Stealth Surface Modification of Surface-Enhanced Raman Scattering Substrates for Sensitive and Accurate Detection in Protein Solutions

Abstract

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.

Hierarchical zwitterionic modification of a SERS substrate enables real-time drug monitoring in blood plasma

“…The boronic acid head groups in 4MPBA can specifically bind to fructose, which breaks the symmetry of the probe molecule and induces ring reorientation and corresponding spectral changes. Our group has previously investigated fructose detection with 4MPBA-modified SERS sensors, in which we used mixed SAMs containing 4MPBA and short zwitterionic thiols to monitor fructose in single protein solutions41. At present, we demonstrate that fructose detection directly in plasma is possible using a hierarchical surface chemistry—the zwitterionic pCBAA brush is key to this advance, as it provides the best available protection from protein fouling.…”

Functionalized plasmonic nanostructure arrays for direct and accurate mapping extracellular pH of living cells in complex media using SERS

“…Gold Q3D-PNAs (50 μm  50 μm) with a square grid of 400 nm diameter and 100 nm spacing were fabricated by electron beam lithography (EBL) following the same method reported previously (Sun et al, 2014(Sun et al, , 2015. Scanning electron microscope (SEM, FEI Sirion) and tapping mode atomic force microscope (AFM, DI MultiMode with Nanoscope Iva controller) were used to characterize the dimensions of the nanostructures.…”

SERS‐Active‐Charged Microgels for Size‐ and Charge‐Selective Molecular Analysis of Complex Biological Samples

“…For example, metal surfaces are coated by a self‐assembled monolayer (SAM) that consists of 4‐mercaptophenylboronic acid and zwitterionic thiol. As the zwitterionic groups bind water molecules and the boronic acid groups capture fructose, proteins are efficiently excluded while a target fructose is concentrated on the metal surface . To utilize SERS‐active metal nanostructures for detection of unspecified small molecules, metal nanoparticles are encapsulated in the lumen of liposomes or by a hydrogel shell .…”