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Albumin-based nanoparticles as contrast medium for MRI: vascular imaging, tissue and cell interactions, and pharmacokinetics of second-generation nanoparticles

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Abstract

This multidisciplinary study examined the pharmacokinetics of nanoparticles based on albumin-DTPA-gadolinium chelates, testing the hypothesis that these nanoparticles create a stronger vessel signal than conventional gadolinium-based contrast agents and exploring if they are safe for clinical use. Nanoparticles based on human serum albumin, bearing gadolinium and designed for use in magnetic resonance imaging, were used to generate magnet resonance images (MRI) of the vascular system in rats (“blood pool imaging”). At the low nanoparticle doses used for radionuclide imaging, nanoparticle-associated metals were cleared from the blood into the liver during the first 4 h after nanoparticle application. At the higher doses required for MRI, the liver became saturated and kidney and spleen acted as additional sinks for the metals, and accounted for most processing of the nanoparticles. The multiple components of the nanoparticles were cleared independently of one another. Albumin was detected in liver, spleen, and kidneys for up to 2 days after intravenous injection. Gadolinium was retained in the liver, kidneys, and spleen in significant concentrations for much longer. Gadolinium was present as significant fractions of initial dose for longer than 2 weeks after application, and gadolinium clearance was only complete after 6 weeks. Our analysis could not account quantitatively for the full dose of gadolinium that was applied, but numerous organs were found to contain gadolinium in the collagen of their connective tissues. Multiple lines of evidence indicated intracellular processing opening the DTPA chelates and leading to gadolinium long-term storage, in particular inside lysosomes. Turnover of the stored gadolinium was found to occur in soluble form in the kidneys, the liver, and the colon for up to 3 weeks after application. Gadolinium overload poses a significant hazard due to the high toxicity of free gadolinium ions. We discuss the relevance of our findings to gadolinium-deposition diseases.

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Abbreviations

%ID:

Percent of initial dose

%IDGd :

Percent of initial dose of gadolinium

AAS:

Atomic absorption spectroscopy

BSA:

Bovine serum albumin

BW:

Body weight

DTPA:

Diethylenetriaminepentaacetic acid

EC:

Endothelial cell(s)

EMA:

European Medicines Agency

FDA:

US Food and Drug Administration

Gd:

Gadolinium

HEPES:

(4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)

HSA:

Human serum albumin

ICP-MS:

Inductively coupled plasma mass spectrometry

ITLC:

Instant thin layer chromatography

ITLC-SG:

Instant thin layer chromatography (ITLC) on silica gel strips

LRO:

Lysosome-related organelle

MPh:

Macrophage(s)

MR, MR(I):

Magnetic resonance (imaging)

NFD:

Nephrogenic fibrosing dermopathy

NSF:

Nephrogenic systemic fibrosis

OSEM:

Ordered subset expectation maximization

PBS:

Phosphate-buffered saline

p.i.:

Post injectionem

PET:

Positron emission tomography

PLA:

Polylactic acid

Rf:

Retention factor

RCP:

Radiochemical purity

RCY:

Radiochemical yield

SPECT:

Single-photon emission computed tomography

TEM:

Transmission electron microscopy

TGN:

Trans-Golgi network

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Acknowledgements

The Austrian Nano-Initiative, the Austrian Science Foundation (FWF) (Project N201-NAN), and the Austrian National Bank Jubilee Program supported this work (Projects 9273, 10844, 11574, and 13096).

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Authors and Affiliations

  1. Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria

    E. A. Wallnöfer, G. C. Thurner, C. Kremser & W. Jaschke

  2. Division of Clinical Biochemistry, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020, Innsbruck, Austria

    H. Talasz

  3. Faculty of Health and Society, Biomedical Laboratory Science, University Hospital MAS, Malmö University, 205 06, Malmö, Sweden

    M. M. Stollenwerk

  4. Department of Nuclear Medicine, Innsbruck Medical University, Anichstrasse 35, 6020, Innsbruck, Austria

    A. Helbok

  5. Division of Histology and Embryology, Department of Anatomy, Histology and Embryology, Medical University of Innsbruck, Müllerstrasse 59, 6020, Innsbruck, Austria

    G. C. Thurner, M. M. Stollenwerk, N. Klammsteiner & P. Debbage

  6. Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 80-82/IV, 6020, Innsbruck, Austria

    K. Albrecht-Schgoer

  7. Institute of Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, Peter-Mayr-Strasse 1a, 6020, Innsbruck, Austria

    K. Albrecht-Schgoer

  8. Central Laboratory Animal Facilities, Innsbruck Medical University, Peter-Mayr-Strasse 4a, 6020, Innsbruck, Austria

    H. Dietrich

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  1. E. A. Wallnöfer
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Wallnöfer, E.A., Thurner, G.C., Kremser, C. et al. Albumin-based nanoparticles as contrast medium for MRI: vascular imaging, tissue and cell interactions, and pharmacokinetics of second-generation nanoparticles. Histochem Cell Biol 155, 19–73 (2021). https://doi.org/10.1007/s00418-020-01919-0

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