Supramolecular Aggregates of Amphiphilic Gadolinium Complexes as Blood Pool MRI/MRA Contrast Agents: Physicochemical Characterization Mauro Vaccaro, ²,‡, | Antonella Accardo, § Diego Tesauro, § Gaetano Mangiapia, ²,‡ David Lo ¨f, | Karin Schille ´n, | Olle So ¨derman, | Giancarlo Morelli,* ,§ and Luigi Paduano* ,²,‡ Department of Chemistry, UniVersity of Naples “Federico II”, Via Cynthia, 80126 Naples, Italy, CSGI (Consorzio per lo SViluppo dei Sistemi a Grande Interfase), Department of Biological Sciences, CIRPeB UniVersity of Naples “Federico II” & IBB CNR, Via Mezzocannone 16, 80134 Naples, and Physical Chemistry 1, Center for Chemistry and Chemical Engineering, Lund UniVersity, P.O. Box 124, SE-221 00 Lund, Sweden ReceiVed December 27, 2005. In Final Form: May 5, 2006 In this paper, we present the development of a new potential blood pool contrast agent for magnetic resonance imaging applications (MRA/MRI) based on gadolinium complexes containing amphiphilic supramolecular aggregates. A novel amphiphilic unimer, containing the DTPAGlu chelating agent covalently bound to two C18 alkylic chains, has been synthesized. DTPAGlu is a well-known chelating agent for a wide number of ions such as the paramagnetic metal ion Gd 3+ used as contrast agent in MRA/MRI. The wide aggregation behavior of this surfactant, as free base or as gadolinium complex, has been studied and compared by means of dynamic light scattering, small-angle neutron scattering and cryogenic transmission electron microscopy techniques. Near neutral pH in both cases, the dominant aggregates are micelles.The high negative actual charge of the surfactant headgroup causes a strong headgroups repulsion, promoting the formation of large and high curvature aggregates. By decreasing pH and less markedly increasing the ionic strength, we observe a micelle-to-vesicle transition driven by a decreased electrostatic repulsion. A straightforward switch between different aggregation states can be particularly useful in the development of pH- responsive MRA/MRI contrast agents. 1. Introduction Magnetic resonance imaging (MRI) is an imaging technique and is one of the most widely used diagnostic tools in clinical practice. Its main advantage is that it allows rapid in vivo acquisition of images, and under specific conditions, it makes imaging at cellular resolution possible. The technique has proven very valuable for the diagnosis of a broad range of pathologic conditions in all parts of the body. 1 Currently, stable Gd 3+ -poly(aminocarboxylate) complexes are widely used as contrast agents in MRI. These agents are intravenously administered to patients, and by reducing the relaxation time of water protons present in the effected tissues, they help to produce a higher quality (higher contrast) image. The efficacy of a contrast agent is commonly expressed by its proton relaxivity r 1 , defined as the paramagnetic longitudinal relaxation rate enhancement of the water protons by unity concentration (mM) of the agent. 2 Although MRI gives very resolved images, due to its very low sensitivity, it needs an elevated concentration of contrast agent (10 -4 M). To reach the required local concentration, many carriers have been developed such as liposomes 3 or other microparticu- lates: 4 micelles, 5 dendrimers, 6 water-soluble fullerenes, 7 linear polymers, 8 or proteins, 9 all of them derivatized with a high number of metal complexes. Among these carriers, micellar and vesicular aggregates have recently drawn much attention owing to their easily controlled properties and good pharmacological charac- teristics. 10 For example, the self-assembling of Gd(III)(DOTA) or Gd(III)(DTPAGlu) complexes derivatized with a lipophilic tail allows high relaxivity MRI contrast agents to be obtained. 5,11 In other words, gadolinium complexes containing amphiphilic supramolecular aggregates present two contemporary and interesting properties: an enhanced ability to change solvent proton relaxation rates (through the occurrence of a long molecular retention time τ R ) and an increased lifetime of the contrast agent in the circulating blood by avoiding the extravasation typical of the small-sized Gd 3+ complexes commonly employed in MRI investigations. 12,13 Their high in vivo stability, short T 1 spin lattice relaxation time, and long vascular retention time make these contrast agents interesting in other magnetic resonance imaging applications * Corresponding author. Tel.: +39081674229. Fax: +39081674090. E-mail: luigi.paduano@unina.it. ² University of Naples “Federico II”. ‡ CSGI. § CIRPeB University of Naples “Federico II”, & IBB CNR. | Lund University. (1) Weissleder, R.; Mahmood, U. Mol. Imaging Radiol. 2001, 219, 316. (2) Aime, S.; Botta, M.; Fasano, M.; Terreno, E. Chem. Soc. ReV. 1998, 27, 19. (3) Glogard, C.; Stensrud, G.; Rovland, R.; Fossheim, S. L. Intern. J. Pharm. 2002, 233, 131. (4) Morel, S.; Terreno, E.; Ugazio, E.; Aime, S.; Gasco, M. R. Eur. J. Pharm. Biopharm. 1998, 45, 157. (5) Accardo, A.; Tesauro, D.; Roscigno, P.; Gianolio, E.; Paduano, L.; D’Errico, G.; Pedone, C.; Morelli, G. J. Am. Chem. Soc. 2004, 126, 3097. (6) Wiener, E. C.; Brechbiel, M. W.; Brothers, H.; Magin, R. L.; Gansow, O. A.; Tomalia, D. A.; Lauterbur, P. C. Magn. Res. Med. 1994, 3, 1. (7) Toth, E.; Bolskar, R. D.; Borel, A.; Gonzalez, G.; Helm, L.; Merbach, A. E.; Sitharaman, B.; Wilson, L. J. J. Am. Chem. Soc. 2005, 127, 799. 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