technology, Anagawa 4-9-1, Inage, Chiba 263-8555, Japan.
authors.forename: Ichio
authors.identifier: 0000-0002-4429-5053
authors.initials: I
authors.lastname: Aoki
authors.affiliation: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan.|Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industry Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.|Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industry Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.|Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.|Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D002130:Calcium Phosphates / Q000737:chemistry / Q000493:pharmacokinetics; D003287:Contrast Media / Q000737:chemistry* / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008345:Manganese / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D009374:Neoplasms, Experimental; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D002130:Calcium Phosphates; D003287:Contrast Media; D011092:Polyethylene Glycols; D008345:Manganese; C020243:calcium phosphate