Imperial College London

Professor Tony Cass

Faculty of Natural SciencesDepartment of Chemistry

Senior Research Investigator
 
 
 
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Contact

 

+44 (0)20 7594 5195t.cass

 
 
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Location

 

301KMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

286 results found

Riezk A, Wilson RC, Cass AEG, Holmes AH, Rawson TMet al., 2024, A low-volume LC/MS method for highly sensitive monitoring of phenoxymethylpenicillin, benzylpenicillin, and probenecid in human serum, Analytical Methods: advancing methods and applications, Vol: 16, Pages: 558-565, ISSN: 1759-9660

Background: The optimization of antimicrobial dosing plays a crucial role in improving the likelihood of achieving therapeutic success while reducing the risks associated with toxicity and antimicrobial resistance. Probenecid has shown significant potential in enhancing the serum exposure of phenoxymethylpenicillin, thereby allowing for lower doses of phenoxymethylpenicillin to achieve similar pharmacokinetic/pharmacodynamic (PK/PD) targets. We developed a triple quadrupole liquid chromatography mass spectrometry (TQ LC/MS) analysis of, phenoxymethylpenicillin, benzylpenicillin and probenecid using benzylpenicillin-d7 and probenecid-d14 as IS in single low-volumes of human serum, with improved limit of quantification to support therapeutic drug monitoring. Methods: Sample clean-up was performed by protein precipitation using acetonitrile. Reverse phase chromatography was performed using TQ LC/MS. The mobile phase consisted of 55% methanol in water + 0.1% formic acid, with a flow rate of 0.4 mL min-1. Antibiotic stability was assessed at different temperatures. Results: Chromatographic separation was achieved within 2 minutes, allowing simultaneous measurement of phenoxymethylpenicillin, benzylpenicillin and probenecid in a single 15 μL blood sample. Validation indicated linearity over the range 0.0015-10 mg L-1, with accuracy of 96-102% and a LLOQ of 0.01 mg L-1. All drugs demonstrated good stability under different storage conditions. Conclusion: The developed method is simple, rapid, accurate and clinically applicable for the quantification of phenoxymethylpenicillin, benzylpenicillin and probenecid in tandem.

Journal article

Freeman DME, Ming DK, Wilson R, Herzog PL, Schulz C, Felice AKG, Chen Y-C, O'Hare D, Holmes AH, Cass AEGet al., 2023, Continuous measurement of lactate concentration in human subjects through direct electron transfer from enzymes to microneedle electrodes, ACS Sensors, Vol: 8, Pages: 1639-1647, ISSN: 2379-3694

Microneedle lactate sensors may be used to continuously measure lactate concentration in the interstitial fluid in a minimally invasive and pain-free manner. First- and second-generation enzymatic sensors produce a redox-active product that is electrochemically sensed at the electrode surface. Direct electron transfer enzymes produce electrons directly as the product of enzymatic action; in this study, a direct electron transfer enzyme specific to lactate has been immobilized onto a microneedle surface to create lactate-sensing devices that function at low applied voltages (0.2 V). These devices have been validated in a small study of human volunteers; lactate concentrations were raised and lowered through physical exercise and subsequent rest. Lactazyme microneedle devices show good agreement with concurrently obtained and analyzed serum lactate levels.

Journal article

Fenech-Salerno B, Holicky M, Yao C, Cass A, Torrisi Fet al., 2023, A sprayed graphene transistor platform for rapid and low-cost chemical sensing, Nanoscale, Vol: 15, Pages: 3243-3254, ISSN: 2040-3364

We demonstrate a novel and versatile sensing platform, based on electrolyte-gated graphene field-effect transistors, for easy, low-cost and scalable production of chemical sensor test strips. The Lab-on-PCB platform is enabled by low-boiling, low-surface-tension sprayable graphene ink deposited on a substrate manufactured using a commercial printed circuit board process. We demonstrate the versatility of the platform by sensing pH and Na+ concentrations in an aqueous solution, achieving a sensitivity of 143 ± 4 μA per pH and 131 ± 5 μA per log10Na+, respectively, in line with state-of-the-art graphene chemical sensing performance.

Journal article

Riezk A, Vasikasin V, Wilson RCC, Rawson TMM, McLeod JGG, Dhillon R, Duckers J, Cass AEG, Holmes AHHet al., 2023, Triple quadrupole LC/MS method for the simultaneous quantitative measurement of cefiderocol and meropenem in serum, Analytical Methods: advancing methods and applications, Vol: 15, Pages: 746-751, ISSN: 1759-9660

Background: therapeutic drug monitoring is a crucial aspect of the management of hospitalized patients. The correct dosage of antibiotics is imperative to ensure their adequate exposure specially in critically ill patients. The aim of this study is to establish and validate a robust and fast liquid chromatography-tandem mass spectrometry (LC/MS) method for the simultaneous quantification of two important antibiotics in critically ill patients, cefiderocol and meropenem in human plasma. Methods: sample clean-up was performed by protein precipitation using acetonitrile. Reverse phase chromatography was performed using triple quadrupole LC/MS. The mobile phase was consisted of 55% methanol in water +0.1% formic acid, with flow rate of 0.4 ml min−1. Antibiotics stability was assessed at different temperatures. Serum protein binding was assessed using ultrafiltration devices. Results: chromatographic separation was achieved within 1.5 minutes for all analytes. Validation has demonstrated the method to be linear over the range 0.0025–50 mg L−1 for cefiderocol and 0.00028–50 mg L−1 for meropenem, with accuracy of 94–101% and highly sensitive, with LLOQ ≈ 0.02 mg L−1 and 0.003 mg L−1 for cefiderocol and meropenem, respectively. Both cefiderocol and meropenem showed a good stability at room temperature over 6 h, and at (4 °C) over 24 h. Cefiderocol and meropenem demonstrated a protein binding of 49–60% and 98%, respectively in human plasma. Conclusion: the developed method is simple, rapid, accurate and clinically applicable for the quantification of cefiderocol and meropenem.

Journal article

Riezk A, Wilson RC, Rawson TM, Vasikasin V, Arkel P, Ferris TJ, Haigh LD, Cass AEG, Holmes AHet al., 2023, A rapid, simple, high-performance liquid chromatography method for the clinical measurement of beta-lactam antibiotics in serum and interstitial fluid, Analytical Methods: advancing methods and applications, Vol: 15, Pages: 829-836, ISSN: 1759-9660

Background: enhanced methods of therapeutic drug monitoring are required to support the individualisation of antibiotic dosing based on pharmacokinetics (PK) parameters. PK studies can be hampered by limited total serum volume, especially in neonates, or by sensitivity in the case of critically ill patients. We aimed to develop a liquid chromatography–mass spectrometry (LC/MS) analysis of benzylpenicillin, phenoxymethylpenicillin and amoxicillin in single low volumes of human serum and interstitial fluid (ISF) samples, with an improved limit of detection (LOD) and limit of quantification (LOQ), compared with previously published assays. Methods: sample clean-up was performed by protein precipitation using acetonitrile. Reverse phase chromatography was performed using triple quadrupole LC/MS. The mobile phase consisted of 55% methanol in water + 0.1% formic acid, with a flow rate of 0.4 mL min−1. Antibiotics stability was assessed at different temperatures. Results: chromatographic separation was achieved within 3 minutes for all analytes. Three common penicillins can now be measured in a single low-volume blood and ISF sample (15 μL) for the first time. Validation has demonstrated the method to be linear over the range 0.0015–10 mg L−1, with an accuracy of 93–104% and high sensitivity, with LOD ≈ 0.003 mg L−1 and LOQ ≈ 0.01 mg L−1 for all three analytes, which is critical for use in dose optimisation/individualisation. All evaluated penicillins indicated good stability at room temperature over 4 h, at (4 °C) over 24 h and at −80 °C for 6 months. Conclusion: the developed method is simple, rapid, accurate and clinically applicable for the quantification of three penicillin classes.

Journal article

Lo Y, Liang S, Dhillo WS, Cass AEG, Tanner JAet al., 2023, Robotic APTamer-Enabled Electrochemical Reader (RAPTER) System for Automated Aptamer-Mediated Electrochemical Analysis., Methods Mol Biol, Vol: 2570, Pages: 271-280

Electrochemical aptamer-based (E-AB) sensors using conformational change-induced electron transfer kinetics are sensitive, reagent-less, and cost-effective tools for molecular sensing. Current advances in this technology can allow continuous drug pharmacokinetic monitoring in living animals (Dauphin-Ducharme et al., ACS Sens 4(10):2832-2837, 2019; Idili et al., Chem Sci 10(35):8164-8170, 2019), as well as automated analysis of hormone pulsatility (Liang et al., Nat Commun 10(1):852, 2019). In this chapter, we provide the methodology for an automated E-AB conformational change-based robotic sensing platform. By using an open-source programmable robotic system, this method can be adapted to a wide range of experimental scenarios.

Journal article

Phongphut A, Chayasombat B, Cass AEG, Phisalaphong M, Prichanont S, Thanachayanont C, Chodjarusawad Tet al., 2022, Biosensors Based on Acetylcholinesterase Immobilized on Clay-Gold Nanocomposites for the Discrimination of Chlorpyrifos and Carbaryl, ACS OMEGA, Vol: 7, Pages: 39848-39859, ISSN: 2470-1343

Journal article

Freeman DME, Cass AEG, 2022, A Perspective on microneedle sensor arrays for continuous monitoring of the body's chemistry, Applied Physics Letters, Vol: 121, ISSN: 0003-6951

Recent advances in the field of microneedle devices are having an impact on both diagnostic and therapeutic approaches to sustaining healthy populations globally. Whether this is for improving drug and vaccine efficacy or for continuous sensing of key molecular indicators, the past five years have seen increased activity in both the academic and commercial sectors. In this Perspective, we focus on solid microneedle biosensors and discuss the advantages of these devices over alternative clinical diagnostic platforms as well as the technical challenges presented. We will emphasize how their use in continuous measurement of molecules in vivo is made possible with a minimally invasive technique that is simple to perform. This Perspective describes the function and current state of microneedle sensor arrays for the in vivo measurement of both endogenous molecules such as glucose and lactate and drugs such as penicillin.

Journal article

Hassan-Nixon HA, Singh N, Cass AEG, 2022, A sensitive impedimetric immunosensor for the detection of Interleukin-8 in nasal epithelial lining fluid of asthma patients, Biosensors and Bioelectronics: X, Vol: 10

We report the development of a label-free, affinity-based impedimetric biosensor for the quantitative detection of interleukin-8 (IL-8) present in the nasal epithelial lining fluid (NELF). Early diagnosis of IL-8 in NELF samples enables prognosis of inflammatory respiratory disorders including asthma, chronic obstructive pulmonary disease, and adult respiratory distress syndrome. The study involves the fabrication of an electrochemical biosensor by immobilising polyclonal anti-IL-8 antibody on the anti-fouling zwitterionic hydrogel; polycarboxybetaine methacrylate (pCBMA). The immunosensor was characterised using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), vertical scanning interferometry (VSI) and scanning electron microscopy (SEM). Faradaic EIS measurements were conducted to explore the performance of the immunosensor via changes in charge transfer resistance. The sensor exhibited a good analytical performance in the detection and quantification of IL-8 in complex biological media. The biosensor showed a wide range of IL-8 detection, ranging from 55 fM to 55 nM with a 10 fM limit of detection (LOD). The biosensor showed a high selectivity to IL-8 and 90% reproducibility using untreated NELF samples, with 15-min time to result. These results provide a promising potential for multiplexing the cytokine platform for the profiling, diagnosis and clinical signaturing of associated respiratory disorders.

Journal article

Tortolini C, Cass AEG, Pofi R, Lenzi A, Antiochia Ret al., 2022, Microneedle-based nanoporous gold electrochemical sensor for real-time catecholamine detection, MICROCHIMICA ACTA, Vol: 189, ISSN: 0026-3672

Journal article

Ming DK, Jangam S, Gowers SAN, Wilson R, Freeman DME, Boutelle MG, Cass AEG, OHare D, Holmes AHet al., 2022, Real-time continuous measurement of lactate through a minimally invasive microneedle patch: a phase I clinical study, BMJ Innovations, Vol: 8, Pages: 87-94, ISSN: 2055-8074

Introduction Determination of blood lactate levels supports decision-making in a range of medical conditions. Invasive blood-sampling and laboratory access are often required, and measurements provide a static profile at each instance. We conducted a phase I clinical study validating performance of a microneedle patch for minimally invasive, continuous lactate measurement in healthy volunteers.Methods Five healthy adult participants wore a solid microneedle biosensor patch on their forearms and undertook aerobic exercise for 30 min. The microneedle biosensor quantifies lactate concentrations in interstitial fluid within the dermis continuously and in real-time. Outputs were captured as sensor current and compared with lactate concentrations from venous blood and microdialysis.Results The biosensor was well-tolerated. Participants generated a median peak venous lactate of 9.25 mmol/L (IQR 6.73–10.71). Microdialysate concentrations of lactate closely correlated with blood. Microneedle biosensor current followed venous lactate concentrations and dynamics, with good agreement seen in all participants. There was an estimated lag-time of 5 min (IQR −4 to 11 min) between microneedle and blood lactate measurements.Conclusion This study provides first-in-human data on use of a minimally invasive microneedle patch for continuous lactate measurement, providing dynamic monitoring. This low-cost platform offers distinct advantages to frequent blood sampling in a wide range of clinical settings, especially where access to laboratory services is limited or blood sampling is infeasible. Implementation of this technology in healthcare settings could support personalised decision-making in a variety of hospital and community settings.

Journal article

Rawson TM, Wilson RC, O'Hare D, Herrero P, Kambugu A, Lamorde M, Ellington M, Georgiou P, Cass A, Hope WW, Holmes AHet al., 2021, Optimizing antimicrobial use: challenges, advances and opportunities, NATURE REVIEWS MICROBIOLOGY, Vol: 19, Pages: 747-758, ISSN: 1740-1526

Journal article

Piersimoni ME, Teng X, Cass AEG, Ying Let al., 2020, Antioxidant lipoic acid ligand-shell gold nanoconjugates against oxidative stress caused by α-Synuclein aggregates, Nanoscale Advances, Vol: 2, Pages: 5666-5681, ISSN: 2516-0230

Gold nanoparticle is becoming a promising platform for the delivery of drugs to treat neurodegenerative diseases. Parkinson’s disease, associated with the aggregation of α-synuclein, is a condition that results in dysfunctional neuronal cells leading to their degeneration and death. Oxidative stress has been strongly implicated as a common feature in this process. The limited efficacy of the traditional therapies and the development of associated severe side effects present an unmet need for preventive and adjuvant therapies. The organosulfur compound lipoic acid, naturally located in the mitochondria, plays a powerful antioxidative role against oxidative stress. However, the efficacy is limited by its low physiological concentration, and the administration is affected by its short half-life and bioavailability due to hepatic degradation. Here we exploited the drug delivery potential of gold nanoparticles to assemble lipoic acid, and administered the system to SH-SY5Y cells, a cellular model commonly used to study Parkinson’s disease. We tested the nanoconjugates, termed GNPs-LA, under an oxidative environment induced by gold nanoparticle/α-synuclein conjugates (GNPs-α-Syn). GNPs-LA were found to be biocompatible and capable of restoring the cell damage caused by high-level reactive oxygen species generated by excessive oxidative stress in the cellular environment. We conclude that GNPs-LA may serve as a promising drug delivery vehicle conveying antioxidant molecules for the treatment of Parkinson’s disease.

Journal article

Ates HC, Roberts JA, Lipman J, Cass AEG, Urban GA, Dincer Cet al., 2020, On-Site Therapeutic Drug Monitoring, TRENDS IN BIOTECHNOLOGY, Vol: 38, Pages: 1262-1277, ISSN: 0167-7799

Journal article

Izzi-Engbeaya C, Abbara A, Cass A, Dhillo Wet al., 2020, Using Aptamers as a Novel Method for Determining GnRH/LH Pulsatility, International Journal of Molecular Sciences, Vol: 21, ISSN: 1422-0067

Aptamers are a novel technology enabling the continuous measurement of analytes in blood and other body compartments, without the need for repeated sampling and the associated reagent costs of traditional antibody-based methodologies. Aptamers are short single-stranded synthetic RNA or DNA that recognise and bind to specific targets. The conformational changes that can occur upon aptamer–ligand binding are transformed into chemical, fluorescent, colour changes and other readouts. Aptamers have been developed to detect and measure a variety of targets in vitro and in vivo. Gonadotropin-releasing hormone (GnRH) is a pulsatile hypothalamic hormone that is essential for normal fertility but difficult to measure in the peripheral circulation. However, pulsatile GnRH release results in pulsatile luteinizing hormone (LH) release from the pituitary gland. As such, LH pulsatility is the clinical gold standard method to determine GnRH pulsatility in humans. Aptamers have recently been shown to successfully bind to and measure GnRH and LH, and this review will focus on this specific area. However, due to the adaptability of aptamers, and their suitability for incorporation into portable devices, aptamer-based technology is likely to be used more widely in the future.

Journal article

Phongphut A, Chayasombat B, Cass AEG, Sirisuk A, Phisalaphong M, Prichanont S, Thanachayanont Cet al., 2020, Clay/au nanoparticle composites as acetylcholinesterase carriers and modified-electrode materials: A comparative study, APPLIED CLAY SCIENCE, Vol: 194, ISSN: 0169-1317

Journal article

Le TT, Bruckbauer A, Tahirbegi B, Magness AJ, Ying L, Ellington AD, Cass AEGet al., 2020, A highly stable RNA aptamer probe for the retinoblastoma protein in live cells, Chemical Science, Vol: 11, Pages: 4467-4474, ISSN: 2041-6520

<p>An RNA G-quadruplex aptamer, specific for the human retinoblastoma protein (RB) and highly stable inside cells, is selected and its application to live cell probing of the protein illustrated.</p>

Journal article

Cass AEG, O'Hare D, Sharma S, 2020, Recent Developments in Continuous Monitoring Diagnostics with Microneedle Arrays, 7th International Conference on the Development of Biomedical Engineering, Publisher: SPRINGER-VERLAG SINGAPORE PTE LTD, Pages: 337-339, ISSN: 1680-0737

Conference paper

Rawson TM, Gowers SAN, Freeman DME, Wilson RC, Sharma S, Gilchrist M, MacGowan A, Lovering A, Bayliss M, Kyriakides M, Georgiou P, Cass AEG, O'Hare D, Holmes AHet al., 2019, Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers, The Lancet Digital Health, Vol: 1, Pages: e335-e343, ISSN: 2589-7500

Background: Enhanced methods of drug monitoring are required to support the individualisation of antibiotic dosing. We report the first-in-human evaluation of real-time phenoxymethylpenicillin monitoring using a minimally invasive microneedle-based β-lactam biosensor in healthy volunteers.Methods: This first-in-human, proof-of-concept study was done at the National Institute of Health Research/Wellcome Trust Imperial Clinical Research Facility (Imperial College London, London, UK). The study was approved by London-Harrow Regional Ethics Committee. Volunteers were identified through emails sent to a healthy volunteer database from the Imperial College Clinical Research Facility. Volunteers, who had to be older than 18 years, were excluded if they had evidence of active infection, allergies to penicillin, were at high risk of skin infection, or presented with anaemia during screening. Participants wore a solid microneedle β-lactam biosensor for up to 6 h while being dosed at steady state with oral phenoxymethylpenicillin (five 500 mg doses every 6 h). On arrival at the study centre, two microneedle sensors were applied to the participant's forearm. Blood samples (via cannula, at −30, 0, 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) and extracellular fluid (ECF; via microdialysis, every 15 min) pharmacokinetic (PK) samples were taken during one dosing interval. Phenoxymethylpenicillin concentration data obtained from the microneedles were calibrated using locally estimated scatter plot smoothing and compared with free-blood and microdialysis (gold standard) data. Phenoxymethylpenicillin PK for each method was evaluated using non-compartmental analysis. Area under the concentration–time curve (AUC), maximum concentration, and time to maximum concentration were compared. Bias and limits of agreement were investigated with Bland–Altman plots. Microneedle biosensor limits of detection were estimated. The study was registered with Clinical

Journal article

Howells O, Rajendran N, Mcintyre S, Amini-Asl S, Henri P, Liu Y, Guy O, Cass AEG, Morris MC, Sharma Set al., 2019, Microneedle array-based platforms for future theranostic applications, ChemBioChem, Vol: 20, Pages: 2198-2202, ISSN: 1439-4227

Theranostics involves finding the biomarkers of a disease, fighting them through site specific drug delivery and following them for prognosis of the disease. Microneedle array technology has been used for drug delivery and extended for continuous monitoring of analytes present in the skin compartment. We envisage the use of microneedle arrays for future theranostic applications. The potential of using combined microneedle array-based drug delivery and diagnostics as part of closed-loop control system for the management of diseases and delivery of precision drugs in individual patients, is reported in this paper.

Journal article

Cass A, Sharma S, O'Hare D, 2019, Minimally invasive microneedle sensor arrays: New window on the body, ACS Fall National Meeting and Exposition, Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727

Conference paper

Chabloz N, Wenzel M, Perry H, Yoon I, Molisso S, Stasiuk G, Elson D, Cass A, Wilton-Ely Jet al., 2019, Polyfunctionalised nanoparticles bearing robust gadolinium surface units for high relaxivity performance in MRI, Chemistry - A European Journal, Vol: 25, Pages: 10895-10906, ISSN: 0947-6539

The first example of an octadentate gadolinium unit based on DO3A (hydration number q = 1) with a dithiocarbamate tether has been designed and attached to the surface of gold nanoparticles (around 4.4 nm in diameter). In addition to the superior robustness of this attachment, the restricted rotation of the Gd complex on the nanoparticle surface leads to a dramatic increase in relaxivity (r1) from 4.0 mM‐1 s‐1 in unbound form to 34.3 mM‐1 s‐1 (at 10 MHz, 37 °C) and 22 ± 2 mM‐1s‐1 (at 63.87 MHz, 25 °C) when immobilised on the surface. The ‘one‐pot’ synthetic route provides a straightforward and versatile way of preparing a range of multifunctional gold nanoparticles. The incorporation of additional surface units improving biocompatibility (PEG and thioglucose units) and targeting (folic acid) lead to little detrimental effect on the high relaxivity observed for these non‐toxic multifunctional materials. In addition to the passive targeting attributed to gold nanoparticles, the inclusion of a unit capable of targeting the folate receptors overexpressed by cancer cells, such as HeLa cells, illustrates the potential of these assemblies.

Journal article

Luu T, Liu M, Chen Y, Hushiarian R, Cass A, Tang BZ, Hong Yet al., 2019, Aptamer-Based Biosensing with a Cationic AIEgen, Australian Journal of Chemistry, Vol: 72, Pages: 620-620, ISSN: 0004-9425

<jats:p>Fabrication of low-cost biosensing platforms with high selectivity and sensitivity is important for constructing portable devices for personal health monitoring. Herein, we report a simple biosensing strategy based on the combination of a cationic AIEgen (aggregation-induced emission fluorogen), TPE-2+, with an aptamer for specific protein detection. The target protein can displace the dye molecules on the dye–aptamer complex, resulting in changes in the fluorescence signal. Selectivity towards different targets can be achieved by simply changing the aptamer sequence. The working mechanism is also investigated.</jats:p>

Journal article

Dhillo W, Liang S, Kinghorn A, Voliotis M, Prague J, Veldhuis J, Tsaneva-Atanasova K, McArdle C, Li R, Cass A, Tanner Jet al., 2019, Measuring LH Pulsatility in Patients with Reproductive Disorders Using a Novel Robotic Aptamer-Enabled Electrochemical Reader (RAPTER), 35th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 125-126, ISSN: 0268-1161

Conference paper

Gowers SAN, Freeman DME, Rawson TM, Rogers ML, Wilson RC, Holmes AH, Cass AE, O'Hare Det al., 2019, Development of a minimally invasive microneedle-based sensor for continuous monitoring of β-lactam antibiotic concentrations in vivo, ACS sensors, Vol: 4, Pages: 1072-1080, ISSN: 2379-3694

Antimicrobial resistance poses a global threat to patient health. Improving the use and effectiveness of antimicrobials is critical in addressing this issue. This includes optimizing the dose of antibiotic delivered to each individual. New sensing approaches that track antimicrobial concentration for each patient in real time could allow individualized drug dosing. This work presents a potentiometric microneedle-based biosensor to detect levels of β-lactam antibiotics in vivo in a healthy human volunteer. The biosensor is coated with a pH-sensitive iridium oxide layer, which detects changes in local pH as a result of β-lactam hydrolysis by β-lactamase immobilized on the electrode surface. Development and optimization of the biosensor coatings are presented, giving a limit of detection of 6.8 μM in 10 mM PBS solution. Biosensors were found to be stable for up to 2 weeks at -20 °C and to withstand sterilization. Sensitivity was retained after application for 6 h in vivo. Proof-of-concept results are presented showing that penicillin concentrations measured using the microneedle-based biosensor track those measured using both discrete blood and microdialysis sampling in vivo. These preliminary results show the potential of this microneedle-based biosensor to provide a minimally invasive means to measure real-time β-lactam concentrations in vivo, representing an important first step toward a closed-loop therapeutic drug monitoring system.

Journal article

Hansel C, Crowder S, Cooper S, Gopal S, Pardelha da Cruz J, De Oliveira Martins L, Keller D, Rothery S, Becce M, Cass A, Bakal C, Chiappini C, Stevens Met al., 2019, Nanoneedle-mediated stimulation of cell mechanotransduction machinery, ACS Nano, Vol: 13, Pages: 2913-2019, ISSN: 1936-0851

Biomaterial substrates can be engineered to present topographical signals to cells which, through interactions between the material and active components of the cell membrane, regulate key cellular processes and guide cell fate decisions. However, targeting mechanoresponsive elements that reside within the intracellular domain is a concept that has only recently emerged. Here, we show that mesoporous silicon nanoneedle arrays interact simultaneously with the cell membrane, cytoskeleton, and nucleus of primary human cells, generating distinct responses at each of these cellular compartments. Specifically, nanoneedles inhibit focal adhesion maturation at the membrane, reduce tension in the cytoskeleton, and lead to remodeling of the nuclear envelope at sites of impingement. The combined changes in actin cytoskeleton assembly, expression and segregation of the nuclear lamina, and localization of Yes-associated protein (YAP) correlate differently from what is canonically observed upon stimulation at the cell membrane, revealing that biophysical cues directed to the intracellular space can generate heretofore unobserved mechanosensory responses. These findings highlight the ability of nanoneedles to study and direct the phenotype of large cell populations simultaneously, through biophysical interactions with multiple mechanoresponsive components.

Journal article

Liang S, Kinghorn AB, Voliotis M, Prague JK, Veldhuis JD, Tsaneva-Atanasova K, McArdle CA, Li RHW, Cass AEG, Dhillo WS, Tanner JAet al., 2019, Measuring luteinising hormone pulsatility with a robotic aptamer-enabled electrochemical reader, Nature Communications, Vol: 10, Pages: 1-10, ISSN: 2041-1723

Normal reproductive functioning is critically dependent on pulsatile secretion of luteinising hormone (LH). Assessment of LH pulsatility is important for the clinical diagnosis of reproductive disorders, but current methods are hampered by frequent blood sampling coupled to expensive serial immunochemical analysis. Here, we report the development and application of a Robotic APTamer-enabled Electrochemical Reader (RAPTER) electrochemical analysis system to determine LH pulsatility. Through selective evolution of ligands by exponential enrichment (SELEX), we identify DNA aptamers that bind specifically to LH and not to related hormones. The aptamers are integrated into electrochemical aptamer-based (E-AB) sensors on a robotic platform. E-AB enables rapid, sensitive and repeatable determination of LH concentration profiles. Bayesian Spectrum Analysis is applied to determine LH pulsatility in three distinct patient cohorts. This technology has the potential to transform the clinical care of patients with reproductive disorders and could be developed to allow real-time in vivo hormone monitoring.

Journal article

Bollella P, Sharma S, Cass AEG, Antiochia Ret al., 2019, Minimally-invasive Microneedle-based Biosensor Array for Simultaneous Lactate and Glucose Monitoring in Artificial Interstitial Fluid, ELECTROANALYSIS, Vol: 31, Pages: 374-382, ISSN: 1040-0397

Journal article

Mie M, Matsumoto R, Mashimo Y, Cass AEG, Kobatake Eet al., 2019, Development of drug-loaded protein nanoparticles displaying enzymatically-conjugated DNA aptamers for cancer cell targeting, Molecular Biology Reports, Vol: 46, Pages: 261-269, ISSN: 0301-4851

Modification of protein-based drug carriers with tumor-targeting properties is an important area of research in the field of anticancer drug delivery. To this end, we developed nanoparticles comprised of elastin-like polypeptides (ELPs) with fused poly-aspartic acid chains (ELP-D) displaying DNA aptamers. DNA aptamers were enzymatically conjugated to the surface of the nanoparticles via genetic incorporation of Gene A* protein into the sequence of the ELP-D fusion protein. Gene A* protein, derived from bacteriophage ϕX174, can form covalent complexes with single-stranded DNA via the latter's recognition sequence. Gene A* protein-displaying nanoparticles exhibited the ability to deliver the anticancer drug paclitaxel (PTX), whilst retaining activity of the conjugated Gene A* protein. PTX-loaded protein nanoparticles displaying DNA aptamers known to bind to the MUC1 tumor marker resulted in increased cytotoxicity with MCF-7 breast cancer cells compared to PTX-loaded protein nanoparticles without the DNA aptamer modification.

Journal article

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