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

Overview

Journal Theranostics

Date 2017 May 23

PMID 28529633

Citations 13

Authors

Wael Al Rawashdeh

Simin Zuo

Andrea Melle

Lia Appold

Susanne Koletnik

Yoanna Tsvetkova

Nataliia Beztsinna

Andrij Pich

Twan Lammers

Fabian Kiessling

Felix Gremse

Affiliations

Soon will be listed here.

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.

Citing Articles

Ex Vivo, In Vitro and In Vivo Bone Health Properties of Grana Padano Cheese.

Martelli C, Ottobrini L, Ferraretto A, Bendinelli P, Cattaneo S, Masotti F Foods. 2025; 14(2).

PMID: 39856939 PMC: 11765351. DOI: 10.3390/foods14020273.

Polymeric Microbubble Shell Engineering: Microporosity as a Key Factor to Enhance Ultrasound Imaging and Drug Delivery Performance.

Moosavifar M, Barmin R, Rama E, Rix A, Gumerov R, Lisson T Adv Sci (Weinh). 2024; 11(40):e2404385.

PMID: 39207095 PMC: 11516050. DOI: 10.1002/advs.202404385.

Endogenous Signaling Molecule Activating (ESMA) CARs: A Novel CAR Design Showing a Favorable Risk to Potency Ratio for the Treatment of Triple Negative Breast Cancer.

Ebbinghaus M, Wittich K, Bancher B, Lebedeva V, Appelshoffer A, Femel J Int J Mol Sci. 2024; 25(1).

PMID: 38203786 PMC: 10779313. DOI: 10.3390/ijms25010615.

Targeting Stage-Specific Embryonic Antigen 4 (SSEA-4) in Triple Negative Breast Cancer by CAR T Cells Results in Unexpected on Target/off Tumor Toxicities in Mice.

Pfeifer R, Al Rawashdeh W, Brauner J, Martinez-Osuna M, Lock D, Herbel C Int J Mol Sci. 2023; 24(11).

PMID: 37298141 PMC: 10252441. DOI: 10.3390/ijms24119184.

A multimodal imaging workflow for monitoring CAR T cell therapy against solid tumor from whole-body to single-cell level.

Pfeifer R, Henze J, Wittich K, Gosselink A, Kinkhabwala A, Gremse F Theranostics. 2022; 12(11):4834-4850.

PMID: 35836798 PMC: 9274742. DOI: 10.7150/thno.68966.

References

Longmire M, Choyke P, Kobayashi H . Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (Lond). 2008; 3(5):703-17. PMC: 3407669. DOI: 10.2217/17435889.3.5.703. View

Ale A, Ermolayev V, Herzog E, Cohrs C, de Angelis M, Ntziachristos V . FMT-XCT: in vivo animal studies with hybrid fluorescence molecular tomography-X-ray computed tomography. Nat Methods. 2012; 9(6):615-20. DOI: 10.1038/nmeth.2014. View

Pich A, Zhang F, Shen L, Berger S, Ornatsky O, Baranov V . Biocompatible hybrid nanogels. Small. 2008; 4(12):2171-5. PMC: 2766817. DOI: 10.1002/smll.200801159. View

Weissleder R, Pittet M . Imaging in the era of molecular oncology. Nature. 2008; 452(7187):580-9. PMC: 2708079. DOI: 10.1038/nature06917. View

Ho C, Dhawan A, Hughes R, Lehec S, Puppi J, Philippeos C . Use of indocyanine green for functional assessment of human hepatocytes for transplantation. Asian J Surg. 2012; 35(1):9-15. DOI: 10.1016/j.asjsur.2012.04.017. View

Figueiredo J, Passerotti C, Sponholtz T, Nguyen H, Weissleder R . A novel method of imaging calcium urolithiasis using fluorescence. J Urol. 2008; 179(4):1610-4. DOI: 10.1016/j.juro.2007.11.100. View

Dutta J, Ahn S, Joshi A, Leahy R . Illumination pattern optimization for fluorescence tomography: theory and simulation studies. Phys Med Biol. 2010; 55(10):2961-82. PMC: 3366281. DOI: 10.1088/0031-9155/55/10/011. View

He W, Zhang G, Pu H, Liu F, Cao X, Luo J . Modified forward model for eliminating the time-varying impact in fluorescence molecular tomography. J Biomed Opt. 2014; 19(5):056012. DOI: 10.1117/1.JBO.19.5.056012. View

Ergen C, Heymann F, Al Rawashdeh W, Gremse F, Bartneck M, Panzer U . Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles. Biomaterials. 2016; 114:106-120. DOI: 10.1016/j.biomaterials.2016.11.009. View

10.

Choi C, Zuckerman J, Webster P, Davis M . Targeting kidney mesangium by nanoparticles of defined size. Proc Natl Acad Sci U S A. 2011; 108(16):6656-61. PMC: 3080986. DOI: 10.1073/pnas.1103573108. View

11.

Ito K, Suzuki H, Horie T, Sugiyama Y . Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport. Pharm Res. 2005; 22(10):1559-77. DOI: 10.1007/s11095-005-6810-2. View

12.

Vasquez K, Casavant C, Peterson J . Quantitative whole body biodistribution of fluorescent-labeled agents by non-invasive tomographic imaging. PLoS One. 2011; 6(6):e20594. PMC: 3120766. DOI: 10.1371/journal.pone.0020594. View

13.

Fokong S, Siepmann M, Liu Z, Schmitz G, Kiessling F, Gatjens J . Advanced characterization and refinement of poly N-butyl cyanoacrylate microbubbles for ultrasound imaging. Ultrasound Med Biol. 2011; 37(10):1622-34. DOI: 10.1016/j.ultrasmedbio.2011.07.001. View

14.

Gremse F, Stark M, Ehling J, Menzel J, Lammers T, Kiessling F . Imalytics Preclinical: Interactive Analysis of Biomedical Volume Data. Theranostics. 2016; 6(3):328-41. PMC: 4737721. DOI: 10.7150/thno.13624. View

15.

Fokong S, Theek B, Wu Z, Koczera P, Appold L, Jorge S . Image-guided, targeted and triggered drug delivery to tumors using polymer-based microbubbles. J Control Release. 2012; 163(1):75-81. DOI: 10.1016/j.jconrel.2012.05.007. View

16.

Vauthier C, Dubernet C, Fattal E, Pinto-Alphandary H, Couvreur P . Poly(alkylcyanoacrylates) as biodegradable materials for biomedical applications. Adv Drug Deliv Rev. 2003; 55(4):519-48. DOI: 10.1016/s0169-409x(03)00041-3. View

17.

Stanescu-Segall D, Jackson T . Vital staining with indocyanine green: a review of the clinical and experimental studies relating to safety. Eye (Lond). 2008; 23(3):504-18. DOI: 10.1038/eye.2008.249. View

18.

Kuepfer L, Lippert J, Eissing T . Multiscale mechanistic modeling in pharmaceutical research and development. Adv Exp Med Biol. 2011; 736:543-61. DOI: 10.1007/978-1-4419-7210-1_32. View

19.

Baiker M, Milles J, Dijkstra J, Henning T, Weber A, Que I . Atlas-based whole-body segmentation of mice from low-contrast Micro-CT data. Med Image Anal. 2010; 14(6):723-37. DOI: 10.1016/j.media.2010.04.008. View

20.

Kunjachan S, Gremse F, Theek B, Koczera P, Pola R, Pechar M . Noninvasive optical imaging of nanomedicine biodistribution. ACS Nano. 2012; 7(1):252-62. PMC: 3743636. DOI: 10.1021/nn303955n. View