Graphene–Gold Nanohybrid-Based Surface-Enhanced Raman Scattering Platform on a Portable Easy-to-Use Centrifugal Prototype for Liquid Biopsy Detection of Circulating Breast Cancer Cells

Abstract

Although, cancer is considered as a localized disease in its premature stages, in certain types of cells, it results in metastasis, which accounts for over 90% of the total cancer deaths in the world. During the metastatic stage, cancer cells migrate from the primary tumor site to secondary sites through the circulating bloodstream, resulting in metastasis at unexpected body parts. This situation makes it critical to identify and quantify the circulating tumor cells (CTCs) during the early stages of tumorigenesis. Despite the clinical importance and progress of liquid biopsy and CTC-based cancer diagnostics, it still remains extremely challenging to develop systems to detect CTCs in cancer patients as its presence is extremely low in number (1−10 CTCs per mL of blood plasma). In this article, we discuss about the design and fabrication of a robust and user-friendly custom-designed nanotag-enabled portable filter-based sensor system for the selective separation and isolation of circulating breast cancer cells from whole blood. The filter sensor platform basically consists of a centrifugal prototype to quickly transfer unprocessed blood samples up to 5 mL within 60 s, isolating the circulating breast cancer cells selectively over the anti-EpCAM antibody-immobilized polycarbonate (PC) filter. Moreover, it is also equipped with a sandwich complex of a surface-enhanced Raman scattering (SERS) nanotag comprising a gold− graphene hybrid integrated with anti-ErbB2 antibody (Au-rGO@anti-ErbB2) for the SERS-assisted quantification of CTCs. As compared to the immunoaffinity-based CTC isolation platforms, the centrifugal force-based SERS nanotag enabled filter sensor system proved to be a clog free, highly sensitive, and selective platform toward the rapid isolation of viable breast cancer cells up to 5 tumor cells/mL from whole blood without any sample pretreatment. The high sensitivity, ease of use, and quick availability of results recommends the current filter sensor platform as a universal liquid biopsy technique for the quantification of CTCs.

Toward Personalized Nanomedicine: The Critical Evaluation of Micro and Nanodevices for Cancer Biomarker Analysis in Liquid Biopsy

“…[143] A portable SERS-based platform was developed to isolate circulating breast cancer cells from whole blood without any sample pre-treatment. [146] The platform consists of a centrifugal prototype to quickly transfer (within 60 s) unprocessed blood samples (up to 5 mL), selectively isolating the CTCs over an anti-EpCAM antibody-immobilized polycarbonate filter. The platform was equipped with a sandwich complex of a SERS nanotag comprising a gold−graphene hybrid with an anti-ErbB2 antibody as part of the SERS-assisted quantification component.…”

“…While portable Raman spectrometers are available, most of the published methods are based on very sophisticated instruments (such as the WITec confocal Raman microscope used by Jibin and colleagues [ 146 ] that may be unsuitable for routine analysis in clinical laboratories. [ 140 ] Additionally, with the emergence of portable Raman spectroscopy devices and fiber optic Raman probes, low‐quality signals are often acquired that hinder the clinical translation of SERS‐based platforms.…”

Recent Advances in Sandwich SERS Immunosensors for Cancer Detection

“…However, the second material was used to determine AFP in two cases [66,67], and to simultaneously detect SCCA and CA 125 [68]. Quartz chips with punched wells [69], glass substrates [70], molybdenum disulfide [71], and polycarbonate filters [72] turned out to be less popular, but this does not preclude their future use.…”

“…To give the reader an idea of the number of modified nanoparticles proposed also with nonmetallic materials/substances, we decided to mention a few such cases. This group includes; e.g., nanotags with hybrid multilayered nanoshells prepared by the layerby-layer assembly of small AgNPs at the surface of silica (SiO 2 ) particles [53] also using poly(ethyleneimine) [74]; AuNP-coated acid-based resin microspheres [32]; silica-coated Ag nanorods [36]; core-shell SiO 2 @Ag [52]; SiO 2 -coated Si NPs [48]; AuNPs with polydopamine resin [33]; ZnO and CoFe 2 O 4 nanocomplexes with Au [39]; AgNPs deposited on graphene oxide [64]; Ag-covered polystyrene spheres [41]; silica-coated gold/silver core-shell nanostars [66]; nanospheres with a silver coating core, an ultrathin continuous silica shell, and high coverage of gold nanospheres satellites [67]; MoS 2 nanoflower@AuNPs [57]; Au-coated 'stellate' mesoporous SiO 2 @Au nanoprobes [49]; Au seeds on Fe 3 O 4 @TiO 2 core-shell NPs [50]; nano-Ag polydopamine nanospheres [68]; and gold-graphene hybrid nanotags [72].…”

“…The SERS-based platform proposed by Jibin et al was developed for detecting circulating tumor cells [72]. For this purpose, AuNPs were modified with reduced graphene oxide and linked with antibodies, and the polycarbonate membrane was biofunctionalized.…”