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WIREs Nanomed Nanobiotechnol
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Recent advances in nanotechnology‐based detection and separation of circulating tumor cells

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Although circulating tumor cells (CTCs) in blood have been widely investigated as a potential biomarker for diagnosis and prognosis of metastatic cancer, their inherent rarity and heterogeneity bring tremendous challenges to develop a CTC detection method with clinically significant specificity and sensitivity. With advances in nanotechnology, a series of new methods that are highly promising have emerged to enable or enhance detection and separation of CTCs from blood. In this review, we systematically categorize nanomaterials, such as gold nanoparticles, magnetic nanoparticles, quantum dots, graphenes/graphene oxides, and dendrimers and stimuli‐responsive polymers, used in the newly developed CTC detection methods. This will provide a comprehensive overview of recent advances in the CTC detection achieved through application of nanotechnology as well as the challenges that these existing technologies must overcome to be directly impactful on human health. WIREs Nanomed Nanobiotechnol 2016, 8:223–239. doi: 10.1002/wnan.1360 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Emerging Technologies
Quantum dot (QD)‐based CTC detection. (a–c) QDs were conjugated with aptamer‐DNA concatemer that has binding affinity to CTCs (QD probes, a). Gold nanoparticles were deposited on polydopamine‐coated multiwall carbon nanotube (Material B, b). The detection of CTCs on the Material B‐conjugated platform was monitored using QD probes (c). (Reprinted with permission from Ref. Copyright 2013 American Chemical Society) (d–e) The biotinylated antibody and DNA linker on QDs (d) were used to capture CTCs on streptavidin‐coated pillars of the device. (Reprinted with permission from Ref. Copyright 2013 Elsevier)
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Immunomagnetic‐based microfluidic devices for CTC detection. (a) A scheme of the device for CTCs labeled by anti‐EpCAM‐MNP being captured in a magnetic field while undergoing flow. The captured COLO205 cells were identified via immunostaining (DAPI (blue), cytokeratin (green), and CD45 (red). (Reprinted with permission from Ref. Copyright 2011 Royal Society of Chemistry) (b) EpCAM‐expression‐level‐dependent CTC sorting. Anti‐EpCAM‐MNP‐labeled CTCs were sorted in a device with multiple velocity valley zones with different linear velocities: EpCAMHigh cells trapped in zone I and EpCAMLow cells trapped in zone IV. (Reprinted with permission from Ref. Copyright 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
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Silver–Gold nanoparticles for CTC detection through surface‐enhanced Raman Scattering. (a) Four families of SERS nanoparticles (Blue: AuNR/Ag/4MBA/anti‐EpCAM, Red: AuNR/Ag/PNTP/anti‐IGF‐1 Receptor β, Green: AuNR/Ag/PATP/anti‐CD44, Magenta: AuNR/Ag/4MSTP/anti‐Keratin18) were used for CTC detection using 2D multi‐color SERS/PT detection technique (b and c). (Reprinted with permission from Ref. Copyright 2004 Nature Publishing Group)
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Magnetic enrichment and gold nanoparticle‐based photoacoustic detection of CTCs in vivo. (a) Gold nanoparticle‐based CTC targeting from 70 mm veins in mouse ear. (b and c) After enrichment using urokinase plasminogen activator‐conjugated MNPs (b) under the external magnet, CTCs in blood vasculature are quantitatively detected using FA‐coated GNP (c) and two‐color photoacoustic detection. (Reprinted with permission from Ref. Copyright 2004 Nature Publishing Group)
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Trend in CTC capture research. Number of publications regarding CTC capture from 1950 to present (Based on a search result for ‘separation or isolation or enrichment or detection or capture or recovery’ and ‘circulating tumor cells’ as keywords from ISI‐Web of Science).
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Stimulus‐responsive release of captured CTCs. (a) Biotin‐functionalized PNIPAAm polymer brushes were used as temperature‐sensitive linkers between anti‐EpCAM and the surface of silicon nanowire substrate, which resulted in the releasing of captured CTCs from the substrate upon cooling down from 37°C to lower than 4°C. (Reprinted with permission from Ref. Copyright 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) (b–c) The surface of a microfluidic device was coated with temperature‐ and mechano‐sensitive gelatin: A bulk release mechanism of captured cells upon a temperature change (c) and a cell‐specific release by applying vibration force of a microtip (d). (Reprinted with permission from Ref. Copyright 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
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Dendrimer‐mediated multivalent binding for enhanced detection of CTCs. (a–c) The dendrimer‐coated surface exhibited greatly enhanced tumor cell detection. Compared to the surface with anti‐EpCAM‐conjugated linear polymers, polyethylene glycol (PEG, b), the dendritic nanoparticle‐immobilized platform captured significantly more tumor cells (a) and improved detection of tumor cells from a mixture with 107 HL‐60 cells (c). (Reprinted with permission from Ref. Copyright 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) (d) A combination of dendrimers and E‐selectin (a cell rolling‐inducing agent), along with multiple antibodies achieved highly sensitive differential detection of tumor cells. (Reprinted with permission from Ref. Copyright 2014 American Chemical Society)
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Graphene‐modified aptasensors. (a) Electrochemical sensor with aptamer, AS1411, and graphene were developed for selective label‐free detection of CTCs. Green labeled HeLa cells were captured on aptasensor (b) and released after 5 µM cDNA treatment (c). The regenerated aptasensor after releasing the cells were able to capture HeLa cells again (d). (e) The cell capture on aptasensor can be monitored by cyclic voltammograms of [Fe(CN)6]3−/4−. (Reprinted with permission from Ref. Copyright 2011 Elsevier)
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