Journal ArticleDOI
Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice
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TLDR
The tumor uptake value obtained from PET imaging had excellent linear correlation with the relative tumor tissue EphA2 expression level measured by Western blot, where r2 equals 0.90 and 0.92 at 18 h and 42 h post injection, respectively, which is, to the authors' knowledge, the first report of quantitative radioimmunoPET imaging of Eph a2 in living subjects.Abstract:
EphA2 receptor tyrosine kinase is significantly overexpressed in a wide variety of cancer types. High EphA2 expression has been correlated with increased metastatic potential and poor patient survival. Although many recent reports have focused on blocking the EphA2 signaling pathway in cancer, the in vivo imaging of EphA2 has not yet been investigated. We labeled 1C1, a humanized monoclonal antibody against both human and murine EphA2, with 64Cu through the chelating agent 1,4,7,10-tetraazacyclododecane N,N′,N″,N″′-tetraacetic acid (DOTA) and carried out positron emission tomography (PET) imaging of eight tumor models with different EphA2 expression levels. Western blotting of tumor tissue lysate was performed to correlate the EphA2 expression level with 64Cu-DOTA-1C1 uptake in the tumors. Immunofluorescence staining and biodistribution studies were also carried out to validate the in vivo results. The radiolabeling yield was 88.9 ± 9.5% (n = 7) and the specific activity of 64Cu-DOTA-1C1 was 1.32 ± 0.14 GBq/mg of 1C1 mAb. The antibody retained antigen-binding affinity/specificity after DOTA conjugation as measured by FACS analysis. The uptake of 64Cu-DOTA-1C1 in CT-26 tumors was as high as 25.1 ± 2.5 %ID/g (n = 3) at 18 h post injection. 64Cu-DOTA-IgG, an isotype-matched control, exhibited minimal non-specific uptake in all eight tumor models. In vivo EphA2 specificity of 64Cu-DOTA-1C1 was confirmed by successful blocking of CT-26 tumor uptake by unlabeled 1C1. Most importantly, the tumor uptake value obtained from PET imaging had excellent linear correlation with the relative tumor tissue EphA2 expression level measured by Western blot, where r
2 equals 0.90 and 0.92 at 18 h and 42 h post injection, respectively. The tumor uptake of 64Cu-DOTA-1C1 measured by microPET imaging reflects tumor EphA2 expression level in vivo. This is, to our knowledge, the first report of quantitative radioimmunoPET imaging of EphA2 in living subjects. Future clinical investigation of 64Cu-DOTA-1C1 is warranted.read more
Citations
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Eph receptors and ephrins in cancer: bidirectional signalling and beyond
TL;DR: The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumour blood vessels, which suggest important roles for their bidirectional signals in many aspects of cancer development and progression.
Journal ArticleDOI
Multimodality molecular imaging of tumor angiogenesis.
Weibo Cai,Xiaoyuan Chen +1 more
TL;DR: The current status of tumor angiogenesis imaging with SPECT, PET, molecular MRI, targeted ultrasound, and optical techniques is summarized and only nanoparticle-based probes, which truly target the tumor vasculature rather than tumor cells because of poor extravasation, are discussed.
Journal ArticleDOI
Eph receptors and ephrins: therapeutic opportunities.
TL;DR: Despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules, and various strategies are being explored to modulate their expression and function.
Journal ArticleDOI
ImmunoPET: Concept, Design, and Applications
TL;DR: The latest immuno PET imaging strategies and their preclinical and clinical applications are presented and current conjugation strategies that can be leveraged to develop next-generation immunoPET probes are emphasized.
Journal ArticleDOI
Emerging strategies for EphA2 receptor targeting for cancer therapeutics
TL;DR: The deregulated signaling by EphA2 and its involvement in oncogenesis provide multiple avenues for the rational design of intervention approaches and has been tested as a drug target using multiple approaches such as agonist antibodies, RNA interference, immunotherapy, virus vector-mediated gene transfer, small-molecule inhibitors and nanoparticles.
References
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Journal ArticleDOI
Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4.
TL;DR: In this paper, it was shown that ephrin-B2, an Eph family transmembrane ligand, marks arterial but not venous endothelial cells from the onset of angiogenesis.
Journal ArticleDOI
In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice
Zhuang Liu,Weibo Cai,Lina He,Nozomi Nakayama,Kai Chen,Xiaoming Sun,Xiaoyuan Chen,Hongjie Dai +7 more
TL;DR: It is found that SWNTs that are functionalized with phospholipids bearing polyethylene-glycol (PEG) are surprisingly stable in vivo, and a high tumour accumulation is attributed to the multivalent effect of theSWNTs.
Journal ArticleDOI
Eph Receptors and Ligands Comprise Two Major Specificity Subclasses and Are Reciprocally Compartmentalized during Embryogenesis
Nicholas W. Gale,Sacha J. Holland,David M. Valenzuela,Ann Flenniken,Li Pan,Terrence E Ryan,Mark Henkemeyer,Klaus Strebhardt,Hisamaru Hirai,David G. Wilkinson,Tony Pawson,Samuel Davis,George D. Yancopoulos +12 more
TL;DR: It is reported that the many Eph-related receptor tyrosine kinases, and their numerous membrane-bound ligands, can each be grouped into only two major specificity subclasses, revealing that the developing embryo is subdivided into domains defined by reciprocal and apparently mutually exclusive expression of a receptor subclass and its corresponding ligands.
Journal ArticleDOI
Therapeutic EphA2 Gene Targeting In vivo Using Neutral Liposomal Small Interfering RNA Delivery
Charles N. Landen,Arturo Chavez-Reyes,Corazon D. Bucana,Rosemarie Schmandt,Michael T. Deavers,Gabriel Lopez-Berestein,Anil K. Sood +6 more
TL;DR: The feasibility of siRNA incorporated into the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) for efficient in vivo siRNA delivery and DOPC-encapsulated siRNA targeting the oncoprotein EphA2 was highly effective in reducing in vivo Eph a2 expression 48 hours after a single dose are shown.
Journal Article
EphA2 overexpression causes tumorigenesis of mammary epithelial cells
TL;DR: It is shown that EphA2 overexpression is sufficient to confer malignant transformation and tumorigenic potential on nontransformed (MCF-10A) mammary epithelial cells and Interestingly, stimulation of EPhA2 reverses the malignant growth and invasiveness of EPHA2-transformed cells.