Improved Detection of preclinical Colorectal Liver Metastases by High Resolution Ultrasound including Molecular Ultrasound Imaging using the targeted Contrast Agent BR55

Hackl, Christina; Schacherer, Doris; Anders, M; Wiedemann, Leanne M.; Mohr, Arno; Schlitt, HJ; Stroszczynski, Christian; Tranquart, F.; Jung, Ernst Michael

doi:10.1055/s-0041-111838

Cited by 32 publications

(9 citation statements)

References 5 publications

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“…7,42,43 BR55 is currently the most successful targeted UCAs, which can effectively enhance ultrasound imaging of tumor tissues and has been reported in the early diagnosis of malignant tumors. [44][45][46][47] However, because the particle size is on the micron scale, BR55 can only achieve intravascular USMI. Nanobubbles with a particle size of less than 700 nm can penetrate the tumor vasculature to achieve USMI of tumor parenchymal cells and targeted delivery of drugs or genes to tumor parenchymal cells.…”

Section: Discussionmentioning

confidence: 99%

CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

Zhu¹,

Wang²,

Liu³

et al. 2018

IJN

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PurposeTargeted nanobubbles can penetrate the tumor vasculature and achieve ultrasound molecular imaging (USMI) of tumor parenchymal cells. However, most targeted nanobubbles only achieve USMI of tumor parenchymal cells from one organ, and their distribution, loading ability, and binding ability in tumors are not clear. Therefore, targeted nanobubbles loaded with carbonic anhydrase IX (CAIX) aptamer were fabricated for USMI of various tumors, and the morphological basis of USMI with targeted nanobubbles was investigated.Materials and methodsThe specificity of CAIX aptamer at the cellular level was measured by immunofluorescence and flow cytometry. Targeted nanobubbles loaded with CAIX aptamer were prepared by a maleimidethiol coupling reaction, and their binding ability to CAIX-positive tumor cells was analyzed in vitro. USMI of targeted and non-targeted nanobubbles was performed in tumor-bearing nude mice. The distribution, loading ability, and binding ability of targeted nanobubbles in xenograft tumor tissues were demonstrated by immunofluorescence.ResultsCAIX aptamer could specifically bind to CAIX-positive 786-O and Hela cells, rather than CAIX-negative BxPC-3 cells. Targeted nanobubbles loaded with CAIX aptamer had the advantages of small size, uniform distribution, regular shape, and high safety, and they could specifically accumulate around 786-O and Hela cells, while not binding to BxPC-3 cells in vitro. Targeted nanobubbles had significantly higher peak intensity and larger area under the curve than non-targeted nanobubbles in 786-O and Hela xenograft tumor tissues, while there was no significant difference in the imaging effects of targeted and non-targeted nanobubbles in BxPC-3 xenograft tumor tissues. Immunofluorescence demonstrated targeted nanobubbles could still load CAIX aptamer after penetrating the tumor vasculature and specifically binding to CAIX-positive tumor cells in xenograft tumor tissues.ConclusionTargeted nanobubbles loaded with CAIX aptamer have a good imaging effect in USMI of tumor parenchymal cells, and can improve the accuracy of early diagnosis of malignant tumors from various organs.

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Section: Discussionmentioning

confidence: 99%

CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

Zhu¹,

Wang²,

Liu³

et al. 2018

IJN

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“…To assess the hepatic tumor load more precisely, staining for H&E (Merck 1.09 249.1000 and 1.09 844.1000) using standard protocols for formalin-fixed tissues was performed on 5μm liver sections serially cut at 100μm intervals. Sections were analyzed at 10x magnification with a Zeiss Axioplan 2 microscope under bright-field conditions, and images captured with a Zeiss Axiocam camera using AxioVision 3.0 software as described before [34] . Total liver area and tumor area were measured using ImageJ and determined as μm 2 .…”

Section: Methodsmentioning

confidence: 99%

Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis

et al. 2018

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Mammalian target of rapamycin complex 2 (mTORC2) with its pivotal component rapamycin-insensitive companion of mTOR (RICTOR) is the major regulator of AKT phosphorylation and is increasingly implicated in tumor growth and progression. In cutaneous melanoma, an extremely aggressive and highly metastatic disease, RICTOR overexpression is involved in tumor development and invasiveness. Therefore, we investigated the impact of RICTOR inhibition in melanoma cells in vitro and in vivo with special emphasis on hepatic metastasis. Moreover, our study focused on the interaction of tumor cells and hepatic stellate cells (HSC) which play a crucial role in the hepatic microenvironment. In silico analysis revealed increased RICTOR expression in melanoma cells and tissues and indicated higher expression in advanced melanoma stages and metastases. In vitro, transient RICTOR knock-down via siRNA caused a significant reduction of tumor cell motility. Using a syngeneic murine splenic injection model, a significant decrease in liver metastasis burden was detected in vivo. Moreover, stimulation of melanoma cells with conditioned medium (CM) from activated HSC or hepatocyte growth factor (HGF) led to a significant induction of AKT phosphorylation and tumor cell motility. Blocking of RICTOR expression in cancer cells diminished constitutive and HGF-induced AKT phosphorylation as well as cell motility. Interestingly, RICTOR blockade also led to an abrogation of CM-induced effects on AKT phosphorylation and motility in melanoma cells. In conclusion, these results provide first evidence for a critical role of mTORC2/RICTOR in melanoma liver metastasis via cancer cell/HSC interactions.

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“…In the future, development of ultrasound processing methods with higher frequency and resolution, as well as 3-D or 4-D imaging, may also improve the diagnostic ability of CH-EUS (Averkiou et al 2020). A new ultrasound contrast agent that has an affinity to the kinase insert domain receptor (one of the key regulators of neoangiogenesis) was developed recently (Hackl et al 2016;Willmann et al 2017). Further studies are needed to apply ultrasound molecular imaging using BR55 to CH-EUS.…”

Section: Discussionmentioning

confidence: 99%

The Asian Federation of Societies for Ultrasound in Medicine and Biology (AFSUMB) Guidelines for Contrast-Enhanced Endoscopic Ultrasound

Kitano

Yamashita

Kamata

et al. 2021

Ultrasound in Medicine & Biology

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The Asian Federation of Societies for Ultrasound in Medicine and Biology aimed to provide information on techniques and indications for contrast-enhanced harmonic endoscopic ultrasound (CH-EUS), and to create statements including the level of recommendation. These statements are based on current scientific evidence reviewed by a Consensus Panel of 15 internationally renowned experts. The reliability of clinical questions was measured by agreement rates after voting. Six statements were made on techniques, including suitable contrast agents for CH-EUS, differences between contrast agents, setting of mechanical index, dual imaging and duration and phases for observation. Thirteen statements were made on indications, including pancreatic solid masses, pancreatic cancer staging, pancreatic cystic lesions and mural nodules, detection of subtle pancreatic lesions, gallbladder sludge and polyps, hepatic lesions, lymph nodes, subepithelial lesions, visceral vascular diseases, guidance of fine needle aspiration and evaluation for local therapy. These international expert consensus guidelines will assist endosonographers in conducting CH-EUS according to evidence-based information.

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Improved Detection of preclinical Colorectal Liver Metastases by High Resolution Ultrasound including Molecular Ultrasound Imaging using the targeted Contrast Agent BR55

Abstract: Detection of metastases by HRU and CEUS was earlier and more accurate than monitoring via bioluminescence. In vivo monitoring of hepatic micrometastases can thus be performed without prior modification of cancer cells using standard technology.

Cited by 32 publications

References 5 publications

CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

CAIX aptamer-functionalized targeted nanobubbles for ultrasound molecular imaging of various tumors

Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis

The Asian Federation of Societies for Ultrasound in Medicine and Biology (AFSUMB) Guidelines for Contrast-Enhanced Endoscopic Ultrasound

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