Nanoparticle contrast-enhanced micro-CT: A preclinical tool for the 3D imaging of liver and spleen in longitudinal mouse studies

Liu, Chang‐Ning; Morin, Jeffrey; Dokmanovich, Melba G.; Bluette, Crystal T.; Goldstein, Richard A.; Manickam, Balasubramanian; Bagi, Cedo M.

doi:10.1016/j.vascn.2019.02.003

Cited by 26 publications

(32 citation statements)

References 34 publications

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“…Image noise could be reduced at the photon statistics level by the PC property of the XPAD3 camera, whereas optimal intrinsic contrast was achieved using targeted contrast agents such as the ExiTron nano 12000. We chose this agent for several properties previously reported, including (1) the in vivo stability over time, (2) the superior performance compared with other contrast agents, (3) the small volume of injection required, and (4) the lack of hepatotoxicity and of pro-inflammatory cytokine release (Boll et al., 2011, Boll et al., 2013, Liu et al., 2019, Mannheim et al., 2016, Wathen et al., 2013). In our studies, we showed that the ExiTron nano 12000 not only induced a significant increase in X-ray attenuation in the liver (about a factor of 5) but also permitted to reveal unexpected changes in the environment of treatment tumors.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, a set of contrast agents has been developed for micro-CT imaging of tumors in the liver for mouse preclinical studies (Anton et al., 2017, Boll et al., 2011, Rothe et al., 2015, Willekens et al., 2009). Among these contrast agents, the commercially available ExiTron nano 12000 (Miltenyi Biotec GmbH, Germany), which can be injected in small volumes, exhibits high amount of X-ray absorption being an alkaline earth metal nanoparticle, thus offering excellent attenuation and contrast enhancement (Boll et al., 2013, Liu et al., 2019, Wathen et al., 2013). ExiTron nano 12000 is phagocytized and accumulated by macrophages in the spleen and Kupffer cells in the reticuloendothelial system of the liver.…”

Section: Introductionmentioning

confidence: 99%

“…Anatomical evaluations of the spleen and the liver in normal and regenerative processes using ExiTron nano 12000 have been reported (Das et al., 2016, Will et al., 2017). Importantly, ExiTron nano 12000 does not cause hepatotoxicity and does not lead to pro-inflammatory cytokine release in the liver or serum, thus ensuring a relatively safe approach for longitudinal pharmacology and toxicology studies (Boll et al., 2011, Boll et al., 2013, Liu et al., 2019, Mannheim et al., 2016). This approach turned out to be very powerful for imaging primary tumors or metastases in the liver, which appear in negative because they lack contrast agents, as opposed to the liver, which is highly contrasted because of the high proportion of macrophages in the reticuloendothelial system (Bour et al., 2014, Pandit et al., 2013).…”

Section: Introductionmentioning

confidence: 99%

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Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography

et al. 2019

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SummaryComputed tomography is a powerful medical imaging modality for longitudinal studies in cancer to follow neoplasia progression and evaluate anticancer therapies. Here, we report the generation of a photon-counting micro-computed tomography (PC-CT) method based on hybrid pixel detectors with enhanced sensitivity and precision of tumor imaging. We then applied PC-CT for longitudinal imaging in a clinically relevant liver cancer model, the Alb-R26Met mice, and found a remarkable heterogeneity in the dynamics for tumors at the initiation phases. Instead, the growth curve of evolving tumors exhibited a comparable exponential growth, with a constant doubling time. Furthermore, longitudinal PC-CT imaging in mice treated with a combination of MEK and BCL-XL inhibitors revealed a drastic tumor regression accompanied by a striking remodeling of macrophages in the tumor microenvironment. Thus, PC-CT is a powerful system to detect cancer initiation and progression, and to monitor its evolution during treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography

et al. 2019

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“…It appears safe to conclude, based on what presented in this editorial, the use of theranostic nanoparticles and micro-CT imaging has a great potential to build a non-invasive imaging modality for various organs macro-morphology examinations. Moreover, such a new rapid and non-invasive imaging modality is of great assistance in longitudinal pharmacology and toxicology studies up to 1 to 6 months [16].…”

Section: Resultsmentioning

confidence: 99%

“…This is incredibly good resolution to investigate the changes of surface area, density and volume of the liver, spleen, kidneys, or even brain for a long period of time post dosing. Also, micro-CT imaging seems to be adequately efficient for liver and spleen evaluation in subacute/chronic pharmacology and toxicology studies [16].…”

Section: Theranostic Nanoparticles and Their Impact On Molecular Micrmentioning

confidence: 99%

How can molecular micro-CT imaging revolutionize drug discovery?

Shakeri‐Zadeh

2019

Expert Opinion on Drug Discovery

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Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice

Vøls

Kjelgaard‐Hansen

Ley

et al. 2020

Anim Models and Exp Med

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BackgroundHemophilic arthropathy is a debilitating morbidity of hemophilia caused by recurrent joint bleeds. We investigated if the joint bleed volume, before initiation of treatment, was linked to the subsequent degree of histopathological changes and the development of bone pathology in a mouse model of hemophilic arthropathy.MethodsFVIII knock‐out (F8‐KO) mice were dosed with a micro‐CT blood pool agent prior to induction of hemarthrosis. Eight hours after induction, the bleed volume was quantified with micro computed tomography (micro‐CT) and recombinant FVIII treatment initiated. On Day 8, inflammation in the knees was characterized by fluorescence molecular tomography. On Day 14, knee pathology was characterized by micro‐CT and histopathology. In a second study, contrast agent was injected into the knee of wild‐type (WT) mice, followed by histopathological evaluation on Day 14.ResultsThe average joint bleed volume before treatment was 3.9 mm3. The inflammation‐related fluorescent intensities in the injured knees were significantly increased on Day 8. The injured knees had significantly increased synovitis scores, vessel counts, and areas of hemosiderin compared to un‐injured knees. However, no cartilage‐ or bone pathology was observed. The bleed volume before initiation of treatment correlated with the degree of synovitis and was associated with high fluorescent intensity on Day 8. In F8‐KO and WT mice, persistence of contrast agent in the joint elicited morphological changes.ConclusionWhen applying a delayed on‐demand treatment regimen to hemophilic mice subjected to an induced knee hemarthrosis, the degree of histopathological changes on Day 14 reflected the bleed volume prior to initiation of treatment.

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Nanoparticle contrast-enhanced micro-CT: A preclinical tool for the 3D imaging of liver and spleen in longitudinal mouse studies

Cited by 26 publications

References 34 publications

Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography

Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography

How can molecular micro-CT imaging revolutionize drug discovery?

Initial joint bleed volume in a delayed on‐demand treatment setup correlates with subsequent synovial changes in hemophilic mice

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