Theranostics 2017; 7(6):1499-1510. doi:10.7150/thno.17263 This issue Cite

Research Paper

Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling

Wa'el Al Rawashdeh1*, Simin Zuo1*, Andrea Melle2, Lia Appold1, Susanne Koletnik1, Yoanna Tsvetkova1, Nataliia Beztsinna3, Andrij Pich2, Twan Lammers1, 3, Fabian Kiessling1, Felix Gremse1✉

1. Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic, Pauwelsstr. 30, 52074 Aachen, Germany;
2. DWI - Leibniz Institute for Interactive Materials, RWTH Aachen University, Forckenbeckstr. 50, 52074 Aachen, Germany;
3. Department of Pharmaceutics, Utrecht University, Universiteitslaan 99, Utrecht, The Netherlands.
* These authors contributed equally to this study

Citation:
Al Rawashdeh W, Zuo S, Melle A, Appold L, Koletnik S, Tsvetkova Y, Beztsinna N, Pich A, Lammers T, Kiessling F, Gremse F. Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling. Theranostics 2017; 7(6):1499-1510. doi:10.7150/thno.17263. https://www.thno.org/v07p1499.htm
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Abstract

Graphic abstract

Fluorescence-mediated tomography (FMT) is a quantitative three-dimensional imaging technique for preclinical research applications. The combination with micro-computed tomography (µCT) enables improved reconstruction and analysis. The aim of this study is to assess the potential of µCT-FMT and kinetic modeling to determine elimination and retention of typical model drugs and drug delivery systems.

We selected four fluorescent probes with different but well-known biodistribution and elimination routes: Indocyanine green (ICG), hydroxyapatite-binding OsteoSense (OS), biodegradable nanogels (NG) and microbubbles (MB). µCT-FMT scans were performed in twenty BALB/c nude mice (5 per group) at 0.25, 2, 4, 8, 24, 48 and 72 h after intravenous injection. Longitudinal organ curves were determined using interactive organ segmentation software and a pharmacokinetic whole-body model was implemented and applied to compute physiological parameters describing elimination and retention.

ICG demonstrated high initial hepatic uptake which decreased rapidly while intestinal accumulation appeared for around 8 hours which is in line with the known direct uptake by hepatocytes followed by hepatobiliary elimination. Complete clearance from the body was observed at 48 h. NG showed similar but slower hepatobiliary elimination because these nanoparticles require degradation before elimination can take place. OS was strongly located in the bones in addition to high signal in the bladder at 0.25 h indicating fast renal excretion. MB showed longest retention in liver and spleen and low signal in the kidneys likely caused by renal elimination or retention of fragments. Furthermore, probe retention was found in liver (MB, NG and OS), spleen (MB) and kidneys (MB and NG) at 72 h which was confirmed by ex vivo data. The kinetic model enabled robust extraction of physiological parameters from the organ curves.

In summary, µCT-FMT and kinetic modeling enable differentiation of hepatobiliary and renal elimination routes and allow for the noninvasive assessment of retention sites in relevant organs including liver, kidney, bone and spleen.

Keywords: Fluorescence-mediated tomography, kinetic modeling, micro-computed tomography, elimination routes, retention sites, OsteoSense, microbubbles, nanogels, indocyanine green.


Citation styles

APA
Al Rawashdeh, W., Zuo, S., Melle, A., Appold, L., Koletnik, S., Tsvetkova, Y., Beztsinna, N., Pich, A., Lammers, T., Kiessling, F., Gremse, F. (2017). Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling. Theranostics, 7(6), 1499-1510. https://doi.org/10.7150/thno.17263.

ACS
Al Rawashdeh, W.; Zuo, S.; Melle, A.; Appold, L.; Koletnik, S.; Tsvetkova, Y.; Beztsinna, N.; Pich, A.; Lammers, T.; Kiessling, F.; Gremse, F. Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling. Theranostics 2017, 7 (6), 1499-1510. DOI: 10.7150/thno.17263.

NLM
Al Rawashdeh W, Zuo S, Melle A, Appold L, Koletnik S, Tsvetkova Y, Beztsinna N, Pich A, Lammers T, Kiessling F, Gremse F. Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling. Theranostics 2017; 7(6):1499-1510. doi:10.7150/thno.17263. https://www.thno.org/v07p1499.htm

CSE
Al Rawashdeh W, Zuo S, Melle A, Appold L, Koletnik S, Tsvetkova Y, Beztsinna N, Pich A, Lammers T, Kiessling F, Gremse F. 2017. Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling. Theranostics. 7(6):1499-1510.

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