Ultrasmall Nanoplatforms as Calcium-Responsive Contrast Agents for Magnetic Resonance Imaging

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 11; no. 37; pp. 4900 - 4909
• Main Authors: Moussaron, Albert, Vibhute, Sandip, Bianchi, Andrea, Gündüz, Serhat, Kotb, Shady, Sancey, Lucie, Motto-Ros, Vincent, Rizzitelli, Silvia, Crémillieux, Yannick, Lux, Francois, Logothetis, Nikos K., Tillement, Olivier, Angelovski, Goran
• Format: Journal Article
• Language: English
• Published: Germany Blackwell Publishing Ltd 07.10.2015; Wiley Subscription Services, Inc
• Subjects: Animals; Biomedical materials; Calcium; Cell Survival - drug effects; Contrast agents; Contrast Media - chemistry; Dynamic Light Scattering; Female; gadolinium; HEK293 Cells; Humans; In vivo tests; Injections, Intravenous; Lasers; Ligands; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Mice; Mice, Inbred BALB C; nanoparticles; Nanoparticles - chemistry; Nanoparticles - toxicity; Nanostructure; Nanotechnology; NMR; Nuclear magnetic resonance; Particle Size; Platforms; Signal-To-Noise Ratio; Spectrum Analysis; Surgical implants; Titrimetry; Toxicity Tests; magnetic resonance imaging; calcium; nanoparticles; contrast agents; gadolinium
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.201500312

The preparation of ultrasmall and rigid platforms (USRPs) that are covalently coupled to macrocycle‐based, calcium‐responsive/smart contrast agents (SCAs), and the initial in vitro and in vivo validation of the resulting nanosized probes (SCA‐USRPs) by means of magnetic resonance imaging (MRI) is reported. The synthetic procedure is robust, allowing preparation of the SCA‐USRPs on a multigram scale. The resulting platforms display the desired MRI activity—i.e., longitudinal relaxivity increases almost twice at 7 T magnetic field strength upon saturation with Ca2+. Cell viability is probed with the MTT assay using HEK‐293 cells, which show good tolerance for lower contrast agent concentrations over longer periods of time. On intravenous administration of SCA‐USRPs in living mice, MRI studies indicate their rapid accumulation in the renal pelvis and parenchyma. Importantly, the MRI signal increases in both kidney compartments when CaCl2 is also administrated. Laser‐induced breakdown spectroscopy experiments confirm accumulation of SCA‐USRPs in the renal cortex. To the best of our knowledge, these are the first studies which demonstrate calcium‐sensitive MRI signal changes in vivo. Continuing contrast agent and MRI protocol optimizations should lead to wider application of these responsive probes and development of superior functional methods for monitoring calcium‐dependent physiological and pathological processes in a dynamic manner. Calcium‐responsive magnetic resonance imaging (MRI) contrast agents are grafted onto ultrasmall and rigid platforms. The resulting nanosized contrast agent remains sensitive to calcium as confirmed with relaxometric titrations. When administered in mice, it accumulates in the renal pelvis and parenchyma, enhancing the MRI contrast upon addition of calcium chloride.