Abstract
Isolation and detection of circulating tumor cells (CTCs) from human blood plays an important role in non- invasive screening of cancer evolution and in predictive therapeutic treatment. Here, we present the novel tool utilizing: (i) the microfluidic device with (ii) incorporated photovoltaic (PV) based SERS-active platform, and (iii) shell-isolated nanoparticles (SHINs) for simultaneous separation and label-free analysis of circulating tumour cells CTCs in the blood specimens with high specificity and sensitivity. The proposed microfluidic chip enables the efficient size – based inertial separation of circulating cancer cells from the whole blood samples. The SERS-active platform incorporated into the microfluidic device permits the label-free detection and identification of isolated cells through the insight into their molecular and biochemical structure. Additionally, the silver nanoparticles coated with an ultrathin shell of silica (Ag@SiO2) was used to improve the detection accuracy and sensitivity of analysed tumor cells via taking advantages of shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS). The empirical analysis of SHINERS spectra revealed that there are some differences among studied (HeLa), renal cell carcinoma (Caki-1), and blood cells. Unique SHINERS features and differences in bands intensities between healthy and cancer cells might be associated with the variations in the quantity and quality of molecules such as lipid, protein, and DNA or their structure during the metastasis cancer formation. To demonstrate the statistical efficiency of the developed method and improve the differentiation for circulating tumors cells detection the principal component analysis (PCA) has been performed for all SHINERS data. PCA method has been applied to recognize the most significant differences in SHINERS data among the three analyzed cells: Caki-1, HeLa, and blood cells. The proposed approach challenges the current multi-steps CTCs detection methods in the terms of simplicity, sensitivity, invasiveness, destructivity, time and cost of analysis, and also prevents the defragmentation/damage of tumor cells and thus leads to improving the accuracy of analysis. The results of this research work show the potential of developed SERS based tool for the separation of tumor cells from whole blood samples in a simple and minimally invasive manner, their detection and molecular characterization using one single technology.
Highlights
Circulating tumor cells (CTCs) are living cancer cells separated from the primary tumor, which are responsible for the development and expansion of the metastasis form of cancer[1]
SERS nanoparticles modified with epidermal growth factor (EGF) antibody have been used as a targeting ligand to successful circulating tumor cells (CTCs) detection even in the presence of white blood cells[35]
The desired SERS-active structures should reveal a high SERS signal enhancement defined by enhancement factor (EF), physical and chemical stability, high reproducibility of recorded signals and the possibility to be produced by cheap and reptile technique
Summary
The SERS efficiency (sensitivity, selectivity, and reproducibility) was demonstrated for p-aminothiophenol (p-ATP), which is commonly used a standard probe molecule and has been described in details in our previous article[38] The SEM images (Fig. 3A,B) confirm that the developed method of SERS-active fabrication offers a homogeneous coverage of the cones surface with the layer of silver To quantitatively asses their size distribution we applied image analysis. The calculated relative standard deviation equals 3.6% Such designed SERS platform has been combined with the microfluidic device (Fig. 2) to perform Raman analysis of renal cell carcinoma (Caki-1) and cervical carcinoma (HeLa) circulating tumor cells spiked into the Figure 4. The proposed strategy for HeLa and Caki-1 cell lines isolation utilizes combination of two effects: (i) inertial lift
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