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Page 16 of 21 Su et al. J Cancer Metastasis Treat 2020;6:19 I http://dx.doi.org/10.20517/2394-4722.2020.48
[6]
Later, in the same group, Loeian et al. reported applying the nanotube chip for capturing CTCs from
peripheral blood samples of breast cancer patients (stages 1-4). The CTCs (based on CK8/18, HER2, and
EGFR) were successfully captured from 7/7 breast cancer patient samples and no CTCs were captured from
[98]
healthy controls (n = 2). Salahandish et al. reported an electrochemical biosensor for detecting as low as
2 cells/mL SK-BR3 breast cancer cells with a fast response time of 30 min. This electrochemical biosensor
demonstrated an efficiency of > 90% for capturing cancer cells in whole blood sample without sample
preparation and cell staining. Other platforms that detect CTCs from non-clinical samples have also been
[99]
reported but are not covered in this review. For example, Tian et al. reported an enzyme-free ELISA for
HER2 detection from serum samples utilizing copper oxide nanoparticles as signal amplification probes.

Haun et al. [100] clinically tested on suspected lesions in 50 patients and validated in an independent cohort
of another 20 patients using this DMR system. For each patient, a one- to two-pass fine-needle aspirate
from a suspected abdominal malignancy was obtained, followed by a series of routine core biopsies for
conventional standard-of-care analysis. Each fine-needle aspirate sample was washed with 1-2 mL of
buffered saline and processed for μNMR measurements of 11 markers. These markers included nine
well-established cancer-related markers (EpCAM (epithelial cell adhesion molecule), MUC-1 (mucin 1,
cell surface associated), HER2, EGFR (epidermal growth factor receptor), B7-H3, CK18, Ki-67, p53, and
vimentin), a count of CD45-positive cells, and total cell density. Their results show the μNMR-based
measurements are comparable with the accepted gold standards such as enzyme-linked immunosorbent
assay (ELISA), fluorescence-activated cell sorting (FACS), and immunohistochemistry (IHC). The
correlation coefficients between μNMR and ELISA, FACS, and IHC measurements for expression of EGFR
are 0.99, 0.98, and 0.93, respectively. It was shown that EGFR and HER2 had a good correlation (coefficient
= 0.6), whereas EpCAM and HER2 had a poor correlation (coefficient = 0.1). The comparison of different
detection technologies for liquid biopsy is shown in Table 1.

CONCLUSION
Liquid biopsy is an emerging research field with great promise in serving as a noninvasive technology for
cancer diagnosis and cancer therapy. Magnetic nanotechnologies play an import role in both biomarker
separation and biomarker detection. MNPs can bound to the target biomarkers through immunoassays and
facilitate the separation of the biomarkers through the magnetophoresis effect. MNPs with high magnetic
moment have been synthesized together with biocompatible surface coatings that can accommodate
the bounding between MNPs and target biomarkers. Besides synthesizing novel MNPs, the research on
magnetic separation also focuses on the optimization of the magnetic field configuration as well as the
integration with other biomarker concentration technologies to achieve high biomarker capture efficiency,
high specificity, and ease of integration with biosensing platforms. To realize precise fluidic control,
minimum biological sample consumption, and better performance in biomarker separation and biosensing,
microfluidic channels have become a key part in the designing of liquid biopsy platforms. Apart from the
traditional mold casting techniques, novel approaches such as 3D printing and laser writing have been
proposed to fabricate microfluidic channels with more complexed structures and higher resolutions.

Biosensors based on magnetic nanotechnologies exhibit low background noise and are less influenced
by the biological and chemical environment during detection, since most of the biological samples are
paramagnetic. Magnetoresistance sensors including GMR and TMR sensors detect the signal from the
MNPs that are brought into proximity of the sensor surface via immunoassays or DNA-based assays.
Various biomarkers have been demonstrated for liquid biopsy applications. Point-of-care devices based on
MR sensors have been developed by several groups, which could pave the way for bedside liquid biopsies
with high sensitivity, high portability, and short detection time. In addition to MR sensors, NMR bioassay
platforms along with MNP contrast agents exploit the magnetic resonance technology for the detection
of cancer cells. Samples containing MNP-labeled cells show faster relaxation in NMR signals due to the