Enhancing Nonfouling and Sensitivity of Surface-Enhanced Raman Scattering Substrates for Potent Drug Analysis in Blood Plasma via Fabrication of a Flexible Plasmonic Patch

Abstract

Surface-enhanced Raman scattering (SERS) is an ultrasensitive analytical technique, which is capable of providing high specificity, thus it can be used for toxicological drug assay (detection and quantification). However, SERS-based drug analysis directly in human biofluids requires mitigation of fouling and non-specificity effects that are commonly appeared from unwanted adsorption of endogenous biomolecules present in biofluids (e.g., blood plasma and serum) onto the SERS substrate. Here we report a bottom-up fabrication strategy to prepare ultrasensitive SERS substrates, firstly by functionalizing chemically synthesized gold triangular nanoprisms (Au TNPs) with poly(ethylene glycol)-thiolate in solid-state to avoid protein fouling, and secondly by generating flexible plasmonic patches to enhance SERS sensitivity via the formation of high intensity electromagnetic hot spots. Poly(ethylene glycol)-thiolate-functionalized Au TNPs in the form of flexible plasmonic patches show two-fold improved signal-to-noise ratio in comparison to triethylamine-passivated Au TNPs. Furthermore, the plasmonic patches display a SERS enhancement factor of 4.5 x 10 7 . Utilizing the Langmuir adsorption model we determine the adsorption constant of drugs for two different surface ligands and observed that the drug molecules display stronger affinity for poly(ethylene glycol) ligands than triethylamine. Our density functional theory calculations unequivocally support the interaction between drug molecules and poly(ethylene glycol) moieties. Furthermore, the universality of the plasmonic patch for SERSbased drug detection is demonstrated for cocaine, JWH-018, and opioids (fentanyl, despropionyl fentanyl, and heroin) and binary mixture (trace amount of fentanyl in heroin) analysis. We demonstrate that applicability of flexible plasmonic patches for the selective assay of fentanyl at picogram/milliliter concentration levels from drug-of-abuse patients' blood plasma. The fentanyl concentration determined in the patients' blood plasma from SERS analysis is in excellent agreement with the values determined by paper spray ionization mass spectrometry technique. We believe that the flexible plasmonic patch fabrication strategy would be widely applicable to any plasmonic nanostructures for SERS-based chemical sensing for clinical toxicology and therapeutic drug monitoring.

Towards practical and sustainable SERS: a review of recent developments in the construction of multifunctional enhancing substrates

“…Alternatively, polymeric macromolecules, such as oligo(ethylene glycol) or zwitterionic polymers can also be used to repel contaminants from the enhancing surface to enable direct SERS analysis of bio-samples. [179][180][181] For example, Jiang, Yu, et al designed an optofluidic system functionalized with antifouling mixed SAMs which allowed quantitative SERS analysis of a variety of clinically relevant molecules in plasma to be achieved by flowing the drug containing plasma samples through the SERS enhancing channels, as shown in Figure 12D. 182 More specifically, the enhancing surface was first modified with a SAM of mercaptoundecyl bromoisobutyrate "initiator", which were used to graft chains of antifouling zwitterionic poly(carboxybetaine acrylamide) to form a mixed monolayer of initiators and zwitterionic polymers, as shown in Figure 12E.…”

“…Au superparticle [144] liquid-liquid extraction farmland, river and fishpond water: unknown contaminants nM (αendosulfan) silicon nanowire array decorated with Ag nanodendrite [157] TLC milk: competitively adsorbing proteins melamine LOD: 2.5 ppm unspecified Au sputtered chromatography paper [159] paper chromatography superhydrohobic Au NPs/nickel foam [165] hydrophobic interactions (1-naphthol) Raman reporter labelled Au NPs-based lateral flow assay strip [174] bio-recognition bacterial pathogen solution: unknown bio-contaminants [176] hydrogen bonding milk: competitively adsorbing proteins; tab water: unknown contaminants 2,4dichlorophenoxyacetic acid demonstrated 1 ng/mL in milk and tab water 0.00147 ng/mL PEG-S functionalized Au triangular nanoprisms patch [180] antifouling diluted human plasma: biocontaminants, mainly protein fentanyl, 4-ANPP, cocaine, heroin, cannabinoids LOD: 3.0 pg/mL (fentanyl); demonstrated 1 nM (4-ANPP, cocaine, heroin, cannabinoids) unspecified metal NPs embedded hydrogel micropellet [186] size exclusion milk: competitively adsorbing proteins; whole blood: biocontaminants, mainly protein melamine, glucose LOD: 10 nM (melamine in milk); 0.01 mM (glucose in whole blood) LOD: 0.01 mM (glucose) polydopamine@Au nanowaxberry [191] size exclusion soil: particulate matter thiram LOD: 0.31 µg/g LOD: 0.5 nM the adenine molecules within the plasmonic hot spots, as illustrated in Figure 13H, which led to a 3× SERS signal increase compared to contrast experiments performed without protein.…”

Rapid Formation of Nanoclusters for Detection of Drugs in Urine Using Surface-Enhanced Raman Spectroscopy

“…Surface-enhanced Raman spectroscopy (SERS) has been used to detect a variety of molecules [ 6 , 7 , 8 , 9 , 10 ] because SERS-based methods only need a small sample and take a few seconds to achieve the multiplexed detection of molecules with high sensitivity. Many studies have reported the SERS detection of drugs, including cannabinoid [ 11 ], cocaine [ 12 , 13 , 14 , 15 , 16 , 17 ], flunitrazepam [ 18 ], alpha-methyltryptamine [ 19 ], heroin [ 17 , 20 ], ketamine [ 21 ], morphine [ 13 , 22 ], benzodiazepine [ 23 ], methamphetamine [ 13 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], amphetamine [ 31 ], opioid [ 32 ], 3,4-methylenedioxymethamphetamine (MDMA) [ 25 , 27 , 28 , 33 ], 4-MMC [ 34 , 35 ], MC [ 25 ], barbiturate [ 36 ], and sulfa drugs [ 37 ]. While the plasmonic properties of nanostructured substrates or nanoparticles used for SERS measurements is critical for the sensitive detection of molecules, it has been demonstrated that sample pretreatment is also very important for the SERS detection of drugs in biological samples such as urine [ 14 , 25 , 27 ,…”

Silver nanoparticle on zinc oxide array for label-free detection of opioids through surface-enhanced raman spectroscopy

“… 4 In recent years, Surface-Enhanced Raman Spectroscopy (SERS) has become a popular method of detecting trace amounts of chemical compounds, especially drugs, 6–15 due to its ability to enhance the Raman scattering signals of detection targets with high sensitivity, rapid detection time, and non-destructive analysis method. 16,17 For example, Masterson et al 9 developed a flexible SERS patch with chemically functionalized Au triangular prisms for detecting highly potent drugs. However, a limitation of many current SERS based opioid detecting devices is that they have not been tested using real blood samples, which is an important step for verifying the device's performance in practical settings for detecting the drug use in people.…”