Since applications of nanotechnologies for life and health sciences are booming, magnetic nanoparticles (NP) have undergone considerable development. They combine physical, chemical and magnetic properties that make them appropriate as contrast agents  for diagnosis using medical imaging techniques such as Magnetic Resonance Imaging (MRI) or ultrasonic imaging. Nanometric contrast agents are made of metallic rare earth elements (Gd) or transition metal (Mn, Fe) oxide cores.

      The storage and catabolism of Ultrasmall Super Paramagnetic Iron Oxide (USPIO) nanoparticles was analyzed through a multiscale approach combining Two Photon Laser Scanning Microscopy (TPLSM) and High-Resolution Transmission Electron Microscopy (HRTEM) at different times after intravenous injection (iv) in an atherosclerotic ApoE^-/- mouse model. The atherotic plaque features and the USPIOs heterogeneous biodistribution were revealed from organ’s scale down to subcellular level. The biotransformation of the nanoparticle iron oxide (maghemite) core into ferritin, the non-toxic form of iron storage, was demonstrated for the first time ex vivo in atherosclerotic plaques as well as in spleen, the iron storage organ. These results rely on an innovative spatial and structural investigation of USPIO’s catabolism in cellular phagolysosomes. This study showed that these nanoparticles were stored as non-toxic iron compounds: maghemite oxide or ferritin, which is promising for MRI detection of atherosclerotic plaques in clinic using these USPIOs [1].

References

[1] VA Maraloiu, F Appaix, A Broisat et al., Nanomedicine: Nanotechnology, Biology and Medicine 12 (1), 191-200 (2016)

Acknowledgement

 The two-photon microscopy studies were performed on the National Platform of Intravital Microscopy in Grenoble (France Life Imaging). This platform was partly funded by the French program “Investissement d’Avenir” run by the “Agence Nationale pour la Recherche”; grant “Infrastructure d’avenir en Biologie Santé – ANR11-INBS-0006”. Researches were partially granted by the French National Agency for Research (ANR) in the frame of the INFLAM project and partially supported by a grant of the Romanian National Authority for Scientific Research, CNCS – UEFISCDI, project number PN-II-RU-PD-2011-3-0067.

Figures:

Figure 1. a) Z-projections (standard deviation fluorescence intensities) of 68 TPLSM images with a slice spacing of 3 μm of atherosclerotic plaques (class 4: atheroma) in non-fixed aortic rings 20 days after USPIOs iv injection. b) Z-projection (average fluorescence intensities) of 47 TPLSM images with a slice spacing of 3 μm of an atherosclerotic plaque (P) in a PFA-fixed aortic ring (W: aortic wall). c) Zoom of white rectangle region in a), showing that USPIO particles were mostly detected under collagen cap (blue, endogenous SHG signals). d) Zoom of white rectangle region in b), showing distribution of USPIO particles (circles) in atherosclerotic plaque.

Figure 2. a) CTEM overview in atherosclerotic plaque at D20 revealing several vesicles; a central vesicle (white arrow) enlarged in (b) having internalised USPIOs, electron diffraction pattern (maghemite)(c); (d) Fitting of size distribution (percentage of particle number Np with a given size over total number of counted particles Nt) for non transformed USPIOs in plaque from CTEM images.

Figure 3. High magnification HRTEM image from the vesicle in the atherosclerotic plaque at D20 reveals details of crystallized USPIOs, with FFTs confirming the maghemite structure and revealing the orientation of the particles A and B.

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EMC Abstracts - https://emc-proceedings.com/abstract/multiscale-investigation-of-uspio-nanoparticles-in-atherosclerotic-plaques-and-their-catabolism-and-storage-in-vivo/