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Biodistribution and Toxicity of X-Ray Iodinated Contrast Agent in Nano-emulsions in Function of Their Size

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Abstract

Purpose

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.

A study on the effect of the size of cholecciferol nano-emulsions, on their in vivo becoming, through X-ray imaging modality.

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Abbreviations

CDCl3 :

Deuterated chloroform

CT:

Computed tomography

DCC:

N,N′-dicyclohexylcarbodiimide

DLS:

Dynamic light scattering

DMAP:

4-dimethylaminopyridine

DMEM:

Dulbecco’s modified Eagle medium

DMSO:

Dimethyl sulfoxide

EPR:

Enhanced permeation and retention

FBS:

Fetal bovine serum

HBSS:

Hank’s balanced salt solution

microCT:

Micro computed tomography

MRI:

Magnetic resonance imaging

MTT:

3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NPs:

Nanoparticles

OR:

Oil ratio

PBS:

Phosphate buffered saline

PDI:

Polydispersity index

PEG:

Polyethyleneglycol

PET:

Positron emission tomography

RES:

Reticuloendothelial system

SOR:

Surfactant / (surfactant + oil) weight ratio

SOWR:

(surfactant + oil) / (surfactant + oil + water) weight ratio

SPECT:

Single photon emission computed tomography

TIBA:

2,3,5-Triiodobenzoic acid

TMS:

Tetramethylsilane

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank for grant “Attractivité IDEX 2013” within University of Strasbourg, France.

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Authors and Affiliations

  1. University of Strasbourg, Faculty of Pharmacy, 74 route du Rhin, 67401, Illkirch Cedex, France

    Mohamed F. Attia, Nicolas Anton, Roman Akasov, Manuela Chiper & Thierry F. Vandamme

  2. 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

    Mohamed F. Attia, Nicolas Anton, Roman Akasov, Manuela Chiper & Thierry F. Vandamme

  3. National Research Center, P.O. 12622, Cairo, Egypt

    Mohamed F. Attia

  4. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, 117997, Moscow, Russia

    Roman Akasov & Elena Markvicheva

Authors
  1. Mohamed F. Attia
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  2. Nicolas Anton
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  6. Thierry F. Vandamme
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Correspondence to Nicolas Anton.

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Attia, M.F., Anton, N., Akasov, R. et al. Biodistribution and Toxicity of X-Ray Iodinated Contrast Agent in Nano-emulsions in Function of Their Size. Pharm Res 33, 603–614 (2016). https://doi.org/10.1007/s11095-015-1813-0

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  • DOI: https://doi.org/10.1007/s11095-015-1813-0

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