Biodistribution and Toxicity of X-Ray Iodinated Contrast Agent in Nano-emulsions in Function of Their Size.
OBJECTIVE
This study aimed to investigate the impact of the size of X-ray iodinated contrast agent in nano-emulsions, on their toxicity and fate in vivo.


METHODS
A new compound, triiodobenzoate cholecalciferol, was synthetized, formulated as nano-emulsions, and followed after i.v. administration in mice by X-ray imaging (micro computed tomography). Physicochemical characterization and process optimization allowed identifying a good compromise between X-ray contrasting properties, monodispersity and stability. This also allowed selecting two formulations with different sizes, hydrodynamic diameters of 55 and 100 nm, but exactly the same composition. In vitro experiments were performed on two cell lines, namely hepatocytes (BNL-CL2) and macrophages (RAW264.7).


RESULTS
Cell viability studies, cell uptake observations by confocal microscopy, and uptake quantification by fluorimetry, disclosed clear differences between two formulations, as well as between two types of cell lines. After i.v. injection of the two iodinated nano-emulsions in mice, CT scans provided the quantification of the pharmacokinetics and biodistributions. We finally showed that the size in the nano-emulsions has not a real impact on the pharmacokinetics and biodistributions, but has a strong influence on their toxicity, corroborating the in vitro results.


CONCLUSIONS
This study shows that the size of the nanocarrier significantly matters, likely due to highly different interactions with cells and tissues. Graphical Abstract A study on the effect of the size of cholecciferol nano-emulsions, on their in vivo becoming, through X-ray imaging modality.
University of Strasbourg, Faculty of Pharmacy, 74 route du Rhin, 67401, Illkirch Cedex, France.|CNRS UMR 7199, Laboratoire de Conception et Application de Molécules Bioactives, équipe de Pharmacie Biogalénique, University of Strasbourg, route du Rhin No. 74, F-67401, Illkirch Cedex, France.|National Research Center, P.O. 12622, Cairo, Egypt.
Mohamed F
MF
Attia
University of Strasbourg, Faculty of Pharmacy, 74 route du Rhin, 67401, Illkirch Cedex, France. nanton@unistra.fr.|CNRS UMR 7199, Laboratoire de Conception et Application de Molécules Bioactives, équipe de Pharmacie Biogalénique, University of Strasbourg, route du Rhin No. 74, F-67401, Illkirch Cedex, France. nanton@unistra.fr.
Nicolas
N
Anton
University of Strasbourg, Faculty of Pharmacy, 74 route du Rhin, 67401, Illkirch Cedex, France.|CNRS UMR 7199, Laboratoire de Conception et Application de Molécules Bioactives, équipe de Pharmacie Biogalénique, University of Strasbourg, route du Rhin No. 74, F-67401, Illkirch Cedex, France.|Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, 117997, Moscow, Russia.
Roman
R
Akasov
University of Strasbourg, Faculty of Pharmacy, 74 route du Rhin, 67401, Illkirch Cedex, France.|CNRS UMR 7199, Laboratoire de Conception et Application de Molécules Bioactives, équipe de Pharmacie Biogalénique, University of Strasbourg, route du Rhin No. 74, F-67401, Illkirch Cedex, France.
Manuela
M
Chiper
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, 117997, Moscow, Russia.
Elena
E
Markvicheva
University of Strasbourg, Faculty of Pharmacy, 74 route du Rhin, 67401, Illkirch Cedex, France.|CNRS UMR 7199, Laboratoire de Conception et Application de Molécules Bioactives, équipe de Pharmacie Biogalénique, University of Strasbourg, route du Rhin No. 74, F-67401, Illkirch Cedex, France.
Thierry F
TF
Vandamme
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002762:Cholecalciferol / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D003287:Contrast Media / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D004655:Emulsions / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007455:Iodine / Q000008:administration & dosage / Q000737:chemistry*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D014018:Tissue Distribution; D014283:Triiodobenzoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D055114:X-Ray Microtomography / Q000379:methods; D014965:X-Rays
D003287:Contrast Media; D004655:Emulsions; D014283:Triiodobenzoic Acids; D002762:Cholecalciferol; D007455:Iodine
cholecalciferol; contrast agent; emulsion size; micro-CT; nano-emulsion