1H NMR RELAXIVITY OF NOVEL COLLOIDAL NANOSTRUCTURED Gd(III)-BASED POTENTIAL CONTRAST AGENTS

Low molecular weight Gd(III) chelates are the most commonly used contrast enhancing agents (CAs) in Magnetic resonance imaging (MRI) clinical practice with over 100 million patients treated worldwide over the past 25 years. Notwithstanding the widespread use of these CAs, extensive research is active in this field with the aim of finding CAs with reduced side-effects due to the toxicity of Gd and with improved contrast properties at magnetic fields of interest. [1] Among the different strategies proposed in recent years, the insertion of Gd in nanostructures, either through the covalent or noncovalent functionalization of nanostructures with multiple Gd(III) complexes or through the encapsulation of Gd3+ ions, has revealed particularly promising. In fact, inclusion in nanostructures improves the kinetic and thermodynamic stability of Gd(III) complexes and the CA target specificity, and at the same time increases contrast enhancement efficiency by slowing down the rotational dynamics. [1,2,3] Furthermore, the nanoscale structure may endow the system with properties suitable for other imaging techniques or therapy, with prospects for theranostic applications. In this context, novel nanostructured potential contrast agents were prepared in the present work following a recently reported procedure [4, 5, 6] in which water insoluble Gd(III) complexes self-assemble into nanosized particles by precipitation from an organic to an aqueous phase. After coating with poly(sodium styrenesulfonate) stable nanostructured colloids with a hard core and a soft shell were obtained. Several complexes of Gd(III) with ligands based either on thiacalix[4]arene or on tetrahydroxy-calix[4]arene decorated with 1,3-diketone groups were exploited (Figure 1). The longitudinal (r1) and transverse (r2) relaxivities of the colloidal systems were measured at 20.8 MHz. 1H FFC NMR relaxometry was applied to determine r1 as a function of Larmor frequency in the 10 kHz to 40 MHz range. Relaxivity dispersions, showing a maximum at around 20-30 MHz (Figure 2), clearly indicated the effective incorporation of the Gd(III) complexes into nanostructures. An analysis of the dispersions is in progress aimed at understanding the mechanism at the basis of the contrast enhancement properties and identifying the key factors affecting the contrast efficiency of the investigated systems, with the ultimate goal of optimizing their formulation for application as MRI CAs. Acknowledgments This work was partially supported by the CA15209 COST Action (EURELAX). References [1] J. Wahsner, E. M. Gale, A. Rodríguez- Rodríguez, P. Caravan, Chem. Rev., 2018, DOI: 10.1021/acs.chemrev.8b00363. [2] M. Botta, L. Tei, Eur. J. Inorg. Chem., 2012, 1945-1960. [3] P. Hermann, J. Kotek, V. Kubí?ek, I. Luke?, Dalton Trans., 2008, 3027-3047. [4] N. A. Shamsutdinova, A. T. Gubaidullin, B. M. Odintsov, R. J. Larsen, V. D. Schepkin, I. R. Nizameev, R. R. Amirov, R. R. Zairov, S. N. Sudakova, S. N. Podyachev, A. R. Mustafina, A. S. Stepanov, ChemistrySelect, 2016, 1, 1377-1383. [5] R. Zairov, A. Mustafina, N. Shamsutdinova, I. Nizameev, B. Moreira, S. Sudakova, S. Podyachev, A. Fattakhova, G. Safina, I. Lundstrom, A. Gubaidullin, A. Vomiero, Sci. Rep., 2017, 7, 40486. [6] R. Zairov, G. Khakimullina, S. Podyachev, I. Nizameev, G. Safiullin, R. Amirov, A. Vomiero, A. Mustafina, Sci. Rep., 2017, 7, 14010.