Fast, sensitive, and specific toxicological drug assays (detection and quantification) in biological fluids are critical to overcome the ongoing drug epidemic. The current gold standard analytical techniques for toxicological drug assays, such as gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/MS (LC/MS), require multiple sample preparation and processing steps, have long assay times, and are seen to have low sensitivity when assaying directly from human biofluids due to interferences of biological matrices. Surface-enhanced Raman spectroscopy (SERS) is an emerging technique for ultrasensitive and specific drug detection in forensic and clinical toxicology due to its short assay time and lack of sample processing, however, SERS-based drug analysis still faces the challenge associated with the biological matrix due to nonspecificity, sensitivity, and fouling effects which occur due to the adsorption of endogenous biomolecules. We present here the fabrication of advanced SERS substrates which utilize chemically synthesized gold triangular nanoprisms (Au TNPs) functionalized with poly(ethylene glycol)-thiolate (PEG-S-) to enhance the nonfouling effect, with a two-fold improved signal to noise ratio compared to Au TNPs without PEG-S-. Additionally, the SERS substrates are fabricated on a flexible substrate, providing an enhanced sensitivity due to the generation of high-intensity electromagnetic hot spots with a SERS enhancement factor of 4.5 x 10<sup>7</sup>. Utilizing this newly-designed SERS substrate, we detect various potent drugs in human plasma, with limit of detection as low as 8.9 pM (3.0 picogram/milliliter), and their binary mixtures (e.g., fentanyl in heroin). Furthermore, the flexible SERS substrate can be effectively used for fentanyl detection from drug-of-abuse patient plasma, with results in excellent agreement with the concentration determined from paper spray ionization mass spectrometry. Taken together, we believe the unprecedentedly high sensitivity and excellent nonfouling effects of flexible SERS substrate could be extremely useful for clinical toxicology and therapeutic drug monitoring purposes.

Optimizing structural parameters of SERS substrates for highly specific and sensitive toxicological drug assays

ACS Fall 2021

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