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Xylazine (XYL), an FDA-approved veterinary tranquilizer, is being abused both as an opioid adulterant in a street-drug known as “Tranq-dope” and as a date rape drug. Given its now nearly ubiquitous use with fentanyl and fentanyl derivatives across the globe, XYL has become a primary target for researchers seeking to develop portable and cost-effective sensors for its detection. Electrochemical sensors based on the oxidation of XYL, while useful, have limitations due to certain interferents and inherent electrode fouling that render the approach less reliable, especially in certain sample matrices. In this work, modified electrode platforms incorporating layers of multi-walled carbon nanotubes for sensitivity along with semi-permeable polyurethane (PU) layers and host–guest chemistry using β-cyclodextrin for selectivity are deployed for XYL detection using complementary adsorptive cathodic stripping analysis. The modified electrode sensors are optimized to minimize high potentials and maintain fouling resistant capabilities and investigated to better understand the function of the PU layer. The use of adsorptive cathodic stripping differential pulse voltammetry indirectly indicates the presence and concentration of XYL within complex sample media (beverages and synthetic urine). When used in this manner, the modified electrodes exhibited an overall average sensitivity of ~35 (±9) nA/μM toward XYL with a limit of quantification of <10 ppm, while also offering adaptability for the analysis of XYL in different types of samples. By expanding the capability of these XYL sensors, this study represents another facet of tool development for use by medical professionals, first-responders, forensic investigators, and drug-users to limit exposure and help stem the dangerous and illegal use of XYL. 

Amperometric electrochemical sensing schemes, which are easily fabricated and can directly relate measured current with analyte concentrations, remain a promising strategy for the development of the portable, in situ detection of commonly employed adulterants. Xylazine (XYL) is a non-narcotic compound designed for veterinary use as a sedative known as Rompun®. XYL is increasingly being abused as a recreational drug, as an opioid adulterant and, because of its chemical properties, has found unfortunate prominence as a date rape drug spiked into beverages. In this study, a systematic exploration and development of fouling-resistant, amperometric XYL sensors is presented. The sensing strategy features layer-by-layer (LBL) modification of glassy carbon electrodes (GCEs) with carbon nanotubes (CNTs) for sensitivity and the engagement of cyclodextrin host–guest chemistry in conjunction with polyurethane (PU) semi-permeable membranes for selectivity. The optimization of different materials and parameters during development created a greater fundamental understanding of the interfacial electrochemistry, allowing for a more informed subsequent design of effective sensors exhibiting XYL selectivity, effective sensitivity, rapid response times (<20 s), and low estimated limits of detection (~1 ppm). Most importantly, the demonstrated XYL sensors are versatile and robust, easily fabricated from common materials, and can effectively detect XYL at <10 ppm in both common alcoholic and non-alcoholic beverages, requiring only minimal volume (20 µL) of the spiked beverage for a standard addition analysis. 

As the opioid crisis continues to wreak havoc on a global scale, it is increasingly critical to develop methodologies to detect the most dangerous drugs such as fentanyl and its derivatives, which have orders of magnitude higher potency than morphine. The scientific challenge for chemical detection of fentanyl and its derivatives is complicated by both the constantly increasing synthetic variations of the drug as well as the expanded use of adulterants. One tragically consequential example is the nocuous street drug known as “Tranq”, which combines fentanyl or a fentanyl derivative with the veterinary sedative Rompun®, chemically identified as xylazine (XYL). This pervasive street cocktail is exacerbating the already staggering number of fentanyl-related deaths as its acute toxicity poses a danger to medical first-responders and complicates their initial assessment and treatment options for overdose victims. Given the widespread use of XYL as an adulterant, an electrochemical XYL sensor capable of on-site operation by non-experts as a fast-screening tool is a notable goal. This work presents a voltammetry-based sensor featuring carbon electrodes modified with carboxylic-acid functionalized multi-walled carbon nanotubes layered with cyclodextrin and polyurethane membranes for sensitivity and selectivity enhancements. The sensor has critical and robust fouling resistance while providing sensitivity at 950 μA/mM∙cm2, a low limit of detection (~5 ppm), and the ability to detect XYL in the presence of fentanyl and/or other non-fentanyl stimulants like cocaine. The demonstrated sensor can be applied to promote public health with its ability to detect and indicate XYL in the presence of opioids, serving to protect drug-users, first responders, medical examiners, and on-site forensic investigators from exposure to these dangerous mixtures. 

Fentanyl (FTN) and synthetic analogs of FTN continue to ravage populations across the globe, including in the United States where opioids are increasingly being used and abused and are causing a staggering and growing number of overdose deaths each year. This growing pandemic is worsened by the ease with which FTN can be derivatized into numerous derivatives. Understanding the chemical properties/behaviors of the FTN class of compounds is critical for developing effective chemical detection schemes using nanoparticles (NPs) to optimize important chemical interactions. Halogen bonding (XB) is an intermolecular interaction between a polarized halogen atom on a molecule and e−-rich sites on another molecule, the latter of which is present at two or more sites on most fentanyl-type structures. Density functional theory (DFT) is used to identify these XB acceptor sites on different FTN derivatives. The high toxicity of these compounds necessitated a “fragmentation” strategy where smaller, non-toxic molecules resembling parts of the opioids acted as mimics of XB acceptor sites present on intact FTN and its derivatives. DFT of the fragments’ interactions informed solution measurements of XB using 19F NMR titrations as well as electrochemical measurements of XB at self-assembled monolayer (SAM)-modified electrodes featuring XB donor ligands. Gold NPs, known as monolayer-protected clusters (MPCs), were also functionalized with strong XB donor ligands and assembled into films, and their interactions with FTN “fragments” were studied using voltammetry. Ultimately, spectroscopy and TEM analysis were combined to study whole-molecule FTN interactions with the functionalized MPCs in solution. The results suggested that the strongest XB interaction site on FTN, while common to most of the drug’s derivatives, is not strong enough to induce NP-aggregation detection but may be better exploited in sensing schemes involving films. 

The incorporation of nanomaterials (NMs) into biosensing schemes is a well-established strategy for gaining signal enhancement. With electrochemical biosensors, the enhanced performance achieved from using NMs is often attributed to the specific physical properties of the chosen nanocomponents, such as their high electronic conductivity, size-dependent functionality, and/or higher effective surface-to-volume ratios. First generation amperometric biosensing schemes, typically utilizing NMs in conjunction with immobilized enzyme and semi-permeable membranes, can possess complex sensing mechanisms that are difficult to study and challenging to understand beyond the observable signal enhancement. This study shows the use of an enzymatic reaction between xanthine (XAN) and xanthine oxidase (XOx), involving multiple electroactive species, as an electrochemical redox probe tool for ascertaining mechanistic information at and within the modified electrodes used as biosensors. Redox probing using components of this enzymatic reaction are demonstrated on two oft-employed biosensing approaches and commonly used NMs for modified electrodes: gold nanoparticle doped films and carbon nanotube interfaces. In both situations, the XAN metabolism voltammetry allows for a greater understanding of the functionality of the semipermeable membranes, the role of the NMs, and how the interplay between the two components creates signal enhancement. 

First-generation amperometric xanthine (XAN) biosensors, assembled via layer-by-layer methodology and featuring xerogels doped with gold nanoparticles (Au-NPs), were the focus of this study and involved both fundamental exploration of the materials as well as demonstrated usage of the biosensor in both clinical (disease diagnosis) and industrial (meat freshness) applications. Voltammetry and amperometry were used to characterize and optimize the functional layers of the biosensor design including a xerogel with and without embedded xanthine oxidase enzyme (XOx) and an outer, semi-permeable blended polyurethane (PU) layer. Specifically, the porosity/hydrophobicity of xerogels formed from silane precursors and different compositions of PU were examined for their impact on the XAN biosensing mechanism. Doping the xerogel layer with different alkanethiol protected Au-NPs was demonstrated as an effective means for enhancing biosensor performance including improved sensitivity, linear range, and response time, as well as stabilizing XAN sensitivity and discrimination against common interferent species (selectivity) over time—all attributes matching or exceeding most other reported XAN sensors. Part of the study focuses on deconvoluting the amperometric signal generated by the biosensor and determining the contribution from all of the possible electroactive species involved in natural purine metabolism (e.g., uric acid, hypoxanthine) as an important part of designing XAN sensors (schemes amenable to miniaturization, portability, or low production cost). Effective XAN sensors remain relevant as potential tools for both early diagnosis of diseases as well as for industrial food monitoring.