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Unità Università degli studi di Milano

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1 Unità Università degli studi di Milano
Dipartimento di Scienze Molecolari Applicate ai Biosistemi Via Trentacoste 2 - Milano Alessandro Lascialfari Francesco Orsini (tecnico) Paolo Arosio (post-doc) Dipartimento di Chimica ed Elettrochimica Marco Scavini Serena Cappelli (tecnico) Altri partecipanti alla ricerca– Dipartimento di Fisica “A. Volta” - Università degli studi di Pavia Maurizio Corti Evrim Umut (dottorando) Andrea Capozzi (laureando, da fine aprile)

2 Experimental apparatuses
DISMAB - Via Trentacoste 2 Atomic force microscopy (AFM) * Atomic Force Microscopy / Scanning Tunneling Microscopy / Magnetic Force Microscopy - Autoprobe CP Research System - Veeco. Working temperature range 0-60°C. Cell for liquids, measurements in solution. * AFM Microscope with force spectroscopy facility, Nanoscope IIIA-Multimode, Veeco Wide-band Nuclear Magnetic Resonance (NMR) * Fourier transform Stelar Spinmaster spectrometer for NMR (also relaxometry), working in the range 5-70 MHz (with electromagnet , magnetic field Tesla) and flux cryostat (3.8 < T < 350K) SMARTracer relaxometer by Stelar for NMR-Fast Field Cycling. Frequencies : 10 KHz < f < 10 MHz. Temperature : 150 < T < 300 K. Muon Spin Rotation  International facilities PSI-Switzerland and ISIS-Didcot(UK) Dipartimento di Chimica Fisica ed Elettrochimica : slides MARCO SCAVINI In strict collaboration, Dept. of Physics, Pavia Wide-band Nuclear Magnetic Resonance (NMR) * Fourier transform Tecmag and Bruker spectrometers for NMR f-range MHz (SC magnet-electromagnets 0-9 Tesla) * Cryostats for T-range 1.5<T<1000K, pressure chambers to reach 15 kbar Magnetometry * SQUID magnetometer for susceptibility and magnetization measurements in the range 0-7 Tesla and K.  Magnetic Resonance Imaging (MRI) Esaote MRI-Imager ARTOSCANfor in-vitro imaging acquisition sequences at low magnetic field 0.2 Tesla Adiabatic and non-adiabatic calorimeters, Non-conventional Electron Paramagnetic Resonance (EPR)

3 Atomic Force Microscopy technique
Multimode - Nanoscope 3d AFM (Veeco). Working temperature range 0-60 °C. Liquid cell for measurements in solution. PicoForce modulus for force spectroscopy measurements AutoProbe CP Research AFM (Veeco). Working temperature range 0-60 °C. Liquid cell for measurements in solution.

4 Nuclear Magnetic Resonance (NMR) technique
Smartracer relaxometer 10 kHz<f<10 MHz (H= Tesla) WIDE BAND NMR not high resolution Stelar Spimaster 5<f<70 MHz (H= Tesla

5 Nuclear Magnetic Resonance
NMR is a spectroscopic technique : Resonant (0 =  B0 e B1 << B0) Microscopic i.e. local probe (it studies the magnetic/electrical interactions between nuclei, atoms and molecules) At radiofrequency ( MHz) It’s widely used in solid and liquid state Physics, Chemistry, pharmacological and bio-medical world From 1975 it is an laternative to TAC; now also better for many applications It does not use ionizing radiations

6 Nuclear Magnetic Resonance
APPARATUS A static magnetic field A rf magnetic field Electronics Cryogenics EXPERIMENTAL PARAMETERS 3 main parameters: spectrum nuclear spin-spin relaxation time T2 nuclear spin-lattice relaxation time T1 LOCAL PROBE Nuclei are local probes  sensitive to local hyperfine interactions Local spin dynamics (mainly T1 and T2) and spin distribution (mainly spectra) can be studied In MRI and relaxometry, sensitivity to spin dynamics and molecular “motion” T1n Nuclei (T2n) Electrons (T2e) Phonons (lattice) T1e T1n

7 Nuclear Magnetic Resonance : statics i.e. spectra
NMR spectra : sensitive to local magnetic field i.e. useful to estimate local field created by e.g. electrons Examples High-resolution NMR (not our group) Wide-band NMR

8 NMR : spin dynamics i.e. relaxation rates
NMR relaxation rates : sensitive to local electron spin dynamics through hyperfine nuclei-electron interaction Spin dynamics vs H at room temperature Spin dynamics vs T at different constant fields

9 MUSR : spin dynamics through a different local probe
MUSR relaxation rates : sensitive to local electron spin dynamics through hyperfine muon-electron interaction Typical muon polarization behaviour Polarization can be studied vs T and H

10 Magnetic Resonance Imaging
Pavia apparatus MRI Timeline 1946 MR phenomenon - Bloch & Purcell 1952 Nobel Prize - Bloch & Purcell NMR developed as analytical tool 1972 Computerized Tomography 1973 Backprojection MRI - Lauterbur 1975 Fourier Imaging - Ernst 1977 Echo-planar imaging - Mansfield 1980 FT MRI demonstrated - Edelstein 1986 Gradient Echo Imaging - NMR Microscope 1987 MR Angiography - Dumoulin 1991 Nobel Prize - Ernst 1992 Functional MRI 1994 Hyperpolarized 129Xe Imaging 2003 Nobel Prize - Lauterbur & Mansfield

11 Research (I) :magnetic nanoparticles in biomedicine
Magnetic Nanoparticles in Theranostics: Diagnostics : MRI CA, fluorescence Therapy : Magnetothermia Biocompatible shell Antibody Fluorescent molecule Drug Molecular Imaging Magnetic nucleus 11

12 Research (II) :Molecular nanomagnets
SMM : finite number N of magnetic centers [e.g. Cr(III), Fe(III)], Single molecule behaviour (very weak intermolecular interaction), AF or F interaction  Non magnetic S=0 or low-spin, high-spin ground state Crystal structure p-NO2.C6F4CNSSN Single molecule of Cr7Fe SCM : magnetic chains with weak intrmolecular interactions and metallic/rare-earth ions alternating to radical groups  slow relaxation of M (NANOWIRES), frustration, peculiar magnetic phases Slowly relaxing CoPhOMe SIM : single rare-earth ions very diluted in the lattice. Good systems for study of quantum tunneling of magnetization (electro-nuclear coupled levels)

13 Effects of plasmons/magnetoplasmons
Role in the project NMR and MUSR Spectra Relaxation rates Electron spin dynamics Effects of plasmons/magnetoplasmons MRI Contrast agents efficiency (r1, r2) Correlation with magnetic and plasmonic properties

14 Possibly 150/200 mg or more of powders NMR-MRI
Requests for samples NMR Possibly 150/200 mg or more of powders NMR-MRI Solution with known magnetic ion concentration Ideal concentration : mg/ml of magn. center MUSR 500 mg or more of powders

15 Main collaborations and projects
Projects (others : C. Lenardi, F. Orsini) FIRB “Investigation of protein structure and function by AFM and physiological studies” (ending) EU FP7 - NANOTHER “Integration of novel NANOparticle based technology for THERapeutics and diagnosis of different types of cancer” EU FP6 - MAGMANet “Molecular Approach to Nanomagnets and Multifunctional Materials ” (ending) Fondazione Cariplo “Processi di funzionalizzazione di polimeri per la modifica della biocompatibilità e dell’adesione di proteine ” (ending) Fondazione Cariplo “Progettazione di nuovi biosensori magnetici per l'applicazione in scienze della salute e ambientali ” (ending) Currently active main collaborations (others : C. Lenardi, F. Orsini) LOCAL, NATIONAL, INTERNATIONAL, INDUSTRIES DISMAB, University of Milano (Italy), Prof. V.F. Sacchi, Dr. P. Perego, Dr. M. Castagna Dept. Pharmacological Sciences, University of Milano, Prof. R. Paoletti, Prof. E.Tremoli, Dr.U.Guerrini, Dr.G.Sironi Dept. Chem. And Electrochem., University of Milano, Dr. M. Scavini S3 CNR-INFM, Modena (Italy) – AFFILIATION – Prof. M. Affronte Dept. Physics “A. Volta” – University of Pavia (Italy) – F. Borsa, M. Corti, P. Carretta, A. Rigamonti, S. Sanna Dept. Chemistry – University of Firenze (Italy) – D. Gatteschi, A. Caneschi, C. Sangregorio, R. Sessoli Dept. Chemistry – University of Cagliari (Italy) – M.F. Casula Dept. Physics, University of Parma (Italy), Dr. L. Romano’, Prof. G. Amoretti, Prof. P. Santini, Dr. S. Carretta National Nanotechnology Laboratory, CNR-INFM, Lecce (Italy), Dr. T. Pellegrino Dept. Physics – University of Firenze, Firenze (Italy) – Prof. A. Rettori Dept. Physics, University of Milano Bicocca, Milano (Italy), gruppo prof. C. Riccardi Dept. Chemistry, Manchester University (UK), prof. R. Winpenny Dept. Physics, University of Zaragoza (Spain), Prof. F. Palacio e Dr. A. Millan Dept. Chemistry, University of Valencia (Spain), prof. E. Coronado Department of Physics, Boston College (USA), Prof. M. J. Graf Inorganic Chemistry Department, University of Bucarest (Romania), prof. M. Andruh CNRS and University of Montpellier (France), Dr. J. Larionova, Dr. Y. Guari Centro Ricerche Colorobbia, Vinci (FI) (Italia), Dr. G. Baldi, Dr. D. Bonacchi

16 MAGNETISM: Scientific fields of interest
MAGMANet (Nanother)

17 Superparamagnetic MRI-contrast agents : a scheme
USPIO SPIO Small Particle of Iron Oxide ( >20 nm ) UltraSmall Particle of Iron Oxide ( < 15 nm ) Core (Fe3O4+Fe2O3) Core (Fe3O4+Fe2O3) Coating (dextran...) Coating (dextran...) Problems : low reproducibility, unknown mixing of ferrites, not-controlled microscopic chemico-physical properties  no real control on the efficacy

18 Magnetic field biosensors
IgG BSA AbIgG-c-Biotin Streptavidin Fe2O3-c-PMA-c-Biotin ppAA They detect protein-”anti”protein interaction Plasma Deposited Poly Acrylic Acid (ppAA) [1] Adsorption of human IgG Blocking of the unreacted surface groups by BSA Reaction with biotinated Ab-IgG molecules at different concentrations Absorption of streptavidin Absorption of biotinated modified γ-Fe2O3 superparamagnetic nanoparticles [2] Technique of detection : SQUID. It uses the presence of magnetic nanoparticles and the labelling of biosensors 18

19 Magnetic field biosensors
Agarose Fe2O3-c-PMA-c-Biotin They detect protein-”anti”protein interaction Hydrogel of Agarose (1%) directly prepared in the glass tube for NMR measurements Diffusion of biotinated modified γ-Fe2O3 superparamagnetic nanoparticles with mild shaking Diffusion of streptavidin <= WORK IN PROGRESS!!! Technique of detection : NMR. It uses the presence of magnetic nanoparticles and the labelling of biosensors 19

20 Very recent studies SMM :
Cr7Fe (NMR, ) – heterometallic ring ST=1/2  distribution of magnetic moment, correlation function Dimers (NMR, )  basic exchange interactions Ni10 (NMR, )  resonant phonon trapping FeCu6, CoCu6 (NMR, ) - ST=1/2 system  single molecule paramagnet Fe4 (MUSR, ) - high-spin system ST=5  transitions to higher ST states SCM : Gd-based chains (NMR)  peculiar phase transitions (Villain’s conjecture) Co or Dy-based chains (NMR, MUSR) – slowly relaxing  two mechanisms of relaxation, size effects SIM : LiYF4:Ho (MUSR)  spin dynamics and tunneling

21 SUPERCONDUCTORS “Zero” resistivity below a critical T=Tc
Cables, wires Magnets (MRI !!) Magnetic Levitation train “Zero” resistivity below a critical T=Tc Repulsion of magnetic field : Meissner effect “High-Tc“ SC

22 Superconducting “fluctuations”
Susceptibility (already subtracted of Pauli term)……….. …..and magnetization curves H T >> TC T  TC Mdia dia H1/2 SF T dia Tc(H) Tc(0) [ Theory with exact solution : Prange (1970), but no field quenching of fluctuating pairs ] First experiments ( Gollub, Tinkham et al.) in metals evidence the breakdown of a description which neglects the effect of the field in suppressing the fluctuating pairs, but only from M(T) curves.

A.Figuerola, A. Fiore, R. Di Corato, A. Falqui, C. Giannini, E. Micotti,A.Lascialfari, M. Corti, R. Cingolani, T. Pellegrino, P. D. Cozzoli and L.Manna. J. Am. Chem. Soc. 130, 1477 (2008) M. Corti, A. Lascialfari, M. Marinone, A. Masotti, E. Micotti, F. Orsini, G. Ortaggi, G. Poletti, C. Innocenti, C. Sangregorio, J. Magn. Magn. Mater. 320 , e316 (2008) M. Corti, A. Lascialfari, E. Micotti, A. Castellano, M. Donativi, A. Quarta, P.D. Cozzoli, L. Manna, T. Pellegrino, C. Sangregorio, J. Magn. Magn. Mater. 320, e320 (2008) A Boni, M Marinone, C Innocenti, C Sangregorio, M Corti, A Lascialfari, M Mariani, F Orsini, G Poletti and M F Casula, J. Phys. D: Appl. Phys. 41, (2008) Y. Guari, J. Larionova, M. Corti, A. Lascialfari, M. Marinone, G. Poletti, K. Molvinger and C. Guérin, Dalton Trans. 28, 3658 (2008), DOI: /b808221a 2) A.Masotti, A. Pitta, G. Ortaggi, M. Corti, C. Innocenti, A. Lascialfari, M. Marinone, P. Marzola, A. Daducci, A. Sbarbati, E. Micotti, F. Orsini, G. Poletti, C. Sangregorio, Magn Reson Mater Phy 22, 77 (2009) P. Sánchez, E. Valero, N.Gálvez, J. M. Domínguez-Vera, M. Marinone, G. Poletti, M. Corti and A. Lascialfari, Dalton Transactions, (2009) L. Lartigue, K. Oumzil, Y. Guari, J. Larionova, C. GueLrin, J.-L. Montero, V. Barragan-Montero, C. Sangregorio, A. Caneschi, C. Innocenti, T. Kalaivani, P. Arosio and A. Lascialfari, Organic Letters 11, 2992 (2009) SC E. Bernardi, A. Lascialfari, A. Rigamonti, and L. Romanó, Phys. Rev. B 77, (2008) S. Cagliero, A. Agostino, M. Mizanur Rahman Khan, M. Truccato, F. Orsini, M. Marinone, G. Poletti, A. Lascialfari, Appl Phys A 95, 479 (2009) A. Lascialfari, A. Rigamonti, E. Bernardi, M. Corti, A. Gauzzi, and J. C. Villegier, Phys. Rev. B 80, (2009) MNM F. Cinti, A. Rettori, M. G. Pini, M. Mariani, E. Micotti, A. Lascialfari, N. Papinutto, A. Amato, A. Caneschi, D. Gatteschi, and M. Affronte, Phys. Rev. Lett. 100, (2008) F. Borsa, Y. Furukawa, A. Lascialfari, Inorg. Chim. Acta 361, 3777 (2008) M.Belesi, E.Micotti, M. Mariani, F.Borsa, A. Lascialfari, S. Carretta, P. Santini, G. Amoretti, E. J. L. Mcinnes, I. S. Tidmarsh, J. Hawkett, Phys. Rev. Lett. 102,  (2009)

24 Some general considerations about Magnetism in bio-medicine
Techniques Magnetic Resonance Imaging (clinic and research) and NMR Magnetic nanoparticles joint to drug delivery/targeting, markers Magnetic hyperthermia Magnetic driven transport of particles Magnetic biosensors’ detectors (NMR, SQUID,....) Magnetoencelography or neuromagnetism (SQUID detection of cerebral activity), Magnetocardiography (by means of SQUIDs) Materials (nanosized) Paramagnetic systems Ferrites (e.g. hard disk in computers) Superparamagnetic systems Molecular nano-particles

25 Aims of the work on MRI contrast agents
To obtain MRI contrast agents based on superparamagnetic cores coated in different ways Samples with controllable size, shape, kind of magnetic ion of the core – narrow distributions of sizes – and coating/functionalization MOTIVATION a) reproducilibity of physical properties/performances ; b) optimization of the chemico-physical characteristics ; c) feedback to synthetic process to optimize the performances / study role of different parameters d) Systematic study of nuclear relaxivity (the efficiency) as a function of the core dimensions, shape, coating, bulk anisotropy, kind of magnetic ion e) Model for the dependence of the nuclear relaxivities of novel contrast agents on anisotropy and molecular reorientation f) Multifunctionality (molecular targeting, hyperthermia, fluorescence....) g) Low toxicity of Fe-oxides

26 Highly-sensitive magnetic field biosensors (MFB)
The scheme of MFB , molecular result of steps I + II : I) biomolecular probe attached to a (nanostructured and functionalized) surface II) complementary biomolecule labelled with a magnetic nanoparticle Examples : antibody-antigene, protein-protein, DNA-DNA, enzyme reactions, etc. APPLICATIONS Labelling to “in vivo” molecular interactions (imaging) Reagents in miniaturized microfluidic systems Affinity ligands for rapid and high-throughput magnetic readouts of arrays probes for Magnetic Force Microscopy Scientific/technological related problems, to be optimized : Nanostructuring (regular) of surface Functionalization of surface Magnetic labelling of biomolecule (choice of magnetic NP) (surface characteristics of NP allow covalent and stoichiomteris attachment of oligonucleotides, nucleic acids, small molecules, peptides, receptor ligands, proteins, antibodies,.....) Choice of system of magnetic detection (Hall s., NMR/MRI, SQUID,....) Development for applications

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