Hybrid &#181;CT-FMT imaging and image analysis

Fluorescence-mediated tomography (FMT) enables longitudinal and quantitative determination of the fluorescence distribution in vivo and can be used to ...

RWTH Aachen University

Molecular apoptosis imaging is frequently discussed to be useful for monitoring cancer therapy. We demonstrate that the sole assessment of therapy effects by apoptosis imaging can be misleading, depending on the therapy effect on the tumor vasculature.

Failure of annexin-based apoptosis imaging in the assessment of antiangiogenic therapy effects.

L&#39;imagerie mol&eacute;culaire de l&#39;apoptose est souvent discut&eacute;e pour &ecirc;tre utiles pour suivre le traitement du cancer. Nous d&eacute;montrons que la seule &eacute;valuation des effets de la th&eacute;rapie par imagerie de l&#39;apoptose peut &ecirc;tre trompeur, selon l&#39;effet de la th&eacute;rapie sur la vascularisation de la tumeur.

&Eacute;chec de l&#39;imagerie de l&#39;apoptose annexine-bas&eacute; dans l&#39;&eacute;valuation des effets de la th&eacute;rapie anti-angiog&eacute;niques.

Imaging molecolare apoptosis &egrave; spesso discusso per essere utile per monitorare la terapia del cancro. Dimostriamo che la sola valutazione degli effetti di terapia da apoptosi imaging pu&ograve; essere fuorviante, a seconda l&#39;effetto della terapia sul sistema vascolare tumorale.

Fallimento dell&#39;apoptosi annexin-based imaging nella valutazione degli effetti di terapia antiangiogenetica.

The putative presence of the erythropoietin receptor (EpoR) on human cancer cells has given rise to controversial discussion about the use of recombinant human erythropoietin (rhuEpo) for treatment of patients with chemotherapy-induced anemia. In vivo analysis of the EpoR status in tumors could help in elucidating the role of erythropoietin in cancer. Thus, the aim of this study was to develop a targeted EpoR probe for the investigation of EpoR expression in human lung cancer xenografts by fluorescence-mediated tomography.

Targeted near-infrared imaging of the erythropoietin receptor in human lung cancer xenografts.

La pr&eacute;sence pr&eacute;sum&eacute;e du r&eacute;cepteur de l&#39;&eacute;rythropo&iuml;&eacute;tine (EpoR) sur des cellules canc&eacute;reuses humaines a donn&eacute; lieu &agrave; une discussion controvers&eacute;e quant &agrave; l&#39;utilisation de l&#39;&eacute;rythropo&iuml;&eacute;tine humaine recombinante (EPOrHu) pour le traitement des patients atteints d&#39;an&eacute;mie induite par la chimioth&eacute;rapie. Analyse in vivo de l&#39;&eacute;tat de EpoR dans les tumeurs pourrait aider &agrave; &eacute;lucider le r&ocirc;le de l&#39;&eacute;rythropo&iuml;&eacute;tine dans le cancer. Ainsi, le but de cette &eacute;tude &eacute;tait de d&eacute;velopper une sonde EpoR cibl&eacute;e pour l&#39;&eacute;tude d&#39;expression EpoR de x&eacute;nogreffe de cancer du poumon humain par fluorescence induite par la tomographie.

Cibl&eacute;es imagerie infrarouge proche du r&eacute;cepteur de l&#39;&eacute;rythropo&iuml;&eacute;tine dans les x&eacute;nogreffes de cancer du poumon chez l&#39;humain.

La presunta presenza del recettore dell&#39;eritropoietina (EpoR) su cellule tumorali umane ha dato origine alla controversa discussione circa l&#39;uso dell&#39;eritropoietina ricombinante umana (rhuEpo) per il trattamento di pazienti con anemia indotta dalla chemioterapia. Analisi in vivo dello status EpoR nei tumori potrebbero aiutare a chiarire il ruolo dell&#39;eritropoietina nel cancro. Cos&igrave;, lo scopo di questo studio era quello di sviluppare una sonda EpoR mirata per la ricerca dell&#39;espressione EpoR in xenotrapianti di cancro del polmone umano di fluorescenza-mediate tomografia.

Mirate near-infrared imaging del recettore dell&#39;eritropoietina in xenotrapianti di cancro del polmone umano.

Recent data suggest that the chemokine receptor CXCR3 is functionally involved in fibroproliferative disorders, including liver fibrosis. Neoangiogenesis is an important pathophysiological feature of liver scarring, but a functional role of angiostatic CXCR3 chemokines in this process is unclear. We therefore investigated neoangiogenesis in carbon tetrachloride (CCl(4))-induced liver fibrosis in Cxcr3(-/-) and wildtype mice by histological, molecular, and functional imaging methods. Furthermore, we assessed the direct role of vascular endothelial growth factor (VEGF) overexpression on liver angiogenesis and the fibroproliferative response using a Tet-inducible bitransgenic mouse model. The feasibility of attenuation of angiogenesis and associated liver fibrosis by therapeutic treatment with the angiostatic chemokine Cxcl9 was systematically analyzed in vitro and in vivo. The results demonstrate that fibrosis progression in Cxcr3(-/-) mice was strongly linked to enhanced neoangiogenesis and VEGF/VEGFR2 expression compared with wildtype littermates. Systemic VEGF overexpression led to a fibrogenic response within the liver and was associated with a significantly increased Cxcl9 expression. In vitro, Cxcl9 displayed strong antiproliferative and antimigratory effects on VEGF-stimulated endothelial cells and stellate cells by way of reduced VEGFR2 (KDR), phospholipase Cγ (PLCγ), and extracellular signal-regulated kinase (ERK) phosphorylation, identifying this chemokine as a direct counter-regulatory molecule of VEGF signaling within the liver. Accordingly, systemic administration of Cxcl9 led to a strong attenuation of neoangiogenesis and experimental liver fibrosis in vivo.

Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice.

This research reports the versatile synthetic strategies for hybrid PBCA microbubbles as contrast agents and drug carriers loaded with fluorescent dyes and magnetic nanoparticles serving in vitro cell labelling and in vivo target imaging. These multifunctional probes therefore prove their potential biomedical applications in cancer diagnostics and treatment.

Versatile synthetic strategies for PBCA-based hybrid fluorescent microbubbles and their potential theranostic applications to cell labelling and imaging.

To compare mesoscopic epi-fluorescence tomography (MEFT) and EPRI-illumination reflectance imaging (EPRI) for quantitative tumour size assessment in mice.

High accuracy of mesoscopic epi-fluorescence tomography for non-invasive quantitative volume determination of fluorescent protein-expressing tumours in mice.

Recombinant human erythropoietin (rhuEpo) is used clinically to treat anaemia. However, rhuEpo-treated cancer patients show decreased survival rates and erythropoietin receptor (EpoR) expression has been found in patient tumour tissue. Thus, rhuEpo application might promote EpoR(+) tumour progression. We therefore developed the positron emission tomography (PET)-probe (68)Ga-DOTA-rhuEpo and evaluated its performance in EpoR(+) A549 non-small-cell lung cancer (NSCLC) xenografts.

In-vivo detection of the erythropoietin receptor in tumours using positron emission tomography.

Recombinant human erythropoietin (rhuEpo) is currently under debate for the treatment of chemotherapy-induced anemia due to clinical trials showing adverse effects in Epo-treated patients and the discovery of the erythropoietin-receptor (EpoR) in tumor and endothelial cells. Here, using Epo-Cy5.5 as theranostic near-infrared fluorescent probe we analyzed the effects of rhuEpo as co-medication to carboplatin in non-small-cell-lung-cancer (NSCLC)-xenografts with different tumor cell EpoR-expression (H838 ~8-fold higher than A549). Nude mice bearing subcutaneous A549 and H838 NSCLC-xenografts received either only carboplatin or carboplatin and co-medication of rhuEpo in two different doses. Tumor sizes and relative blood volumes (rBV) were longitudinally measured by 3D-contrast-enhanced ultrasound (3D-US). Tumoral EpoR-levels were determined by combined fluorescence molecular tomography (FMT)/ micro computed tomography (µCT) hybrid imaging. We found that rhuEpo predominantly acted on the tumor endothelium. In both xenografts, rhuEpo co-medication significantly increased vessel densities, diameters and the amount of perfused vessels. Accordingly, rhuEpo induced EpoR-phoshorylation and stimulated proliferation of endothelial cells. However, compared with solely carboplatin-treated tumors, tumor growth was significantly slower in the groups co-medicated with rhuEpo. This is explained by the Epo-mediated vascular remodeling leading to improved drug delivery as obvious by a more than 2-fold higher carboplatin accumulation and significantly enhanced tumor apoptosis. In addition, co-medication of rhuEpo reduced tumor hypoxia and diminished intratumoral EpoR-levels which continuously increased during carboplatin (Cp) -treatment. These findings suggest that co-medication of rhuEpo in well balanced doses can be used to improve the accumulation of anticancer drugs. Doses and indications may be personalized and refined using theranostic EpoR-probes.

Article	Year
Failure of annexin-based apoptosis imaging in the assessment of antiangiogenic therapy effects. EJNMMI research\| PubMed ID: 22214377	2011
Targeted near-infrared imaging of the erythropoietin receptor in human lung cancer xenografts. Journal of nuclear medicine : official publication, Society of Nuclear Medicine\| PubMed ID: 22228796	2012
Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology (Baltimore, Md.)\| PubMed ID: 22237831	2012
Versatile synthetic strategies for PBCA-based hybrid fluorescent microbubbles and their potential theranostic applications to cell labelling and imaging. Chemical communications (Cambridge, England)\| PubMed ID: 22516972	2012
High accuracy of mesoscopic epi-fluorescence tomography for non-invasive quantitative volume determination of fluorescent protein-expressing tumours in mice. European radiology\| PubMed ID: 22544295	2012
In-vivo detection of the erythropoietin receptor in tumours using positron emission tomography. European radiology\| PubMed ID: 25196361	2015
Erythropoietin improves the accumulation and therapeutic effects of Carboplatin by enhancing tumor vascularization and perfusion. Theranostics\| PubMed ID: 26000061	2015

Dennis Doleschel

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