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Functional lymphatic imaging in tumor-bearing mice.

ABSTRACT: The lymphatic system provides a route for dissemination of metastatic cancer cells. Yet to date transient changes in lymphatic drainage pathways and function as a result of tumor growth and metastasis have not been completely elucidated. Herein, we non-invasively imaged functional and architectural lymphatic changes in mice with regional, palpable lymph node (LN) involvement using dynamic near-infrared (NIR) fluorescence imaging with intradermal injection of indocyanine green (ICG) to both tumor-free mice and mice bearing C6/LacZ rat glioma tumors in the tail or hindlimb. We found that lymphatic drainage pathways were transiently altered and the contractile function of regional conducting lymphatic vessels was reduced or lost with progressive disease. Therefore, transient changes in the regional lymphatic architecture and function that occur with progressive disease, can be imaged using NIR fluorescence, and may provide a new method to stage disease.

SUBMITTER: Kwon S

PROVIDER: S-EPMC2924912 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Functional lymphatic imaging in tumor-bearing mice.

Kwon Sunkuk S Sevick-Muraca Eva M EM

Journal of immunological methods 20100630 1-2

The lymphatic system provides a route for dissemination of metastatic cancer cells. Yet to date transient changes in lymphatic drainage pathways and function as a result of tumor growth and metastasis have not been completely elucidated. Herein, we non-invasively imaged functional and architectural lymphatic changes in mice with regional, palpable lymph node (LN) involvement using dynamic near-infrared (NIR) fluorescence imaging with intradermal injection of indocyanine green (ICG) to both tumor ...[more]

PMID: 20600076

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Project description:IntroductionUltrasound (US) imaging enables tissue visualization in high spatial resolution with short examination times. Thus, it is often applied in preclinical research. Diagnostic US, including contrast-enhanced ultrasound (CEUS), are considered to be well tolerated by laboratory animals although no systematic study has been performed to confirm this claim. Therefore, the aim of this study was to screen for possible effects of US and CEUS examinations on welfare of healthy mice. Additionally, the potential influence of CEUS and molecular CEUS on well-being and therapy response to regorafenib was investigated in breast cancer-bearing mice.Material and methods40 healthy Balb/c mice were randomly assigned for examination with US or CEUS (3x/week) for four weeks. Untreated healthy mice and mice receiving only isoflurane anesthesia served as controls (n= 10/group). Ninety-four 4T1 tumor-bearing Balb/c mice were allocated randomly to the following groups: no imaging, isoflurane anesthesia, CEUS and molecular CEUS. They either received 10 mg/kg regorafenib or vehicle solution daily by oral gavage. Animals were examined three times within two weeks. CEUS measurements were performed using phospholipid-microbubbles and phospholipid-microbubbles targeting the vascular endothelial growth factor receptor-2 were applied for molecular CEUS. Welfare evaluation was performed by daily observational score sheets, measuring the heart rate, Rotarod performance and fecal corticosterone metabolites twice per week. On the last day, pathological changes of serum corticosterone concentrations, hemograms, and organ weights were obtained. Moreover, a potential influence of isoflurane anesthesia, CEUS and molecular CEUS on regorafenib response in tumor-bearing mice was examined. Analysis of variance and Dunnett post hoc test were performed as statistical analyses.ResultsSeverity parameters were not altered after repeated US and CEUS examinations of healthy mice, but spleen sizes were significantly lower after isoflurane anesthesia. In tumor-bearing mice, no effect on animal-welfare after repeated CEUS and molecular CEUS could be observed. However, leukocyte counts and spleen weights of tumor-bearing mice were significantly lower in animals examined with CEUS and molecular CEUS compared to the control groups. This effect was not visible in regorafenib-treated animals.ConclusionsRepeated US and (molecular) CEUS have no detectable impact on animal welfare in healthy and tumor-bearing mice. However, CEUS and molecular CEUS in combination with isoflurane anesthesia might attenuate immunological processes in tumor-bearing animals and may consequently affect responses to anti-tumor therapy.

Project description:BackgroundA novel [64Cu]Cu-NOTA-aCD40 immunoPET tracer was developed to image a CD40+ pancreatic tumor model in C57BL/6 mice and to study the biodistribution profile of the agonist CD40 (aCD40) monoclonal antibody (mAb) alone or combined with other mAbs.ProceduresCopper-64 ([64Cu]Cu) labeled NOTA-aCD40 and NOTA-IgG (10 μg; 7 MBq) were injected intravenously into C57BL/6 mice with subcutaneous mT4 tumors to assess specificity 48 h post injection (p.i.) through positron emission tomography/computed tomography (PET/CT) imaging and biodistribution studies (n = 5). [64Cu]Cu-NOTA-aCD40 was injected alone or simultaneously in combination with a therapeutic mass of cold aCD40 (100 μg), aPD-1 (200 μg) and aCTLA-4 (200 μg) mAbs. A group of mice with or without tumor received the second round of injections 1 or 3 weeks apart, respectively. PET/CT imaging and biodistribution studies were performed at 48 h p.i. The organ dose for [64Cu]Cu was estimated based on biodistribution studies with 2 μg [64Cu]Cu-NOTA-aCD40 (corresponds to 5 mg patient dose) in non-tumor bearing mice.Results[64Cu]Cu-NOTA-aCD40 accumulation was 2.3- and 7.8-fold higher than [64Cu]Cu-NOTA-IgG in tumors and spleen, respectively, indicating the specificity of aCD40 mAb in a mouse pancreatic tumor model. Tumor accumulation of [64Cu]Cu-NOTA-aCD40 was 21.2 ± 7.3%ID/g at 48 h after injection. Co-injection of [64Cu]Cu-NOTA-aCD40 with cold aCD40 mAb alone or with PD-1 and CTLA-4 mAbs reduced both spleen and tumor uptake, whereas liver uptake was increased. With the second round of injections, the liver was the only organ with substantial uptake. With a 2 μg administered dose of [64Cu]Cu-NOTA-aCD40 in a dosimetry study, the liver to spleen ratio was greater compared to the 10 μg dose (2.8 vs 0.37; respectively). The human equivalent for the highest dose organ (liver) was 198 ± 28.7 μSv/MBq.ConclusionsA CD40-immunoreactive [64Cu]Cu-NOTA-aCD40 probe was developed. The ratio of spleen to liver accumulation exceeded that of the IgG isotype and was greatest with a single small, injected mass. The safety of human patient imaging with [64Cu]Cu was established based on extrapolation of the organ specificity to human imaging.

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Functional lymphatic imaging in tumor-bearing mice.

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Functional lymphatic imaging in tumor-bearing mice.

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