Label-Free Electrochemical Biosensors for Triple-Negative Breast Cancer Biomarkers: Emerging Recognition Strategies, Nanomaterials, and Clinical Translation

Abstract

Triple-negative breast cancer (TNBC) is when the patient does not have the three most targeted molecules (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 or HER2) and the patient resorts to chemotherapy (cytotoxic), and poor prognosis due to the fact that the three most targeted molecules are the ones that are monitored. There has been growing interest in the measurement of alternative circulating markers e.g. epidermal growth factor receptor (EGFR), soluble programmed death-ligand 1 (sPD-L1), exosomal PD-L1, CD44, mucin-1, tumour-derived microRNAs (miR-10b, miR-21, miR-652), and circulating tumour cells (CTCs) that do not require repeated tissue biopsies. Label-free electrochemical biosensors that can detect a binding event as a change in charge-transfer resistance, capacitance or redox current instead of a secondary enzymatic or fluorescent reporter provide a means of fast, inexpensive, and perhaps point-of-care measurement of these markers. In this review, the recognition strategies that have been used to impart selectivity to these platforms (antibodies, aptamers, molecularly imprinted polymers, peptides and nucleic-acid probes) and the nanomaterial transducers (graphene and its derivatives, 2D MXenes, metal and bimetallic nanoparticles, metal/covalent-organic frameworks) that have been used to amplify the signal generated by these platforms are reviewed. The platforms used to detect HER2, EGFR, PD-L1, CD44 and TNBC-specific miRs that were representative in the last 5 years are compared and the special lack of TNBC-specific multi-marker, clinically validated devices is highlighted. The review ends with a discussion of issues that present practical problems to address, namely sample-matrix fouling, recognition-layer stability, reproducibility/regulatory validation between the lab-scale sensors and the deployable point-of-care biosensors and diagnostics, and prioritizes the multiplexed clinically translatable TNBC biosensing.