GUARDIA ET AL. VOL. 6 ’ NO. 4 ’ 3080–3091 ’ 2012 www.acsnano.org 3080 April 11, 2012 C 2012 American Chemical Society Water-Soluble Iron Oxide Nanocubes with High Values of Specific Absorption Rate for Cancer Cell Hyperthermia Treatment Pablo Guardia, † Riccardo Di Corato, †,‡ Lenaic Lartigue, § Claire Wilhelm, § Ana Espinosa, ^ Mar Garcia-Hernandez, ^ Florence Gazeau, § Liberato Manna, † and Teresa Pellegrino †,‡, * † Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy, ‡ National Nanotechnology Laboratory of CNR-NANO, via per Arnesano km 5, 73100 Lecce, Italy, § Laboratoire Matière et Systèmes Complexes (MSC), UMR 7057, CNRS and Université Paris Diderot, 10 rue Alice Domon et Léonie Duquet, 75205 Paris cedex 13, France, and ^ Instituto de Ciencia de Materiales de Madrid, Consejo Superior de Investigaciones Científicas, Cantoblanco, 28049 Madrid, Spain M agnetic nanoparticles (MNPs) pro- vide a valuable platform with potential exploitation in bio- medicine. MNPs have been proposed as magnetic guidance in drug delivery and magnetic separation, as contrast agents in magnetic resonance imaging (MRI), or as heat mediators in hyperthermia treat- ments. 1À4 The latter represents a novel therapeutic concept to cancer treatment and is based on the evidence that cancer cells are more sensitive than healthy cells to temperatures higher than 41 °C. 5,6 Among the various approaches proposed to raise the body temperature, 7À9 magnetically mediated hyperthermia is based on the generation of heat via an oscillating mag- netic field exploiting MNPs as heating foci. MNPs can offer several advantages: (i) the nanoscale size of the heat probe would allow for their intravenous injection and their delivery via the bloodstream to tumors that could not be reached otherwise; (ii) the high surface to volume ratio of the MNPs allows for surface tailoring with few or multiple recognition molecules, which can guarantee targeting toward specific tumor tissues; (iii) the remote heating of MNPs by the externally applied magnetic field allows the heat action only to the zone of accumu- lation of nanoparticles. The heating ability of MNPs under an alternating magnetic field is expressed by the specific absorption rate (SAR) which provides a measure of the rate at which energy is absorbed per unit mass of the magnetic material (the nanoparticles in this case) when exposed to a radio frequency. 10 The heat generation results either from hysteresis losses or from Néel or Brown relaxation processes. 5,11 SAR values depend on the structure and composition of the nanoparticles but also on the frequency (f) and the amplitude of the magnetic field (H) applied during the measurements. 11 For an efficient heat treatment with minimal inva- siveness for the patient, the search for new magnetic nanomaterials which show the * Address correspondence to teresa.pellegrino@iit.it. Received for review December 9, 2011 and accepted March 16, 2012. Published online 10.1021/nn2048137 ABSTRACT Iron oxide nanocrystals (IONCs) are appealing heat mediator nanoprobes in magnetic-mediated hyperthermia for cancer treatment. Here, specific absorption rate (SAR) values are reported for cube- shaped water-soluble IONCs prepared by a one-pot synthesis approach in a size range between 13 and 40 nm. The SAR values were determined as a function of frequency and magnetic field applied, also spanning technical conditions which are considered biomedically safe for patients. Among the di fferent sizes tested, IONCs with an average diameter of 19 ( 3 nm had signi ficant SAR values in clinical conditions and reached SAR values up to 2452 W/g Fe at 520 kHz and 29 kAm À1 , which is one of the highest values so far reported for IONCs. In vitro trials carried out on KB cancer cells treated with IONCs of 19 nm have shown efficient hyperthermia performance, with cell mortality of about 50% recorded when an equilibrium temperature of 43 °C was reached after 1 h of treatment. KEYWORDS: hyperthermia treatment . specific absorption rate . SAR values . iron oxide nanoparticles . magnetic nanoparticles . biomedical applications . magnetosome-like nanoparticles ARTICLE