Engineering surface-enhanced Raman scattering strategies for liquid biopsy analyses: a step towards precision medicine in cancer management

Abstract

Precision medicine is poised to have an impact on cancer management by guiding treatment decisions based on molecular landscapes of tumours. Normally, the molecular profile of a tumour is established from a surgically-obtained biopsy tissue sample. As tumours are highly heterogeneous and dynamic, tissue-based molecular profiling is subject to temporal and/or spatial sampling bias. Additionally, biopsies from some tumour sites remain difficult, which could result in an inadequate amount of tissue for subsequent testing. To fully enable precision medicine, it is desirable to have an easily accessible, minimally invasive way to determine and monitor the molecular make-up of tumour subclones in real-time. Liquid biopsies are such an approach, from which a number of circulating cancerassociated biomolecules can be non-invasively isolated for subsequent analyses to better reflect the overall molecular make-ups of primary and metastatic tumours. These circulating biomolecules released by tumours including circulating tumour cells (CTCs), extracellular vesicles (EVs), circulating soluble cancer proteins, and circulating nucleic acids, are extremely rare, thus posing challenges in downstream analyses. Recent developments in microfluidic chips and nanotechnologies have significantly advanced liquid biopsy analyses. Nevertheless, these techniques are still limited by either insufficient sensitivity, low multiplexing capacity, or high-cost reagents. To enable liquid biopsy applications in precision medicine, there is thus a clear need for a highly sensitive and cost-effective technology with high multiplexing capability. The application of surface-enhanced Raman spectroscopy (SERS) as an analytical tool for liquid biopsy analyses is gaining ground due to its ultrasensitivity and multiplexing capacity. Principally, SERS refers to amplified Raman signals of molecules on or near the surface of SERS substrates (mainly plasmonic nanomaterials). According to this concept, liquid biopsy biomarkers could be identified based on their unique molecular structures or by SERS nanotags (i.e., plasmonic nanomaterials functionalised with Raman reporters and/or target-specific ligands). Majority of current SERS techniques in liquid biopsies focus on the technique development; and their clinical translation is rarely attempted/explored. The research described in this thesis includes the design and clinical evaluation of cuttingedge SERS strategies that enable comprehensive characterisation of various circulating biomolecules.