IEEE SENSORS JOURNAL, VOL. 13, NO. 6, JUNE 2013 2341 Iron Oxide-Gold Core-Shell Nanoparticles as Multimodal Imaging Contrast Agent Luca Menichetti, Leonardo Manzoni, Luigi Paduano, A. Flori, Claudia Kusmic, Daniele De Marchi, Sergio Casciaro, Francesco Conversano, Massimo Lombardi, Vincenzo Positano, and Daniela Arosio Abstract— Nanoparticles (NPs) are emerging as a potential medical tool for novel diagnostic, drug delivery, and therapeutic approaches. Among them, a spherical NP with a core-shell structure is a way to combine multiple functionalities on the nanoscale. In this paper, we describe the preparation characteri- zation and applications of core-shell iron oxide-gold nanoparticles (Fe 3 O 4 @Au NPs). A comprehensive set of experiments, including transmission electron microscopy, dynamic light scattering, small angle neutron scattering, and ultraviolet visible spectroscopy is applied to characterize their chemical, physical, and optical properties. We also study their applicability as contrast agents for magnetic resonance imaging (MRI): the measurement of longitudinal and transverse relaxation times of Fe 3 O 4 @Au NPs in vitro and in vivo allowed the assessment of longitudinal (R 1 ) and transverse (R 2 ) relaxivities at 1.5 and 3 T. Finally, a procedure for functionalizing NPs with integrin targeting cyclic Arginine- Glycine-Aspartate peptidomimetic is reported, leading to the development of nanoscale probes for α v β 3 integrin, particularly attractive in terms of resolution and 3-D imaging capabilities. The resulting multifunctional nanoprobes offer suitable blood- circulation time and contrast for microimaging as well as for gradient-echo MRI, and could enable new imaging magnetoplas- monic applications. Index Terms— Core-shell nanoparticles, gradient-echo, magnetic resonance imaging (MRI), integrin, magnetic nanoparticles, nanoprobe, RGD functionalized nanoparticles. Manuscript received December 14, 2012; accepted March 6, 2013. Date of publication March 20, 2013; date of current version April 26, 2013. This work was supported in part by the National Research Council and a grant from the Fondazione Monte dei Paschi di Siena, Italy. This is an expanded paper from the IEEE SENSORS 2011 Conference. The associate editor coordinating the review of this paper and approving it for publication was Dr. Chang-Soo Kim. L. Menichetti is with the Institute of Clinical Physiology, CNR, Pisa I-56124, Italy, and also with the CNR–Regione Toscana Fondazione G. Monasterio, Pisa 56124, Italy (e-mail: luca.menichetti@ifc.cnr.it). L. Manzoni and D. Arosio are with Institute of Sciences and molecular technology, CNR, Milan 20133, Italy (e-mail: leonardo.manzoni@istm.cnr.it; daniela.arosio@istm.cnr.it). L. Paduano is with the Chemistry Department, University of Naples “Federico II,” Naples 80138, Italy (e-mail: luigi.paduano@unina.it). A. Flori is with the Istituto di Scienze della Vita, Scuola Superiore Sant’Anna, Pisa 56127, Italy (e-mail: alessandra.flori@sssup.it). C. Kusmic is with the Institute of Clinical Physiology, CNR, Pisa I-56124, Italy (e-mail: kusmic@ifc.cnr.it). D. De Marchi, M. Lombardi, and V. Positano are with the CNR–Regione Toscana Fondazione G. Monasterio, Pisa 56124, Italy (e-mail: demada@ ftgm.it; lomass@ftgm.it; vincenzo.positano@ftgm.it). S. Casciaro and F. Conversano are with the Institute of Clinical Physiology, CNR, Lecce 73100, Italy (e-mail: casciaro@ifc.cnr.it; conversano@ifc.cnr.it). Color versions of one or more of the figures in this paper are available online at http://ieeexplore.ieee.org. Digital Object Identifier 10.1109/JSEN.2013.2253215 I. I NTRODUCTION A MONG the number of inorganic nanoparticles (NPs) potentially able to display both diagnostic and therapeutic properties, iron oxide/gold core-shell NPs (Fe 3 O 4 @Au NPs) have recently attracted increasing attention due to their hybrid nature. Fe 3 O 4 @Au NPs possess both magnetic and optical properties and can also be considered a smart platform for three-dimensional multipresentation (i.e., multivalency) due to their globular shape, tunable size, and simple surface chemistry [1]–[4]. Thus, Fe 3 O 4 @Au nanoparticles, which consist of an Au plasmonic coating and an iron oxide core, could provide a promising platform for the development of multimodal imaging tools [1], [5]–[13]. They combine two features in a single NP displaying both magnetic and plasmonic properties. Iron oxide forms focal clusters of magnetic inhomogeneity, leading to a dramatic reduction in the protons’ transverse relaxation time that can be assessed by spin-echo (T2) techniques or gradient-echo (T2*) techniques. Hence, they act as a potent negative magnetic resonance imaging (MRI) contrast agent, well-detectable also at very low concentration. Moreover, their plasmonic proper- ties make them suitable for dark field spectroscopy, Surface Enhanced Raman Spectroscopy [4] and for photoacoustic detection [12]–[14]. In biomedical applications, in particular for in vivo imaging, nanoparticles should possess good colloidal stability and low toxicity in a biological environment. Therefore, modifying the surface of nanoparticles is essential to endow them with hydrophilic properties. Gold coating of magnetic NPs repre- sent one of several established solutions for meeting these requirements, both because gold is considered rather biocom- patible and at the same time it furnish an easily functionaliz- able surface [3], [13]–[16]. In this study, we explored the use of polyethileneglycol (PEG) as a coating in order to obtain biocompatible, water soluble nanoparticles and we also pre- pared cyclic-RGD (cRGD) peptidomimetic [17] functionalize nanoparticles targeted to integrin α v β 3 . Integrins has become increasingly important in assessment of a number of patho- logical conditions, such as tumors, inflammation, degenerative diseases and remodelling [17]–[20]. Of the integrin receptors, α v β 3 have been identified as a promising target for diagnostic, therapeutic and potentially in combined (“theranostic”) inter- ventions. 1530-437X/$31.00 © 2013 IEEE