Hybrid multimodal contrast agent for multiscale investigation of neuroinflammation

• Published in: Nanoscale Vol. 13; no. 6; pp. 3767 - 3781
• Main Authors: Karpati, Szilvia, Hubert, Violaine, Hristovska, Inès, Lerouge, Frédéric, Chaput, Frédéric, Bretonnière, Yann, Andraud, Chantal, Banyasz, Akos, Micouin, Guillaume, Monteil, Maëlle, Lecouvey, Marc, Mercey-Ressejac, Marion, Dey, Arindam K, Marche, Patrice N, Lindgren, Mikael, Pascual, Olivier, Wiart, Marlène, Parola, Stephane
• Format: Journal Article
• Published: 18.02.2021
• ISSN: 2040-3364; 2040-3372
• DOI: 10.1039/d0nr07026b

Neuroinflammation is a process common to several brain pathologies. Despites its medical relevance, it still remains poorly understood; there is therefore a need to develop new in vivo preclinical imaging strategies to monitor inflammatory processes longitudinally. We here present the development of a hybrid imaging nanoprobe named NP3 , that was specifically designed to get internalized by phagocytic cells and imaged in vivo with MRI and bi-photon microscopy. NP3 is composed of a 16 nm core of gadolinium fluoride (GdF 3 ), coated with bisphosphonate polyethylene glycol (PEG) and functionalized with a Lemke-type fluorophore. It has a hydrodynamic diameter of 28 ± 8 nm and a zeta potential of −42 ± 6 mV. The MR relaxivity ratio at 7 T is r 1 / r 2 = 20; therefore, NP3 is well suited as a T 2 / T 2 * contrast agent. In vitro cytotoxicity assessments performed on four human cell lines revealed no toxic effects of NP3 . In addition, NP3 is internalized by macrophages in vitro without inducing inflammation or cytotoxicity. In vivo , uptake of NP3 has been observed in the spleen and the liver. NP3 has a prolonged vascular remanence, which is an advantage for macrophage uptake in vivo . The proof-of-concept that NP3 may be used as a contrast agent targeting phagocytic cells is provided in an animal model of ischemic stroke in transgenic CX3CR1-GFP/+ mice using three complementary imaging modalities: MRI, intravital two-photon microscopy and phase contrast imaging with synchrotron X-rays. In summary, NP3 is a promising preclinical tool for the multiscale and multimodal investigation of neuroinflammation. Hybrid nanoprobe specifically designed to use as a contrast agent targeting phagocytic cells in an animal model of ischemic stroke and imaging using MRI, intravital two-photon microscopy and phase contrast X-rays imaging.