The composition and intercellular interactions of tumor cells in the tissues dictate the biochemical and metabolic properties of the tumor microenvironment. The metabolic rewiring has a profound impact on the properties of the microenvironment, to an extent that monitoring such perturbations could harbor diagnostic and therapeutic relevance. A growing interest in these phenomena has inspired the development of novel technologies with sufficient sensitivity and resolution to monitor metabolic alterations in the tumor microenvironment. In this context, surface-enhanced Raman scattering (SERS) can be used for the label-free detection and imaging of diverse molecules of interest among extracellular components. Herein, the application of nanostructured plasmonic substrates comprising Au nanoparticles, self-assembled as ordered superlattices, to the precise SERS detection of selected tumor metabolites, is presented. The potential of this technology is first demonstrated through the analysis of kynurenine, a secreted immunomodulatory derivative of the tumor metabolism and the related molecules tryptophan and purine derivatives. SERS facilitates the unambiguous identification of trace metabolites and allows the multiplex detection of their characteristic fingerprints under different conditions. Finally, the effective plasmonic SERS substrate is combined with a hydrogel-based three-dimensional cancer model, which recreates the tumor microenvironment, for the real-time imaging of metabolite alterations and cytotoxic effects on tumor cells.
The development of continuous monitoring systems requires in situ sensors that are capable of screening multiple chemical species and providing real-time information. Such in situ measurements, in which the sample is analyzed at the point of interest, are hindered by underlying problems derived from the recording of successive measurements within complex environments. In this context, surface-enhanced Raman scattering (SERS) spectroscopy appears as a noninvasive technology with the ability of identifying low concentrations of chemical species as well as resolving dynamic processes under different conditions. To this aim, the technique requires the use of a plasmonic substrate, typically made of nanostructured metals such as gold or silver, to enhance the Raman signal of adsorbed molecules (the analyte). However, a common source of uncertainty in real-time SERS measurements originates from the irreversible adsorption of (analyte) molecules onto the plasmonic substrate, which may interfere in subsequent measurements. This so-called "SERS memory effect" leads to measurements that do not accurately reflect varying conditions of the sample over time. We introduce herein the design of plasmonic substrates involving a nonpermeable poly(lactic-co-glycolic acid) (PLGA) thin layer on top of the plasmonic nanostructure, toward controlling the adsorption of molecules at different times. The polymeric layer can be locally degraded by irradiation with the same laser used for SERS measurements (albeit at a higher fluence), thereby creating a micrometer-sized window on the plasmonic substrate available to molecules present in solution at a selected measurement time. Using SERS substrates coated with such thermolabile polymer layers, we demonstrate the possibility of performing over 10,000 consecutive measurements per substrate as well as accurate continuous monitoring of analytes in microfluidic channels and biological systems. KEYWORDS: surface-enhanced Raman spectroscopy, real-time monitoring, plasmonic heating, in situ sensing S urface-enhanced Raman scattering (SERS) spectroscopy is a highly sensitive vibrational spectroscopy technique that facilitates the identification of trace analytes and allows the multiplexed detection of their characteristic vibrational fingerprints. 1 On this account, SERS has emerged as a promising chemical monitoring method, with applications in various fields including biosensing, 2 food control, 3 and detection of hazardous materials, 4 among others. SERS relies on the plasmonic properties of noble metal nanostructures to enhance the Raman signal of adsorbed molecules. The confinement of light at nanoscale volumes by plasmonic nanomaterials is responsible for a dramatic increase in sensitivity, which can go as far as single-molecule detection. 5 Key features of SERS are its noninvasive character and labelfree detection, which promise the potential of implementing in situ measurements, for example, in the clinic or in the field. However, to achieve in situ monitoring, not only further development ...
the plasmon resonance wavelength and the excitation source. [3,4] Plasmon resonances can be engineered through nanostructure composition and morphology, as well as the refractive index of the environment. [5,6] In the case of superlattices, for example in the form of periodically arranged clusters of gold nanoparticles, another control parameter comes into play, [7] namely the lattice period. Lattice resonances result from diffractively coupled localized surface plasmons of a substructure within a periodic arrangement. [8] The periodicity, the center-to-center distance between adjacent plasmonic meta-atoms, is the key parameter for constructive (radiative) far-field coupling.In the case of resonant excitation, lattice plasmons can generate intense electromagnetic fields, [9][10][11] as required for ultrasensitive SERS spectroscopy. We have recently shown that the resonance band of square-array 2D supercrystals, fabricated by template-assisted colloidal selfassembly of gold nanoparticles (NPs), can be tuned throughout the visible and near-infrared (NIR) range, as a function of the lattice parameter. [12] The highest SERS performance was achieved at best match with the laser excitation. Combining short-and long-range interactions in such arrays can result in higher field enhancements. Tuning both the lattice period and the size of the substructures requires iterative remodeling of
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