SERS sensing for cancer biomarker: Approaches and directions

Abstract

These days, cancer is thought to be more than just one illness, with several complex subtypes that require different screening approaches. These subtypes can be distinguished by the distinct markings left by metabolites, proteins, miRNA, and DNA. Personalized illness management may be possible if cancer is categorized according to its biomarkers. In order to stop cancer from spreading and posing a significant risk to patient survival, early detection and prompt treatment are essential. Traditional cancer screening techniques are tedious, time-consuming, and require expert personnel for analysis. This has led scientists to reevaluate screening methodologies and make use of emerging technologies to achieve better results. Using time and money saving techniques, these methodologies integrate the procedures from sample preparation to detection in small devices with high accuracy and sensitivity. With its proven potential for biomedical use, surface-enhanced Raman scattering (SERS) has been widely used in biosensing applications, particularly in biomarker identification. Consideration was given especially to the potential of SERS as a portable clinical diagnostic tool. The approaches to SERS-based sensing technologies for both invasive and non-invasive samples are reviewed in this article, along with sample preparation techniques and obstacles. Aside from these significant constraints in the detection approach and techniques, the review also takes into account the complexity of biological fluids, the availability of biomarkers, and their sensitivity and selectivity, which are generally lowered. Massive ways to maintain sensing capabilities in clinical samples are being developed recently to get over this restriction. SERS is known to be a reliable diagnostic method for treatment judgments. Nonetheless, there is still room for advancement in terms of portability, creation of diagnostic apps, and interdisciplinary AI-based applications. Therefore, we will outline the current state of technological maturity for SERS-based cancer biomarker detection in this article. The review will meet the demand for reviewing various sample types (invasive and non-invasive) of cancer biomarkers and their detection using SERS. It will also shed light on the growing body of research on portable methods for clinical application and quick cancer detection.

Keywords: Cancer biomarkers; Invasive and non-invasive biomarkers; Microfluidic devices; Point of care detection; Surface-enhanced Raman scattering (SERS).

A graphical abstract presents the various types of invasive and non-invasive sample and cancer biomarkers used with SERS technology for cancer screening.

Fig. 1

A schematic presentation of various biomarkers present in non-invasive and invasive type samples used in SERS detection approaches for cancer screening.

Fig. 2

Schematic illustration of the direct (label-free) and indirect (label-based) SERS detection. (A) The direct SERS for the detection of any RAMAN active molecule that interacts with the plasmonic metal surface. (B) The indirect SERS for the detection of the target molecule when it interacts with the binding part of the SERS tag thanks to the plasmonic metal nanoparticle functionalized with a Raman reporter molecule.

Fig. 3

(A) An example of sputum sample biomarker-based SERS detection for lung cancer patients [64]. Copyright © 2018, American Chemical Society(B) Silver nanoparticles applied to generate SERS signals for biomarkers to detect prostate cancer in urine samples [96]. Copyright © 2018, American Chemical Society(C) SERS sensor integrating reduced graphene oxide and gold nanoparticles to differentiate early gastric cancer [95]. Copyright © 2016, American Chemical Society.(D) Schematic representation invasive and non-invasive sample assay used with RNA biomarker extraction and amplification. Various SERS nanotags are used with complementary DN probe hybridization and purification steps. The multiplexed detection by SERS for quantitative analysis of biomarker is performed to achieve sensitive detection of each SERS nanotag in a very short time frame (80 min) of PoC application [60]. Copyright © 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Fig. 4

(A) A size-based centrifugal force separation for CTCs from peripheral blood samples [121]. Copyright 2023 American Chemical Society. (B) The scheme illustrates the multiplex PCR/SERS assay and the utilization of SERS nanotags. In this approach, specific primers targeting multiple mutations were employed to amplify tumor DNA. The resulting amplicons were then labeled with mutation-specific SERS nanotags, enriched through magnetic beads and finally detected by Raman spectroscopy. The spectral peaks indicate the presence of the mutation of interest [129]. Copyright © Ivyspring International Publisher.(C) The system presents the heating and hybridizing approach for detaching the SERS tag for signal determination [143]. Copyright (2021), with permission from Elsevier.

Fig. 5

(A) Schematic of immunohistochemistry analysis of HER2 combined spectroscopic and morphological diagnostic method based on label-free surface-enhanced Raman scattering (SERS) [163]. Copyright 2023 American Chemical Society. (B) Schematic for EV phenotyping by phenotype analyzer chip. (a) A melanoma cell harboring a BRAF V600E mutation releases extracellular vehicles (EVs) into the bloodstream or cell culture medium. (b) The sample containing these EVs is directly introduced into the EPAC (EV Phenotype Analyzer Chip), where a nano mixing technique is employed to enhance interactions between the EVs, capture antibodies, and SERS nanotags. This process selectively removes non-target molecules and unbound SERS nanotags. (c) The EV phenotypes are then characterized using SERS mapping, where false-color SERS spectral images are generated based on the intensity of characteristic peaks exhibited by the SERS nanotags [147]. Copyright 2021 American Association for the Advancement of Science.

Fig. 6

(A) Illustration of a plasmonic based POC device for direct detection of cancer in clinical samples using a magnetic bead-based RNA sample extraction and purification system. Inset the hybridization mechanism and elements [182]. Copyright © 2020 Published by Elsevier B.V.(B) A portable Raman based endoscope developed to perform clinical procedures. It used a single-mode illumination fiber surrounded by multimode collection fibers. The excitation laser light illuminates a spot size of ∼1.2 mm in diameter. This helps to perform direct detection at the molecular level [183]. Copyright © 2013 Published by PNAS.