Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive analytical technique with molecular specificity, making it an ideal candidate for therapeutic drug monitoring (TDM). However, in critical diagnostic media including blood, nonspecific protein adsorption coupled with weak surface affinities and small Raman activities of many analytes hinder the TDM application of SERS. Here we report a hierarchical surface modification strategy, first by coating a gold surface with a self-assembled monolayer (SAM) designed to attract or probe for analytes and then by grafting a non-fouling zwitterionic polymer brush layer to effectively repel protein fouling. We demonstrate how this modification can enable TDM applications by quantitatively and dynamically measuring the concentrations of several analytes—including an anticancer drug (doxorubicin), several TDM-requiring antidepressant and anti-seizure drugs, fructose and blood pH—in undiluted plasma. This hierarchical surface chemistry is widely applicable to many analytes and provides a generalized platform for SERS-based biosensing in complex real-world media.
Reliable surface-enhanced Raman scattering (SERS) based biosensing in complex media is impeded by nonspecific protein adsorptions. Because of the near-field effect of SERS, it is challenging to modify SERS-active substrates using conventional nonfouling materials without introducing interference from their SERS signals. Herein, we report a stealth surface modification strategy for sensitive, specific and accurate detection of fructose in protein solutions using SERS by forming a mixed self-assembled monolayer (SAM). The SAM consists of a short zwitterionic thiol, N,N-dimethyl-cysteamine-carboxybetaine (CBT), and a fructose probe 4-mercaptophenylboronic acid (4-MPBA). The specifically designed and synthesized CBT not only resists protein fouling effectively, but also has very weak Raman activity compared to 4-MPBA. Thus, the CBT SAM provides a stealth surface modification to SERS-active substrates. The surface compositions of mixed SAMs were investigated using X-ray photoelectron spectroscopy (XPS) and SERS, and their nonfouling properties were studied with a surface plasmon resonance (SPR) biosensor. The mixed SAM with a surface composition of 94% CBT demonstrated a very low bovine serum albumin (BSA) adsorption (∼3 ng/cm(2)), and moreover, only the 4-MPBA signal appeared in the SERS spectrum. With the use of this surface-modified SERS-active substrate, quantification of fructose over clinically relevant concentrations (0.01-1 mM) was achieved. Partial least-squares regression (PLS) analysis showed that the detection sensitivity and accuracy were maintained for the measurements in 1 mg/mL BSA solutions. This stealth surface modification strategy provides a novel route to introduce nonfouling property to SERS-active substrates for SERS biosensing in complex media.
a b s t r a c tThe extracellular pH (pH e ) of living cells is one of the major factors that influence cell behaviors including cycle progression, migration, and proliferation, as well as metastasis and invasion of tumor cells. Thus, accurate sensing and mapping of the pH e is still a critical yet challenging task in the study of pH e -dependent cell behaviors. In this work, we present a method to map pH e of living cells based on surface-enhanced Raman spectroscopy (SERS). We immobilized a pH probe molecule, 4-mercaptobenzoic acid (4-MBA), on a gold quasi three-dimensional plasmonic nanostructure array (Q3D-PNA) to enable an exceptionally sensitive and reproducible pH measurement. We prudentially investigated the influences of cations and complexity of detecting solutions on the responses of 4-MBA SERS spectra to pH variations to ensure the accuracy. Herein, a normal cell line (NIH/3T3) and a tumor cell line (HepG2) were cultured on the 4-MBA modified SERS substrates. Localized pH e was detected and mapped with good spatial resolution and pH sensitivity showing pH e domains on both cells. Moreover, the averaged pH e of tumor cells was shown to be more acidic compared with that of normal cells.
As the prevalence of antibiotic-resistant bacteria continues to rise, biosensing technologies are needed to enable rapid diagnosis of bacterial infections. Furthermore, understanding the unique biochemistry of resistance mechanisms can facilitate the development of next generation therapeutics. Surface-enhanced Raman scattering (SERS) offers a potential solution to real-time diagnostic technologies, as well as a route to fundamental, mechanistic studies. In the current review, SERS-based approaches to the detection and characterization of antibiotic-resistant bacteria are covered. The commonly used nanomaterials (nanoparticles and nanostructured surfaces) and surface modifications (antibodies, aptamers, reporters, etc.) for SERS bacterial detection and differentiation are discussed first, and followed by a review of SERS-based detection of antibiotic-resistant bacteria from environmental/food processing and clinical sources. Antibiotic susceptibility testing and minimum inhibitory concentration testing with SERS are then summarized. Finally, recent developments of SERS-based chemical imaging/mapping of bacteria are reviewed.
Surface-enhanced Raman spectroscopy (SERS), which utilizes nanogaps between noble-metal nanostructures as hot spots to yield ultrasensitive SERS signals, is an outstanding label-free and straightforward tool for DNA methylation analysis. Herein, a plasmonic gold nanohole array (PGNA) with well-controlled hot spots and an open surface was designed as a SERS substrate for DNA methylation detection. A finite-difference time-domain (FDTD) simulation was first employed to investigate the electric field distributions of the PGNA as a function of the geometric parameters. The plasmonic response was tuned to 785 cm −1 to match the ring breathing vibrational band of cytosine, the intensity change of which was revealed to be a marker of DNA methylation. Then, guided by the FDTD simulation results, the PGNA was fabricated via the electron beam lithography (EBL) technique. The fabricated PGNA had an open and easily accessible surface topology, a SERS enhancement factor of ∼10 6 , and a relative standard deviation (RSD) of 7.1% for 500 repetitions over an area of 20 × 20 μm 2 using 1 μM Rhodamine 6G as the Raman reporter. The fabricated PGNA was further used as a platform for determining DNA methylation. The proposed method exhibited a sensitivity for detecting 1% of methylation changes. Moreover, insight into the dynamic information on methylation events was obtained by combining principal component analysis (PCA) with 2D correlation spectroscopy analysis. Finally, clear discrimination of the different methylation sites, such as 5-methylcytosine and N6-methyladenine, was demonstrated.
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