Editors' ChoiceCancer

Nanospherical Scouts on the Lookout for Circulating Tumor Cells

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Science Translational Medicine  08 Jan 2014:
Vol. 6, Issue 218, pp. 218ec4
DOI: 10.1126/scitranslmed.3008235

Early during the formation and growth of a primary epithelial tumor, cells disseminate through the bloodstream to distant organs. These circulating tumor cells (CTCs) hold information about the tumor that may revolutionize cancer detection and management. Cancer patients have only between 5 and 50 CTCs per teaspoon of blood; hence, the identification of these rare cells requires extremely sensitive analytical methods for enrichment and detection. Wen et al. have developed magnetic nanospheres with tunable magnetic response and size using layer-by-layer assembly to enhance capture and detection of CTCs.

Magnetic particles are beneficial in cell isolation, and their size determines performance. Whereas magnetic microbeads provide a fast magnetic response, magnetic nanoparticles require a strong magnet for separation and suffer a higher rate of loss. However, nanospheres provide a higher surface area for binding and higher capture efficiency. Wen et al. combined the advantages of microbeads and nanoparticles by using poly(styrene/acrylamide) polymer nanospheres encapsulating an iron oxide template that was further modified by five alternating coating layers of polymer and iron oxide to enhance the speed and efficiency of CTC capture. The authors further modified the particles with antibodies against epithelial cell-adhesion molecule (EpCAM) expressed by CTCs but not healthy blood cells. This enabled the particles to bind to the CTCs, and the CTCs could then be isolated from blood by using a magnetic field. Because the CTC fraction contained a substantial number of leukocytes after enrichment, tumor cells were distinguished from normal blood cells with fluorescence staining, in which CTCs were identified as the CK+/CD45/DAPI+ cells [cytokeratin positive, leukocyte antigen CD45 negative, and 4´,6-diamidino-2-phenylindole (DAPI) nuclear dye positive]. The efficacy of the particles in detecting CTCs selectively was evaluated by using a clinical blood-sample mimic in which SK-BR-3 breast cancer cells were spiked into blood samples from healthy individuals at 50 cells/ml. Using the triple-stain method, it was found that CTCs were selectively captured with negligible contamination by nonspecifically bound white blood cells. The modified nanospheres showed high reproducibility with 10% standard deviation between five sample groups as compared with 18% using commercial assays. The nanospheres captured greater than 94% of CTCs, with an incubation time of 5 min. High efficiency was also proved by using whole blood samples from 19 cancer patients and 16 healthy individuals.

The combination of nanotechnology, layer-by-layer assembly, and surface immuno-modification provided superior selectivity, identification, and isolation of CTCs from whole blood. CTC characterization could be used to guide specific tumor-targeted therapies, but continued research is needed in order to define the clinical value of CTCs and to elucidate their relationship to the primary tumor.

C.-Y. Wen et al., Quick-response magnetic nanospheres for rapid, efficient capture and sensitive detection of circulating tumor cells. ACS Nano, published online 6 December 2013 (10.1021/nn405744f). [Abstract]

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