Microneedle Aptamer-Based Sensors for Continuous, Real-Time Therapeutic Drug MonitoringClick to copy article linkArticle link copied!
- Yao WuYao WuDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21202, United StatesMore by Yao Wu
- Farshad TehraniFarshad TehraniDepartment of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Farshad Tehrani
- Hazhir TeymourianHazhir TeymourianDepartment of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Hazhir Teymourian
- John MackJohn MackBiochemistry, Cellular and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21202, United StatesMore by John Mack
- Alexander ShaverAlexander ShaverDepartment of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21202, United StatesMore by Alexander Shaver
- Maria ReynosoMaria ReynosoDepartment of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Maria Reynoso
- Jonathan KavnerJonathan KavnerDepartment of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Jonathan Kavner
- Nickey HuangNickey HuangDepartment of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Nickey Huang
- Allison FurmidgeAllison FurmidgeDepartment of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Allison Furmidge
- Andrés DuvvuriAndrés DuvvuriDepartment of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Andrés Duvvuri
- Yuhang NieYuhang NieDepartment of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Yuhang Nie
- Lori M. LaffelLori M. LaffelJoslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, United StatesMore by Lori M. Laffel
- Francis J. Doyle IIIFrancis J. Doyle IIIHarvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Allston, Massachusetts 02134, United StatesMore by Francis J. Doyle III
- Mary-Elizabeth PattiMary-Elizabeth PattiJoslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, United StatesMore by Mary-Elizabeth Patti
- Eyal DassauEyal DassauHarvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Allston, Massachusetts 02134, United StatesMore by Eyal Dassau
- Joseph Wang*Joseph Wang*Email: [email protected]Department of Nanoengineering, University of California San Diego, La Jolla, California 92093, United StatesMore by Joseph Wang
- Netzahualcóyotl Arroyo-Currás*Netzahualcóyotl Arroyo-Currás*Email: [email protected]Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21202, United StatesBiochemistry, Cellular and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21202, United StatesMore by Netzahualcóyotl Arroyo-Currás
Abstract
The ability to continuously monitor the concentration of specific molecules in the body is a long-sought goal of biomedical research. For this purpose, interstitial fluid (ISF) was proposed as the ideal target biofluid because its composition can rapidly equilibrate with that of systemic blood, allowing the assessment of molecular concentrations that reflect full-body physiology. In the past, continuous monitoring in ISF was enabled by microneedle sensor arrays. Yet, benchmark microneedle sensors can only detect molecules that undergo redox reactions, which limits the ability to sense metabolites, biomarkers, and therapeutics that are not redox-active. To overcome this barrier, here, we expand the scope of these devices by demonstrating the first use of microneedle-supported electrochemical, aptamer-based (E-AB) sensors. This platform achieves molecular recognition based on affinity interactions, vastly expanding the scope of molecules that can be sensed. We report the fabrication of microneedle E-AB sensor arrays and a method to regenerate them for multiple uses. In addition, we demonstrate continuous molecular measurements using these sensors in flow systems in vitro using single and multiplexed microneedle array configurations. Translation of the platform to in vivo measurements is possible as we demonstrate with a first E-AB measurement in the ISF of a rodent. The encouraging results reported in this work should serve as the basis for future translation of microneedle E-AB sensor arrays to biomedical research in preclinical animal models.
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Note Added after ASAP Publication
This paper was originally published ASAP on June 2, 2022, with an error in Figure 6G. The corrected version was reposted on June 3, 2022.
Figure 1
Figure 1. Wearable microneedle aptamer-based sensors for continuous, real-time therapeutic drug monitoring. (A) Our wearable microneedle sensor patch is designed to allow painless on-body molecular tracking in research animals. The patch consists of a microneedle sensor array integrated with electronics and a battery, all contained within a wearable case. The sensor array contains 16 gold working, 4 platinum counter, and one central reference microneedles with a form factor that allows painless penetration of the upper strata of the reticular dermis. (B) At the core of our sensing technology are electrochemical aptamer-based (E-AB) sensors, which consist of a mixed self-assembled monolayer of electrode-blocking alkanethiols with alkanethiol- and redox reporter-modified aptamers. In the presence of a target, the aptamers undergo reversible binding-induced conformational changes that affect electron transfer (eT) between the reporter and the gold needles. This sensing mechanism is reversible. (C) To enable continuous drug monitoring, the sensors are serially interrogated by square-wave voltammetry (SWV) with a time interval between 4.5 and 12 s. The sensors can be calibrated at the point of manufacture by building target titration curves, allowing correlation of current changes to changes in target concentration.
Experimental Section
Microneedle Preparation
Microneedle Cleaning Protocol
Sensor Preparation
Electrochemical Measurements
In Vivo Measurements
Results and Discussion
Real-Time Molecular Sensing on Microneedles Irrespective of Target Reactivity
Figure 2
Figure 2. Microneedle E-AB sensor arrays support real-time molecular monitoring in vitro. (A) 3D-printed flow cell for continuous molecular monitoring. The microneedle sensor array is glued at the bottom of the cell and connected to a hand-held potentiostat to enable serial electrochemical interrogation. (B) Micrograph showing blunt microneedles used for rapid testing. The microneedle height is ∼2.3 mm, and the diameter ∼170 μm. We functionalized these using tobramycin-binding aptamers, which are modified to have covalently attached alkanethiol linkers and the redox reporter methylene blue. (C) Microneedle E-AB sensor arrays (MNs) achieve identical calibration curves relative to sensors fabricated on commercial disc macroelectrodes (MEs, 2 mm in diameter). Circles represent the average of six sensors fabricated on MEs; diamonds represent the average of three sensors fabricated on MNs; error bars represent their standard deviation. (D) Continuous, real-time monitoring of tobramycin in the flow system. Voltammetric measurements were performed every 4.5 s in 20 mM Tris, 100 mM NaCl, 5 mM MgCl2 (pH = 7.4). (E) Kinetic differential measurements (KDM) obtained after subtracting the data collected at 150 Hz (signal-off output) from data collected at 800 Hz (signal-on output).
Multiuse Devices Achieving Highly Reproducible Measurements


Figure 3
Figure 3. Microneedle arrays can be reused multiple times. The newly developed chemical and electrochemical cleaning protocol reported in this work allows the reuse of microneedle devices multiple times during rapid prototyping and testing. (A) Here, for example, we show the performance of E-ABs fabricated on a single device that was reused three times. The colored data corresponds to the average of three identical measurements performed on the same device after each round of cleaning and functionalization with aptamers. Baseline peak currents at 800 Hz are ∼9 ± 0.5 mA. The shaded areas indicate the standard deviation between measurements. (B) Use of KDM for baseline correction further highlights the reproducibility achieved via the cleaning protocol. (C) For reference, untreated microneedles show lower signal output and higher baseline noise. Baseline peak currents at 800 Hz are ∼1.8 mA, 80% lower than the currents for treated microneedles.
Multiplexed Monitoring of Molecular Targets via Multichannel Devices
Figure 4
Figure 4. Dual-channel microneedle E-AB devices enable simultaneous evaluation of aptamer specificity. (A) Different from Figure 2A, the 3D-printed cell was adapted to have two separate injection lines at opposite sides of the central support. By connecting these lines to the syringe pump, we could automatically inject and mix the prodrug irinotecan and its major metabolite SN-38 in the left and right chambers, respectively. (B) We functionalized the microneedles in both chambers with irinotecan-binding aptamers. In the presence of irinotecan, the E-AB sensors undergo binding-induced changes in eT between the reporter and the microneedles. However, the metabolite SN-38 induces minor conformational changes relative to irinotecan binding. (C) Microneedle E-AB sensor arrays display higher signal gain when challenged with irinotecan than with the metabolite SN-38 at square-wave frequencies of 100 Hz. (D) Demonstration of continuous, reproducible irinotecan monitoring following three boluses at a target concentration of 2 μM irinotecan in the left chamber. (E) Similarly, when challenging the right chamber with the metabolite SN-38, lower gains were obtained following three serial boluses. Voltammetric measurements were performed every 11 s in 20 mM phosphate solution containing 137 mM NaCl, 2.7 mM KCl, 2 mM MgCl2, and 1 mM CaCl2 (pH = 6.0).
Figure 5
Figure 5. Dual-channel microneedle E-AB devices enable multiplexed sensing. (A) We functionalized the microneedles in each chamber with either irinotecan-binding or doxorubicin-binding aptamers. (B) Mean calibration curves of six irinotecan-binding and doxorubicin-binding E-ABs obtained using commercial disc macroelectrodes (2 mm in diameter) demonstrate that both sensors showed high affinity when challenged with their targets. (C) When simultaneously injecting irinotecan and doxorubicin in either chamber of the microneedle device, it was possible to successfully monitor E-AB signals induced by target binding to the respective E-ABs. In the case of the irinotecan-binding sensor, irinotecan boluses of increasing concentrations produced corresponding E-AB responses. Challenging the same E-ABs with doxorubicin, a known DNA intercalator, also produced large signal changes. (D) Likewise, challenging the doxorubicin-binding E-ABs with doxorubicin boluses of increasing concentration caused proportional E-AB responses. Challenging these sensors with 4 μM irinotecan did not induce E-AB signal changes. Voltammetric measurements were performed every 12 s in 20 mM phosphate, 137 mM NaCl, 2.7 mM KCl, 2 mM MgCl2, and 1 mM CaCl2 (pH = 6.0).
Wearable, Continuous, and Real-Time Molecular Monitoring in Vivo
Figure 6
Figure 6. Continuous molecular monitoring of tobramycin concentration in ISF. Proof-of-concept monitoring of tobramycin levels in the dermis of one rat following IV administration of the drug at a dose of 20 mg/kg. (A) We fabricated sharper microneedles that were 150 μm in diameter and 1.1 mm in length. (B) The microneedles were placed on the freshly shaved abdomen of one male rat. (C) Removal of the device from the skin revealed the expected pattern of micropunctures. (D) H&E-stained skin tissue illustrating different histological features of the rat’s skin and one penetrating track left after insertion of the microneedles. (E) Hue- and contrast-adjusted duplicate image highlighting the track mark after microneedle removal. (F) Although noisy, electrochemical interrogation of the microneedle array resulted in discernible square-wave voltammograms in ISF that strongly responded to tobramycin following an IV bolus injected into the right jugular vein of the rat (drop from blue to orange). (G) Real-time processing of the voltammograms using SACMES allowed us to visualize the sensor response, here plotted as relative signal after tobramycin dosing. SACMES uses rolling average and polynomial fit algorithms to remove noise from voltammograms, thus enabling the extraction of high signal-to-noise E-AB data. Unfortunately, progressive degradation of the sensors in ISF made it impossible to distinguish signals past t = 60 min. The red line shows a regression analysis to a two-compartment drug absorption pharmacokinetic model using the data points available.
Conclusions
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.analchem.2c00829.
Expanded Methods cleaning protocol monitoring) and additional data (PDF)
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Acknowledgments
This work was supported by The Leona M. and Harry B. Helmsley Charitable Trust under award number 7505508-5108014 (2018PG-TI0061).
References
This article references 53 other publications.
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- 2Arroyo-Currás, N.; Ortega, G.; Copp, D. A.; Ploense, K. L.; Plaxco, Z. A.; Kippin, T. E.; Hespanha, J. P.; Plaxco, K. W. High-precision control of plasma drug levels using feedback-controlled dosing. ACS Pharmacol. Transl. Sci. 2018, 1, 110– 118, DOI: 10.1021/acsptsci.8b00033Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVGlsrfO&md5=b35cad3fe9f053d0651e69e6ad1c9e44High-Precision Control of Plasma Drug Levels Using Feedback-Controlled DosingArroyo-Curras, Netzahualcoyotl; Ortega, Gabriel; Copp, David A.; Ploense, Kyle L.; Plaxco, Zoe A.; Kippin, Tod E.; Hespanha, Joao P.; Plaxco, Kevin W.ACS Pharmacology & Translational Science (2018), 1 (2), 110-118CODEN: APTSFN; ISSN:2575-9108. (American Chemical Society)By, in effect, rendering pharmacokinetics an exptl. adjustable parameter, the ability to perform feedback-controlled dosing informed by high-frequency in vivo drug measurements would prove a powerful tool for both pharmacol. research and clin. practice. Efforts to this end, however, have historically been thwarted by an inability to measure in vivo drug levels in real time and with sufficient convenience and temporal resoln. In response, we describe a closed-loop, feedback-controlled delivery system that uses drug level measurements provided by an in vivo electrochem. aptamer-based (E-AB) sensor to adjust dosing rates every 7 s. The resulting system supports the maintenance of either const. or predefined time-varying plasma drug concn. profiles in live rats over many hours. For researchers, the resultant high-precision control over drug plasma concns. provides an unprecedented opportunity to (1) map the relationships between pharmacokinetics and clin. outcomes, (2) eliminate inter- and intrasubject metabolic variation as a confounding exptl. variable, (3) accurately simulate human pharmacokinetics in animal models, and (4) measure minute-to-minute changes in a drug's pharmacokinetic behavior in response to changing health status, diet, drug-drug interactions, or other intrinsic and external factors. In the clinic, feedback-controlled drug delivery would improve our ability to accurately maintain therapeutic drug levels in the face of large, often unpredictable intra- and interpatient metabolic variation. This, in turn, would improve the efficacy and safety of therapeutic intervention, particularly for the most gravely ill patients, for whom metabolic variability is highest and the margin for therapeutic error is smallest.
- 3Arroyo-Currás, N.; Somerson, J.; Vieira, P. A.; Ploense, K. L.; Kippin, T. E.; Plaxco, K. W. Real-time measurement of small molecules directly in awake, ambulatory animals. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, 645– 650, DOI: 10.1073/pnas.1613458114Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmslWktA%253D%253D&md5=04842755081ae2272a933ce3461cd953Real-time measurement of small molecules directly in awake, ambulatory animalsArroyo-Curras, Netzahualcoyotl; Somerson, Jacob; Vieira, Philip A.; Ploense, Kyle L.; Kippin, Tod E.; Plaxco, Kevin W.Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (4), 645-650CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The development of a technol. capable of tracking the levels of drugs, metabolites, and biomarkers in the body continuously and in real time would advance our understanding of health and our ability to detect and treat disease. It would, for example, enable therapies guided by high-resoln., patient-specific pharmacokinetics (including feedback-controlled drug delivery), opening new dimensions in personalized medicine. In response, we demonstrate here the ability of electrochem. aptamer-based (E-AB) sensors to support continuous, real-time, multihour measurements when emplaced directly in the circulatory systems of living animals. Specifically, we have used E-AB sensors to perform the multihour, real-time measurement of four drugs in the bloodstream of even awake, ambulatory rats, achieving precise mol. measurements at clin. relevant detection limits and high (3 s) temporal resoln., attributes suggesting that the approach could provide an important window into the study of physiol. and pharmacokinetics.
- 4Vieira, P. A.; Shin, C. B.; Arroyo-Currás, N.; Ortega, G.; Li, W.; Keller, A. A.; Plaxco, K. W.; Kippin, T. E. Ultra-high-precision, in-vivo pharmacokinetic measurements highlight the need for and a route toward more highly personalized medicine. Front. Mol. Biosci. 2019, 6, 69, DOI: 10.3389/fmolb.2019.00069Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXms1Wms78%253D&md5=f802c240c1a5e4f8fe4b5f718f6fbf8dUltra-high-precision, in-vivo pharmacokinetic measurements highlight the need for and a route toward more highly personalized medicineVieira, Philip A.; Shin, Christina B.; Arroyo-Curras, Netzahualcoyotl; Ortega, Gabriel; Li, Weiwei; Keller, Arturo A.; Plaxco, Kevin W.; Kippin, Tod E.Frontiers in Molecular Biosciences (2019), 6 (), 69CODEN: FMBRBS; ISSN:2296-889X. (Frontiers Media S.A.)A review. Clin. drug dosing would, ideally, be informed by high-precision, patient-specific data on drug metab. The direct detn. of patient-specific drug pharmacokinetics ("peaks and troughs"), however, currently relies on cumbersome, lab.-based approaches that require hours to days to return pharmacokinetic ests. based on only one or two plasma drug measurements. In response clinicians often base dosing on age, body mass, pharmacogenetic markers, or other indirect estimators of pharmacokinetics despite the relatively low accuracy of these approaches. Here, in contrast, we explore the use of indwelling electrochem. aptamer-based (E-AB) sensors as a means of measuring pharmacokinetics rapidly and with high precision using a rat animal model. Specifically, measuring the disposition kinetics of the drug tobramycin in Sprague-Dawley rats we demonstrate the seconds resolved, real-time measurement of plasma drug levels accompanied by measurement validation via HPLC-MS on ex vivo samples. The resultant data illustrate the significant pharmacokinetic variability of this drug even when dosing is adjusted using body wt. or body surface area, two widely used pharmacokinetic predictors for this important class of antibiotics, highlighting the need for improved methods of detg. its pharmacokinetics.
- 5Wolkowicz, K. L.; Aiello, E. M.; Vargas, E.; Teymourian, H.; Tehrani, F.; Wang, J.; Pinsker, J. E.; Doyle, F. J., 3rd; Patti, M. E.; Laffel, L. M.; Dassau, E. A review of biomarkers in the context of type 1 diabetes: Biological sensing for enhanced glucose control. Bioeng. Transl. Med. 2021, 6, e10201 DOI: 10.1002/btm2.10201Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1yrurzM&md5=9c63251fb79cdcdac7856ef612f118d8A review of biomarkers in the context of type 1 diabetes: Biological sensing for enhanced glucose controlWolkowicz, Kelilah L.; Aiello, Eleonora M.; Vargas, Eva; Teymourian, Hazhir; Tehrani, Farshad; Wang, Joseph; Pinsker, Jordan E.; Doyle, Francis J. III; Patti, Mary-Elizabeth; Laffel, Lori M.; Dassau, EyalBioengineering & Translational Medicine (2021), 6 (2), e10201CODEN: BTMIAQ; ISSN:2380-6761. (John Wiley & Sons, Inc.)A review. As wearable healthcare monitoring systems advance, there is immense potential for biol. sensing to enhance the management of type 1 diabetes (T1D). The aim of this work is to describe the ongoing development of biomarker analytes in the context of T1D. Technol. advances in transdermal biosensing offer remarkable opportunities to move from research labs. to clin. point-of-care applications. In this review, a range of analytes, including glucose, insulin, glucagon, cortisol, lactate, epinephrine, and alc., as well as ketones such as beta-hydroxybutyrate, will be evaluated to det. the current status and research direction of those analytes specifically relevant to T1D management, using both in-vitro and on-body detection. Understanding state-of-the-art developments in biosensing technologies will aid in bridging the gap from bench-to-clinic T1D analyte measurement advancement.
- 6Aiello, E. M.; Deshpande, S.; Özaslan, B.; Wolkowicz, K. L.; Dassau, E.; Pinsker, J. E.; Doyle, F. J. Review of automated insulin delivery systems for individuals with type 1 diabetes: Tailored solutions for subpopulations. Curr. Opin. Biomed. Eng. 2021, 19, 100312, DOI: 10.1016/j.cobme.2021.100312Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVGrurzN&md5=53265677f8577011c950e788f6ca0f9cReview of automated insulin delivery systems for individuals with type 1 diabetes: tailored solutions for subpopulationsAiello, Eleonora M.; Deshpande, Sunil; Ozaslan, Basak; Wolkowicz, Kelilah L.; Dassau, Eyal; Pinsker, Jordan E.; Doyle, Francis J. IIICurrent Opinion in Biomedical Engineering (2021), 19 (), 100312CODEN: COBEB4; ISSN:2468-4511. (Elsevier Inc.)A review. Automated insulin delivery (AID) systems have proven safe and effective in improving glycemic outcomes in individuals with type 1 diabetes. Clin. evaluation of this technol. has progressed to large randomized, controlled outpatient studies and recent com. approval of AID systems for children and adults. However, several challenges remain in improving these systems for different subpopulations (e.g. young children, athletes, pregnant women, seniors, and those with hypoglycemia unawareness). In this review, we highlight the requirements and challenges in AID design for selected subpopulations and discuss current advances from recent clin. studies.
- 7Li, J.; Liang, J. Y.; Laken, S. J.; Langer, R.; Traverso, G. Clinical opportunities for continuous biosensing and closed-loop therapies. Trends Chem. 2020, 2, 319– 340, DOI: 10.1016/j.trechm.2020.02.009Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslejsL%252FJ&md5=6c2fe008aa2832b4d175f4b309fa94f1Clinical Opportunities for Continuous Biosensing and Closed-Loop TherapiesLi, Jason; Liang, Jia Y.; Laken, Steven J.; Langer, Robert; Traverso, GiovanniTrends in Chemistry (2020), 2 (4), 319-340CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)A review. Continuous glucose monitors (CGMs) and closed-loop drug delivery systems have revolutionized patient care in diabetes and anesthesia. Here, we review the current state of continuous chem. sensor development, titratable drug delivery systems, and closed-loop therapies to identify clin. meaningful trends that, if realized, can have significant impact on medical practice and patient outcome. In particular, we focus on novel wearable and implantable demonstrations that stand to redefine the patient experience. Finally, we put forth a roadmap towards identifying crit. unmet clin. opportunities to motivate future technol. development towards applications beyond glucose, to both improve patient care across diverse fields of medicine and realize the full potential of these technologies to improve therapeutic outcome.
- 8Ferguson, B. S.; Hoggarth, D. A.; Maliniak, D.; Ploense, K.; White, R. J.; Woodward, N.; Hsieh, K.; Bonham, A. J.; Eisenstein, M.; Kippin, T. E.; Plaxco, K. W.; Soh, H. T. Real-time, aptamer-based tracking of circulating therapeutic agents in living animals. Sci. Transl. Med. 2013, 5, 213ra165, DOI: 10.1126/scitranslmed.3007095Google ScholarThere is no corresponding record for this reference.
- 9Arroyo-Currás, N.; Dauphin-Ducharme, P.; Ortega, G.; Ploense, K. L.; Kippin, T. E.; Plaxco, K. W. Subsecond-resolved molecular measurements in the living body using chronoamperometrically interrogated aptamer-based sensors. ACS Sens. 2018, 3, 360– 366, DOI: 10.1021/acssensors.7b00787Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslynu7nL&md5=71345b6d63ba81e4474706be1d55091dSubsecond-Resolved Molecular Measurements in the Living Body Using Chronoamperometrically Interrogated Aptamer-Based SensorsArroyo-Curras, Netzahualcoyotl; Dauphin-Ducharme, Philippe; Ortega, Gabriel; Ploense, Kyle L.; Kippin, Tod E.; Plaxco, Kevin W.ACS Sensors (2018), 3 (2), 360-366CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)Electrochem., aptamer-based (E-AB) sensors support the continuous, real-time measurement of specific small mols. directly in situ in the living body over the course of many hours. They achieve this by employing binding-induced conformational changes to alter electron transfer from a redox-reporter-modified, electrode-attached aptamer. Previously the authors have used voltammetry (cyclic, a.c., and square wave) to monitor this binding-induced change in transfer kinetics indirectly. Here, however, the authors demonstrate the potential advantages of employing chronoamperometry to measure the change in kinetics directly. In this approach target concn. is reported via changes in the lifetime of the exponential current decay seen when the sensor is subjected to a potential step. Because the lifetime of this decay is independent of its amplitude (e.g., insensitive to variations in the no. of aptamer probes on the electrode), chronoamperometrically interrogated E-AB sensors are calibration-free and resistant to drift. Chronoamperometric measurements can also be performed in a few hundred milliseconds, improving the previous few-second time resoln. of E-AB sensing by an order of magnitude. To illustrate the potential value of the approach the authors demonstrate here the calibration-free measurement of the drug tobramycin in situ in the living body with 300 ms time resoln. and unprecedented, few-percent precision in the detn. of its pharmacokinetic phases.
- 10Falagas, M. E.; Karageorgopoulos, D. E. Adjustment of dosing of antimicrobial agents for bodyweight in adults. Lancet 2010, 375, 248– 251, DOI: 10.1016/s0140-6736(09)60743-1Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c%252FlslGitA%253D%253D&md5=2ff938785d3b73c0374b198192d1787aAdjustment of dosing of antimicrobial agents for bodyweight in adultsFalagas Matthew E; Karageorgopoulos Drosos ELancet (London, England) (2010), 375 (9710), 248-51 ISSN:.There is no expanded citation for this reference.
- 11Shuter, B.; Aslani, A. Body surface area: Du bois and du bois revisited. Eur. J. Appl. Physiol. 2000, 82, 250– 254, DOI: 10.1007/s004210050679Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M%252FjsFSgsg%253D%253D&md5=61b4b1fa1755f2f4aaca173630040cc8Body surface area: Du Bois and Du Bois revisitedShuter B; Aslani AEuropean journal of applied physiology (2000), 82 (3), 250-4 ISSN:1439-6319.The Du Bois and Du Bois body surface area (BSA) equation is used widely to normalise physiological parameters. However, that only nine subjects were used in its derivation does not appear to be well known and does not justify its ubiquitous application. Furthermore, the derivation appears to be hampered by a lack of modern statistical methods and the omission of a large amount of available data. We have shown that the omitted data, obtained by measurement of the length of body parts, were identical to the data obtained by encasing subjects in moulds BSA (moulds; cm2) = [1.00 (0.02)] x BSA (linear measurements) + [123 (347)] . Non-linear regression analysis of the BSA of all 42 subjects reported by Du Bois and Du Bois gave new values for the constants of the model BSA (cm2) = 94.9 x [weight (kg)0.441] x [height (cm)0.655] . Although the original equation obtained by Du Bois and Du Bois was found to be adequate in adults, we recommend that it should not be used in daily practice, owing to the low number of subjects used in its derivation. The work presented here has placed the original results of Du Bois and Du Bois on a more robust statistical footing, yielding values for the model constants that would have been obtained if Du Bois and Du Bois had had access to modern statistical methods.
- 12Neely, M. N.; Kato, L.; Youn, G.; Kraler, L.; Bayard, D.; van Guilder, M.; Schumitzky, A.; Yamada, W.; Jones, B.; Minejima, E. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob. Agents Chemother. 2018, 62, e02042 DOI: 10.1128/AAC.02042-17Google ScholarThere is no corresponding record for this reference.
- 13Zhang, T.; Cai, S.; Forrest, W. C.; Mohr, E.; Yang, Q.; Forrest, M. L. Development and validation of an inductively coupled plasma mass spectrometry (icp-ms) method for quantitative analysis of platinum in plasma, urine, and tissues. Appl. Spectrosc. 2016, 70, 1529– 1536, DOI: 10.1177/0003702816662607Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVOntrs%253D&md5=b77d346ad9611570b54ecc77fa6c4788Development and validation of an inductively coupled plasma mass spectrometry (ICP-MS) method for quantitative analysis of platinum in plasma, urine, and tissuesZhang, Ti; Cai, Shuang; Forrest, Wai Chee; Mohr, Eva; Yang, Qiuhong; Forrest, M. LairdApplied Spectroscopy (2016), 70 (9), 1529-1536CODEN: APSPA4; ISSN:0003-7028. (Sage Publications)Cisplatin, a platinum chemotherapeutic, is one of the most commonly used chemotherapeutic agents for many solid tumors. In this work, we developed and validated an inductively coupled plasma mass spectrometry (ICP-MS) method for quant. detn. of platinum levels in rat urine, plasma, and tissue matrixes including liver, brain, lungs, kidney, muscle, heart, spleen, bladder, and lymph nodes. The tissues were processed using a microwave accelerated reaction system (MARS) system prior to anal. on an Agilent 7500 ICP-MS. According to the Food and Drug Administration guidance for industry, bioanal. validation parameters of the method, such as selectivity, accuracy, precision, recovery, and stability were evaluated in rat biol. samples. Our data suggested that the method was selective for platinum without interferences caused by other presenting elements, and the lower limit of quantification was 0.5 ppb. The accuracy and precision of the method were within 15% variation and the recoveries of platinum for all tissue matrixes examd. were detd. to be 85-115% of the theor. values. The stability of the platinum-contg. solns., including calibration stds., stock solns., and processed samples in rat biol. matrixes was investigated. Results indicated that the samples were stable after three cycles of freeze-thaw and for up to three months.
- 14Zhong, X.; Tong, X.; Ju, Y.; Du, X.; Li, Y. Interpersonal factors in the pharmacokinetics and pharmacodynamics of voriconazole: Are cyp2c19 genotypes enough for us to make a clinical decision?. Curr. Drug Metab. 2018, 19, 1152– 1158, DOI: 10.2174/1389200219666171227200547Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsl2ntw%253D%253D&md5=647959d96d5eabb0a5c7ce188ca2a054Interpersonal Factors in the Pharmacokinetics and Pharmacodynamics of Voriconazole: Are CYP2C19 Genotypes Enough for Us to Make a Clinical DecisionZhong, Xuefeng; Tong, Xunliang; Ju, Yang; Du, Xiaoman; Li, YanmingCurrent Drug Metabolism (2018), 19 (14), 1152-1158CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. Objective: We reviewed studies on how genotypes affect the pharmacokinetics and pharmacodynamics of voriconazole, and attempted to det. a method to decide on dosage adjustments based on genotypes, after which, the main characteristic of voriconazole was clarified in details. The pharmacokinetics of voriconazole are influenced by various inter and intrapersonal factors, and for certain populations, such as geriatric patients and pediatric patients, these influences must be considered. CYP2C19 genotype represents the main part of the interpersonal variability related to voriconazole blood concns. Thus monitoring the concn. of voriconazole is needed in clin. scenarios to minimize the neg. influences of inter and intrapersonal factors. Several studies provided evidence on the stable trough concn. range from 1-2 to 4-6 mg/L, which was combined to consider the efficacy and toxicity. However, the therapeutic drug concn. needs to be narrowed down and evaluated by large-scale clin. trials. Conclusion: Though there is insufficient evidence on the relationship between CYP2C19 genotypes and clin. outcomes, there is a great potential for the initial voriconazole dose selection to be guided by the CYP2C19 genotype. Finally, voriconazole therapeutic drug monitoring is essential to provide patient-specific dosing recommendations, leading to more effective anti-fungal regimens to increase clin. efficacy and reduce adverse drug reactions.
- 15Payne, K. D.; Hall, R. G. Dosing of antibacterial agents in obese adults: does one size fit all?. Expert Rev. Anti-Infect. Ther. 2014, 12, 829– 854, DOI: 10.1586/14787210.2014.912942Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpsVGlsL4%253D&md5=eae045e59c32a4a92d9120088a53bcd7Dosing of antibacterial agents in obese adults: does one size fit all?Payne, Kenna D.; Hall, Ronald G, IIExpert Review of Anti-Infective Therapy (2014), 12 (7), 829-854CODEN: ERATCK; ISSN:1478-7210. (Informa Healthcare)A review. Obesity is a global pandemic affecting 33% of adults in the United States. Obese persons receiving cefazolin or fluconazole have been shown to have worse outcomes with suboptimal dosing. Studies evaluating the safety of colistin, daptomycin, and vancomycin have shown increased wt. or obesity may potentially increase toxicity. Many antimicrobials lack pharmacokinetic data to support dose individuation in obese persons, due in part to the lack of obese patients in drug development studies. A one size fits all approach to dose optimization for obese patients is not likely. Current expert opinion suggests some antimicrobials (i.e. vancomycin) be dosed according to total body wt., whereas others (i.e. aminoglycosides) require adjusted body wt. for dose calcns. Yet other antimicrobials are reported to need no dose adjustment, largely based on studies using body mass index groups. Therefore, each drug should be individually evaluated to det. the proper dose for obese persons.
- 16Tran, B. Q.; Miller, P. R.; Taylor, R. M.; Boyd, G.; Mach, P. M.; Rosenzweig, C. N.; Baca, J. T.; Polsky, R.; Glaros, T. Proteomic characterization of dermal interstitial fluid extracted using a novel microneedle-assisted technique. J. Proteome Res. 2018, 17, 479– 485, DOI: 10.1021/acs.jproteome.7b00642Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVGgtrzO&md5=d471d7ccc19eee31fad145b85b30096cProteomic Characterization of Dermal Interstitial Fluid Extracted Using a Novel Microneedle-Assisted TechniqueTran, Bao Quoc; Miller, Philip R.; Taylor, Robert M.; Boyd, Gabrielle; Mach, Phillip M.; Rosenzweig, C. Nicole; Baca, Justin T.; Polsky, Ronen; Glaros, TrevorJournal of Proteome Research (2018), 17 (1), 479-485CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)As wearable fitness devices have gained com. acceptance, interest in real-time monitoring of an individual's physiol. status using noninvasive techniques has grown. Microneedles have been proposed as a minimally invasive technique for sampling the dermal interstitial fluid (ISF) for clin. monitoring and diagnosis, but little is known about its compn. In this study, a novel microneedle array was used to collect dermal ISF from three healthy human donors and compared with matching serum and plasma samples. Using a shotgun quant. proteomic approach, 407 proteins were quantified with at least one unique peptide, and of those, 135 proteins were differently expressed at least 2-fold. Collectively, these proteins tended to originate from the cytoplasm, membrane bound vesicles, and extracellular vesicular exosomes. Proteomic anal. confirmed previously published work that indicates that ISF is highly similar to both plasma and serum. In this study, less than one percent of proteins were uniquely identified in ISF. Taken together, ISF could serve as a minimally invasive alternative for blood-derived fluids with potential for real-time monitoring applications.
- 17Samant, P. P.; Niedzwiecki, M. M.; Raviele, N.; Tran, V.; Mena-Lapaix, J.; Walker, D. I.; Felner, E. I.; Jones, D. P.; Miller, G. W.; Prausnitz, M. R. Sampling interstitial fluid from human skin using a microneedle patch. Sci. Transl. Med. 2020, 12, eaaw0285 DOI: 10.1126/scitranslmed.aaw0285Google ScholarThere is no corresponding record for this reference.
- 18Siegmund, T.; Heinemann, L.; Kolassa, R.; Thomas, A. Discrepancies Between Blood Glucose and Interstitial Glucose-Technological Artifacts or Physiology: Implications for Selection of the Appropriate Therapeutic Target. J. Diabetes Sci. Technol. 2017, 11, 766– 772, DOI: 10.1177/1932296817699637Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czptVGqsg%253D%253D&md5=4810205e57fc783ee9b0f0016d0cf9f5Discrepancies Between Blood Glucose and Interstitial Glucose-Technological Artifacts or Physiology: Implications for Selection of the Appropriate Therapeutic TargetSiegmund Thorsten; Heinemann Lutz; Kolassa Ralf; Thomas AndreasJournal of diabetes science and technology (2017), 11 (4), 766-772 ISSN:.BACKGROUND: For decades, the major source of information used to make therapeutic decisions by patients with diabetes has been glucose measurements using capillary blood samples. Knowledge gained from clinical studies, for example, on the impact of metabolic control on diabetes-related complications, is based on such measurements. Different to traditional blood glucose measurement systems, systems for continuous glucose monitoring (CGM) measure glucose in interstitial fluid (ISF). The assumption is that glucose levels in blood and ISF are practically the same and that the information provided can be used interchangeably. Thus, therapeutic decisions, that is, the selection of insulin doses, are based on CGM system results interpreted as though they were blood glucose values. METHODS: We performed a more detailed analysis and interpretation of glucose profiles obtained with CGM in situations with high glucose dynamics to evaluate this potentially misleading assumption. RESULTS: Considering physical activity, hypoglycemic episodes, and meal-related differences between glucose levels in blood and ISF uncover clinically relevant differences that can make it risky from a therapeutic point of view to use blood glucose for therapeutic decisions. CONCLUSIONS: Further systematic and structured evaluation as to whether the use of ISF glucose is more safe and efficient when it comes to acute therapeutic decisions is necessary. These data might also have a higher prognostic relevance when it comes to long-term metabolic consequences of diabetes. In the long run, it may be reasonable to abandon blood glucose measurements as the basis for diabetes management and switch to using ISF glucose as the appropriate therapeutic target.
- 19Teymourian, H.; Tehrani, F.; Mahato, K.; Wang, J. Lab under the skin: Microneedle based wearable devices. Adv. Healthcare Mater. 2021, 10, e2002255 DOI: 10.1002/adhm.202002255Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXltlejtrc%253D&md5=912945b4a718eb3c08bc95671feb7b90Lab under the Skin: Microneedle Based Wearable DevicesTeymourian, Hazhir; Tehrani, Farshad; Mahato, Kuldeep; Wang, JosephAdvanced Healthcare Materials (2021), 10 (17), 2002255CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)While the current smartwatches and cellphones can readily track mobility and vital signs, a new generation of wearable devices is rapidly developing to enable users to monitor their health parameters at the mol. level. Within this emerging class of wearables, microneedle-based transdermal sensors are in a prime position to play a key role in synergizing the significant advantages of dermal interstitial fluid (ISF) as a rich source of clin. indicators and painless skin pricking to allow the collection of real-time diagnostic information. While initial efforts of microneedle sensing focused on ISF extn. coupled with either on-chip anal. or off-chip instrumentation, the latest trend has been oriented toward assembling electrochem. biosensors on the tip of microneedles to allow direct continuous chem. measurements. In this context, significant advances have recently been made in exploiting microneedle-based devices for real-time monitoring of various metabolites, electrolytes, and therapeutics and toward the simultaneous multiplexed detection of key chem. markers; yet, there are several grand challenges that still exist. In this review, we outline current progress, recent trends, and new capabilities of microneedle-empowered sensors, along with the current unmet challenges and a future roadmap toward transforming the latest innovations in the field to com. products.
- 20Miller, P. R.; Taylor, R. M.; Tran, B. Q.; Boyd, G.; Glaros, T.; Chavez, V. H.; Krishnakumar, R.; Sinha, A.; Poorey, K.; Williams, K. P.; Branda, S. S.; Baca, J. T.; Polsky, R. Extraction and biomolecular analysis of dermal interstitial fluid collected with hollow microneedles. Commun. Biol. 2018, 1, 173, DOI: 10.1038/s42003-018-0170-zGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvks1CgtQ%253D%253D&md5=22fe34aba32973b987646d6e045345c2Extraction and biomolecular analysis of dermal interstitial fluid collected with hollow microneedlesMiller Philip R; Chavez Victor H; Polsky Ronen; Taylor Robert M; Baca Justin T; Tran Bao Quoc; Boyd Gabrielle; Glaros Trevor; Krishnakumar Raga; Sinha Anupama; Poorey Kunal; Williams Kelly P; Branda Steven SCommunications biology (2018), 1 (), 173 ISSN:.Dermal interstitial fluid (ISF) is an underutilized information-rich biofluid potentially useful in health status monitoring applications whose contents remain challenging to characterize. Here, we present a facile microneedle approach for dermal ISF extraction with minimal pain and no blistering for human subjects and rats. Extracted ISF volumes were sufficient for determining transcriptome, and proteome signatures. We noted similar profiles in ISF, serum, and plasma samples, suggesting that ISF can be a proxy for direct blood sampling. Dynamic changes in RNA-seq were recorded in ISF from induced hypoxia conditions. Finally, we report the first isolation and characterization, to our knowledge, of exosomes from dermal ISF. The ISF exosome concentration is 12-13 times more enriched when compared to plasma and serum and represents a previously unexplored biofluid for exosome isolation. This minimally invasive extraction approach can enable mechanistic studies of ISF and demonstrates the potential of ISF for real-time health monitoring applications.
- 21van der Maaden, K.; Jiskoot, W.; Bouwstra, J. Microneedle technologies for (trans)dermal drug and vaccine delivery. J. Controlled Release 2012, 161, 645– 655, DOI: 10.1016/j.jconrel.2012.01.042Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFWkuro%253D&md5=e8a28f652a364d28c0e460164c46ef41Microneedle technologies for (trans)dermal drug and vaccine deliveryvan der Maaden, Koen; Jiskoot, Wim; Bouwstra, JokeJournal of Controlled Release (2012), 161 (2), 645-655CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review:Microneedles have been used for the dermal and transdermal delivery of a broad range of drugs, such as small mol. wt. drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses. However, until now there are no microneedle-based (trans)dermal drug delivery systems on the market. In the past decade various types of microneedles have been developed by a no. of prodn. processes. Numerous geometries of microneedles have been designed from various materials. These microneedles have been used for different approaches of microneedle-based (trans)dermal drug delivery. Following a brief introduction about dermal and transdermal drug delivery, this review describes different prodn. methods for solid and hollow microneedles as well as conditions that influence skin penetration. Besides, the four microneedle-based (trans)dermal drug delivery approaches are discussed: "poke and flow", "poke and patch", "poke and release", and "coat and poke". A sep. section of this review is devoted to the use of microneedles for the delivery of therapeutic proteins and vaccines. Finally, we give our view on research and development that is needed to render microneedle-based (trans)dermal drug delivery technologies clin. useful in the near future.
- 22Singh, P.; Carrier, A.; Chen, Y.; Lin, S.; Wang, J.; Cui, S.; Zhang, X. Polymeric microneedles for controlled transdermal drug delivery. J. Controlled Release 2019, 315, 97– 113, DOI: 10.1016/j.jconrel.2019.10.022Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFSjtbnP&md5=75b15d588e2bfea21f978e1e1c5dd351Polymeric microneedles for controlled transdermal drug deliverySingh, Parbeen; Carrier, Andrew; Chen, Yongli; Lin, Sujing; Wang, Jinlin; Cui, Shufen; Zhang, XuJournal of Controlled Release (2019), 315 (), 97-113CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Polymeric microneedle (MN) systems are interesting transdermal drug delivery systems because of their controlled drug delivery, tunable properties, and ease of patient self-administration. They are biocompatible and can easily and painlessly penetrate the stratum corneum, delivering their contents into the dermis where they can be adsorbed into systemic circulation. Polymeric MNs can facilitate appropriate therapeutic dosing by controlling the release kinetics of pre-loaded drugs, targeting specific tissues, or responding to changing physiol. conditions. This can be accomplished by modifying the degrdn. and swelling profiles of the host polymer and the diffusion profiles of the encapsulated drugs. In this various mechanisms of controlled drug delivery using polymeric MNs, including new strategies, applications, and their future outlook are summarized and evaluated.
- 23Goud, K. Y.; Moonla, C.; Mishra, R. K.; Yu, C.; Narayan, R.; Litvan, I.; Wang, J. Wearable electrochemical microneedle sensor for continuous monitoring of levodopa: Toward parkinson management. ACS Sens. 2019, 4, 2196– 2204, DOI: 10.1021/acssensors.9b01127Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFClsr3K&md5=c35c1f890a3f2acd6ebd10c7f0fae245Wearable Electrochemical Microneedle Sensor for Continuous Monitoring of Levodopa: Toward Parkinson ManagementGoud, K. Yugender; Moonla, Chochanon; Mishra, Rupesh K.; Yu, Chunmei; Narayan, Roger; Litvan, Irene; Wang, JosephACS Sensors (2019), 4 (8), 2196-2204CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)Levodopa is the most effective medication for treating Parkinson's disease (PD). However, because dose optimization is currently based on patients' report of symptoms, which are difficult for patients to describe, the management of PD is challenging. We report on a microneedle sensing platform for continuous minimally invasive orthogonal electrochem. monitoring of levodopa (L-Dopa). The new multimodal microneedle sensing platform relies on parallel simultaneous independent enzymic-amperometric and nonenzymic voltammetric detection of L-Dopa using different microneedles on the same sensor array patch. Such real-time orthogonal L-Dopa sensing offers a built-in redundancy and enhances the information content of the microneedle sensor arrays. This is accomplished by rapid detection of L-Dopa using square-wave voltammetry and chronoamperometry at unmodified and tyrosinase-modified carbon-paste microneedle electrodes, resp. The new wearable microneedle sensor device displays an attractive anal. performance with the enzymic and nonenzymic L-Dopa microneedle sensors offering different dimensions of information while displaying high sensitivity (with a low detection limit), high selectivity in the presence of potential interferences, and good stability in artificial interstitial fluid (ISF). The attractive anal. performance and potential wearable applications of the microneedle sensor array have been demonstrated in a skin-mimicking phantom gel as well as upon penetration through mice skin. The design and attractive anal. performance of the new orthogonal wearable microneedle sensor array hold considerable promise for reliable, continuous, minimally invasive monitoring of L-Dopa in the ISF toward optimizing the dosing regimen of the drug and effective management of Parkinson disease.
- 24Mohan, A. M. V.; Windmiller, J. R.; Mishra, R. K.; Wang, J. Continuous minimally-invasive alcohol monitoring using microneedle sensor arrays. Biosens. Bioelectron. 2017, 91, 574– 579, DOI: 10.1016/j.bios.2017.01.016Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFKkt7Y%253D&md5=73c7edcdbcf6b5befeda34cbbff3ded9Continuous minimally-invasive alcohol monitoring using microneedle sensor arraysMohan, A. M. Vinu; Windmiller, Joshua Ray; Mishra, Rupesh K.; Wang, JosephBiosensors & Bioelectronics (2017), 91 (), 574-579CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)The present work describes an attractive skin-worn microneedle sensing device for the minimally invasive electrochem. monitoring of s.c. alc. The device consists of an assembly of pyramidal microneedle structures integrated with Pt and Ag wires, each with a microcavity opening. The microneedle aperture was modified by electropolymg. o-phenylene diamine onto the Pt wire microtransducer, followed by the immobilization of alc. oxidase (AOx) in an intermediate chitosan layer, along with an outer Nafion layer. The resulting microneedle-based enzyme electrode displays an interference-free ethanol detection in artificial interstitial fluid without compromising its sensitivity, stability and response time. The skin penetration ability and the efficaciousness of the biosensor performance towards s.c. alc. monitoring was substantiated by the ex vivo mice skin model anal. Our results reveal that the new microneedle sensor holds considerable promise for continuous non-invasive alc. monitoring in real-life situations.
- 25Mishra, R. K.; Vinu Mohan, A. M.; Soto, F.; Chrostowski, R.; Wang, J. A microneedle biosensor for minimally-invasive transdermal detection of nerve agents. Analyst 2017, 142, 918– 924, DOI: 10.1039/c6an02625gGoogle Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitlGgtL4%253D&md5=76b2c98a42d68d9f342dbdaadfe7b556A microneedle biosensor for minimally-invasive transdermal detection of nerve agentsMishra, Rupesh K.; Vinu Mohan, A. M.; Soto, Fernando; Chrostowski, Robert; Wang, JosephAnalyst (Cambridge, United Kingdom) (2017), 142 (6), 918-924CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)A microneedle electrochem. biosensor for the minimally invasive detection of organophosphate (OP) chem. agents is described. The new sensor relies on the coupling of the effective biocatalytic action of organophosphorus hydrolase (OPH) with a hollow-microneedle modified carbon-paste array electrode transducer, and involves rapid square-wave voltammetric (SWV) measurements of the p-nitrophenol product of the OPH enzymic reaction in the presence of the OP substrate. The scanning-potential SWV transduction mode offers an addnl. dimension of selectivity compared to common fixed-potential OPH-amperometric biosensors. The microneedle device offers a highly linear response for Me paraoxon (MPOx) over the range of 20-180 μM, high selectivity in the presence of excess co-existing ascorbic acid and uric acid and a high stability sensor upon exposure to the interstitial fluid (ISF). The OPH microneedle sensor was successfully tested ex vivo using mice skin samples exposed to MPOx, demonstrating its promise for minimally-invasive monitoring of OP agents and pesticides and as a wearable sensor for detecting toxic compds., in general.
- 26Windmiller, J. R.; Valdés-Ramírez, G.; Zhou, N.; Zhou, M.; Miller, P. R.; Jin, C.; Brozik, S. M.; Polsky, R.; Katz, E.; Narayan, R.; Wang, J. Bicomponent microneedle array biosensor for minimally-invasive glutamate monitoring. Electroanalysis 2011, 23, 2302– 2309, DOI: 10.1002/elan.201100361Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht12kurbK&md5=e7fbdde390eb68c0f2eb585388843be1Bicomponent Microneedle Array Biosensor for Minimally-Invasive Glutamate MonitoringWindmiller, Joshua Ray; Valdes-Ramirez, Gabriela; Zhou, Nandi; Zhou, Ming; Miller, Philip R.; Jin, Chunming; Brozik, Susan M.; Polsky, Ronen; Katz, Evgeny; Narayan, Roger; Wang, JosephElectroanalysis (2011), 23 (10), 2302-2309CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)This article describes the design of a new and attractive minimally-invasive bicomponent microneedle sensing device for the electrochem. monitoring of the excitatory neurotransmitter glutamate and glucose. The new device architecture relies on the close integration of solid and hollow microneedles into a single biosensor array device contg. multiple microcavities. Such microcavities facilitate the electropolymeric entrapment of the recognition enzyme within each microrecess. The resulting microneedle biosensor array can be employed as a minimally-invasive on-body transdermal patch, obviating the extn./sampling of the biol. fluid, thereby simplifying device requirements. The new concept is demonstrated for the electropolymeric entrapment of glutamate oxidase and glucose oxidase within a poly(o-phenylenediamine) (PPD) thin film. The PPD-based enzyme entrapment methodol. enables the effective rejection of coexisting electroactive interferents without compromising the sensitivity or response time of the device. The resulting microneedle-based glutamate and glucose biosensors thus exhibit high selectivity, sensitivity, speed, and stability in both buffer and undiluted human serum. High-fidelity glutamate measurements down to the 10 μM level were obtained in serum. The attractive recess design also serves to protect the enzyme layer upon insertion into the skin. This simple, yet robust microneedle design is well-suited for diverse biosensing applications in which real-time metabolite monitoring is a core requirement.
- 27Teymourian, H.; Moonla, C.; Tehrani, F.; Vargas, E.; Aghavali, R.; Barfidokht, A.; Tangkuaram, T.; Mercier, P. P.; Dassau, E.; Wang, J. Microneedle-based detection of ketone bodies along with glucose and lactate: Toward real-time continuous interstitial fluid monitoring of diabetic ketosis and ketoacidosis. Anal. Chem. 2020, 92, 2291– 2300, DOI: 10.1021/acs.analchem.9b05109Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVKktbjJ&md5=3f63a4164e331b231e2b7624dce0225dMicroneedle-Based Detection of Ketone Bodies along with Glucose and Lactate: Toward Real-Time Continuous Interstitial Fluid Monitoring of Diabetic Ketosis and KetoacidosisTeymourian, Hazhir; Moonla, Chochanon; Tehrani, Farshad; Vargas, Eva; Aghavali, Reza; Barfidokht, Abbas; Tangkuaram, Tanin; Mercier, Patrick P.; Dassau, Eyal; Wang, JosephAnalytical Chemistry (Washington, DC, United States) (2020), 92 (2), 2291-2300CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)Diabetic ketoacidosis (DKA), a severe complication of diabetes mellitus with potentially fatal consequences, is characterized by hyperglycemia and metabolic acidosis due to the accumulation of ketone bodies, which requires people with diabetes to monitor both glucose and ketone bodies. However, despite major advances in diabetes management mainly since the emergence of new-generation continuous glucose monitoring (CGM) devices capable of in vivo monitoring of glucose directly in the interstitial fluid (ISF), the continuous monitoring of ketone bodies is yet to be addressed. Here, the authors present the first use of a real-time continuous ketone bodies monitoring (CKM) microneedle platform. The system is based on the electrochem. monitoring of β-hydroxybutyrate (HB) as the dominant biomarker of ketone formation. Such real-time HB detection has been realized using the β-hydroxybutyrate dehydrogenase (HBD) enzymic reaction and by addressing the major challenges assocd. with the stable confinement of the enzyme/cofactor couple (HBD/NAD+) and with a stable and selective low-potential fouling-free anodic detection of NADH. The resulting CKM microneedle device displays an attractive anal. performance, with high sensitivity (with low detection limit, 50μM), high selectivity in the presence of potential interferences, along with good stability during prolonged operation in artificial ISF. The potential applicability of this microneedle sensor toward minimally invasive monitoring of ketone bodies has been demonstrated in a phantom gel skin-mimicking model. The ability to detect HB along with glucose and lactate on a single microneedle array has been demonstrated. These findings pave the way for CKM and for the simultaneous microneedle-based monitoring of multiple diabetes-related biomarkers toward a tight glycemic control.
- 28Mishra, R. K.; Goud, K. Y.; Li, Z.; Moonla, C.; Mohamed, M. A.; Tehrani, F.; Teymourian, H.; Wang, J. Continuous opioid monitoring along with nerve agents on a wearable microneedle sensor array. J. Am. Chem. Soc. 2020, 142, 5991– 5995, DOI: 10.1021/jacs.0c01883Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltl2mt7o%253D&md5=0ea09259607b9e1d3db134f04ea9d46dContinuous Opioid Monitoring along with Nerve Agents on a Wearable Microneedle Sensor ArrayMishra, Rupesh K.; Goud, K. Yugender; Li, Zhanhong; Moonla, Chochanon; Mohamed, Mona A.; Tehrani, Farshad; Teymourian, Hazhir; Wang, JosephJournal of the American Chemical Society (2020), 142 (13), 5991-5995CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)There are urgent needs for sensing devices capable of distinguishing between episodes of opioid overdose and nerve agent poisoning. This work presents a wearable microneedle sensor array for minimally invasive continuous electrochem. detection of opioid (OPi) and organophosphate (OP) nerve agents on a single patch platform. The new multimodal microneedle sensor array relies on unmodified and organophosphorus hydrolase (OPH) enzyme-modified carbon paste (CP) microneedle electrodes for square wave voltammetric (SWV) detection of the fentanyl and nerve agent targets, resp. Such real-time simultaneous sensing provides distinct unique information, along with attractive anal. performance, including high sensitivity, selectivity, and stability, for real-time on-body OPi-OP anal. The patch represents the first sensing device capable of continuously monitoring fentanyl down to the nanomolar level through a nanomaterial-based multilayered surface architecture. Applicability of the sensor array toward opioids screening is demonstrated for morphine and norfentanyl. Successful OPi-OP detection conducted in a skin-mimicking phantom gel demonstrates the suitability of the device for rapid on-body sensing. Such progress toward continuous minimally invasive transdermal anal. of drugs of abuse and nerve agents holds promise for rapid countermeasures for protecting soldiers, civilians, and healthcare personnel.
- 29Xiao, Y.; Lubin, A. A.; Heeger, A. J.; Plaxco, K. W. Label-free electronic detection of thrombin in blood serum by using an aptamer-based sensor. Angew. Chem., Int. Ed. 2005, 44, 5456– 5459, DOI: 10.1002/anie.200500989Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpvF2ksLg%253D&md5=03fba0f9b28e0c7c8375e8fef4a5446fLabel-free electronic detection of thrombin in blood serum by using an aptamer-based sensorXiao, Yi; Lubin, Arica A.; Heeger, Alan J.; Plaxco, Kevin W.Angewandte Chemie, International Edition (2005), 44 (34), 5456-5459CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A methylene blue (MB) tagged, thrombin-binding DNA aptamer immobilized on a gold surface undergoes a large conformational change upon target binding and inhibits electron transfer. This folding produces a large, readily measurable change in redox current and allows the electrochem. detection of thrombin in blood serum.
- 30Tuerk, C.; Gold, L. Systematic evolution of ligands by exponential enrichment: Rna ligands to bacteriophage t4 DNA polymerase. Science 1990, 249, 505– 510, DOI: 10.1126/science.2200121Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXlt1OltLY%253D&md5=a40a28db9df4a5da4c1b1652a34aa715Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymeraseTuerk, Craig; Gold, LarryScience (Washington, DC, United States) (1990), 249 (4968), 505-10CODEN: SCIEAS; ISSN:0036-8075.A novel method was developed for rapidly selecting preferred binding sequences from a population of random sequences. The method is designated systematic evolution of ligands by exponential enrichment (SELEX). High-affinity nucleic acid ligands for a protein were isolated by a procedure that depends on alternate cycles of ligand selection from pools of variant sequences and amplification of the bound species. Multiple rounds exponentially enrich the population for the highest affinity species that can be clonally isolated and characterized. In particular one eight-base region of an RNA that interacts with the T4 DNA polymerase was chosen and randomized. Two different sequences were selected by this procedure from the calcd. pool of 65,536 species. One is the wild-type sequence found in the bacteriophage mRNA; one is varied from wild type at four positions. The binding consts. of these two RNA's to T4 DNA polymerase are equiv. These protocols with minimal modification can yield high-affinity ligands for any protein that binds nucleic acids as part of its function; high affinity ligands could conceivably be developed for any target mol.
- 31Ellington, A. D.; Szostak, J. W. In vitro selection of rna molecules that bind specific ligands. Nature 1990, 346, 818– 822, DOI: 10.1038/346818a0Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXitVGgsw%253D%253D&md5=522ad1b4f0284ee88173b02035f9e9c5In vitro selection of RNA molecules that bind specific ligandsEllington, Andrew D.; Szostak, Jack W.Nature (London, United Kingdom) (1990), 346 (6287), 818-22CODEN: NATUAS; ISSN:0028-0836.Subpopulations of RNA mols. that bind specifically to a variety of org. dyes have been isolated from a population of random sequence RNA mols. Roughly one in 1010 random sequence RNA mols. folds in such a way as to create a specific binding site for small ligands.
- 32Wu, Y.; Belmonte, I.; Sykes, K. S.; Xiao, Y.; White, R. J. Perspective on the future role of aptamers in analytical chemistry. Anal. Chem. 2019, 91, 15335– 15344, DOI: 10.1021/acs.analchem.9b03853Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFCns7jE&md5=da66671382b5e90ffd90a9ebc3ad7a46Perspective on the Future Role of Aptamers in Analytical ChemistryWu, Yao; Belmonte, Israel; Sykes, Kiana S.; Xiao, Yi; White, Ryan J.Analytical Chemistry (Washington, DC, United States) (2019), 91 (24), 15335-15344CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)A review. It has been almost 30 years since the invention of SELEX (Systematic Evolution of Ligands by Exponential Enrichment) methodol. and the description of the first aptamers. In retrospect over the past 30 years, advances in aptamer development and application have demonstrated that aptamers are potentially useful reagents that can be employed in diverse areas within anal. chem., biotechnol., biomedicine, and mol. biol. While often touted as artificial antibodies with an ability to be selected for any target, aptamer development, unfortunately, lags behind development of anal. methodologies that employ aptamers, hindering deeper integration into the application of anal. tool development. This perspective covers recent advances in SELEX methodol. coupled with post-selection procedures all aimed at enhancing affinity and specificity of the selected aptamers - what we view as a crit. barrier in the future role of aptamers in anal. chem. We discuss post-selection modifications that can be used for enhancing performance of the selected aptamers in anal. device by including understanding intermol. interaction forces in the binding domain. While highlighting promising properties of aptamers that enable several anal. advances, we provide discussion on the challenges of penetration of aptamers in the anal. field.
- 33Yi, K.; Wang, Y.; Shi, K.; Chi, J.; Lyu, J.; Zhao, Y. Aptamer-decorated porous microneedles arrays for extraction and detection of skin interstitial fluid biomarkers. Biosens. Bioelectron. 2021, 190, 113404, DOI: 10.1016/j.bios.2021.113404Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVWgsr%252FF&md5=a13387a1f4051515f0ce0639ab3f9d98Aptamer-decorated porous microneedles arrays for extraction and detection of skin interstitial fluid biomarkersYi, Kexin; Wang, Yuetong; Shi, Keqing; Chi, Junjie; Lyu, Jianxin; Zhao, YuanjinBiosensors & Bioelectronics (2021), 190 (), 113404CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)The detection of biomarkers in body fluids plays a great role in the diagnosis, treatment, and prognosis of diseases. Here, we present novel aptamer-decorated porous microneedles (MNs) arrays to realize the extn. and detection of biomarkers in skin interstitial fluid (ISF) in situ. The porous MNs arrays are fabricated by replicating the neg. molds comprising glass microspheres with a UV-curable ethoxylated trimethylolpropane triacrylate (ETPTA). As the MNs arrays combine the superiorities of porous structure and aptamers, their sp. surface area increased significantly to 6.694 m2/g, thus vast of stable aptamer probes with a concn. of 0.9459μM could be immobilized. In addn., the MNs arrays could ext. skin ISF into their porous structure on the basis of the capillarity principle, and subsequently capture and detect skin ISF biomarkers without sample post-process. Taking advantage of these features, we further demonstrated a highly sensitive and rapid detection of ISF endotoxin in the concn. ranges of 0.0342 EU/mL to 8.2082 EU/mL from rats model injected with endotoxin via tail vein by using such aptamer-decorated porous MNs arrays, with the limit of detection (LOD) of 0.0064 EU/mL. These results indicated that the aptamer-decorated porous MNs arrays possess great potential for non-invasive extn. and detection of biomarkers in clin. applications.
- 34Shaver, A.; Curtis, S. D.; Arroyo-Currás, N. Alkanethiol monolayer end groups affect the long-term operational stability and signaling of electrochemical, aptamer-based sensors in biological fluids. ACS Appl. Mater. Interfaces 2020, 12, 11214– 11223, DOI: 10.1021/acsami.9b22385Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFKqsro%253D&md5=5f10c2efa8960f892202a6184bf9d63aAlkanethiol Monolayer End Groups Affect the Long-Term Operational Stability and Signaling of Electrochemical, Aptamer-Based Sensors in Biological FluidsShaver, Alexander; Curtis, Samuel D.; Arroyo-Curras, NetzahualcoyotlACS Applied Materials & Interfaces (2020), 12 (9), 11214-11223CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)Electrochem. aptamer-based (E-AB) sensors achieve highly precise measurements of specific mol. targets in untreated biol. fluids. This unique ability, together with their measurement frequency of seconds or faster, has enabled the real-time monitoring of drug pharmacokinetics in live animals with unprecedented temporal resoln. However, one important weakness of E-AB sensors is that their bioelectronic interface degrades upon continuous electrochem. interrogation-a process typically seen as a drop in faradaic and an increase in charging currents over time. This progressive degrdn. limits their in vivo operational life to 12 h at best, a period that is much shorter than the elimination half-life of the vast majority of drugs in humans. Thus, there is a crit. need to develop novel E-AB interfaces that resist continuous electrochem. interrogation in biol. fluids for prolonged periods. In response, our group is pursuing the development of better packed, more stable self-assembled monolayers (SAMs) to improve the signaling and extend the operational life of in vivo E-AB sensors from hours to days. By invoking hydrophobicity arguments, we have created SAMs that do not desorb from the electrode surface in aq. physiol. solns. and biol. fluids. These SAMs, formed from 1-hexanethiol solns., decrease the voltammetric charging currents of E-AB sensors by 3-fold relative to std. monolayers of 6-mercapto-1-hexanol, increase the total faradaic current, and alter the electron transfer kinetics of the platform. Moreover, the stability of our new SAMs enables uninterrupted, continuous E-AB interrogation for several days in biol. fluids, like undiluted serum, at a physiol. temp. of 37°C.
- 35Arroyo-Currás, N.; Dauphin-Ducharme, P.; Scida, K.; Chávez, J. L. From the beaker to the body: Translational challenges for electrochemical, aptamer-based sensors. Anal. Methods 2020, 12, 1288– 1310, DOI: 10.1039/d0ay00026dGoogle ScholarThere is no corresponding record for this reference.
- 36Dauphin-Ducharme, P.; Ploense, K. L.; Arroyo-Currás, N.; Kippin, T. E.; Plaxco, K. W. Electrochemical aptamer-based sensors: A platform approach to high-frequency molecular monitoring in situ in the living body. Biomedical Engineering Technologies; Methods in Molecular Biology; Ossandon, M. R., Baker, H., Rasooly, A., Eds.; Springer US: Humana, New York, NY, 2022; Vol. 2393, pp 479– 492.Google ScholarThere is no corresponding record for this reference.
- 37Carvalhal, R. F.; Sanches Freire, R.; Kubota, L. T. Polycrystalline gold electrodes: A comparative study of pretreatment procedures used for cleaning and thiol self-assembly monolayer formation. Electroanalysis 2005, 17, 1251– 1259, DOI: 10.1002/elan.200403224Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXntlCmt7g%253D&md5=b11109b738ba7cc3c2a8d1d123dcc166Polycrystalline gold electrodes: A comparative study of pretreatment procedures used for cleaning and thiol self-assembly monolayer formationCarvalhal, Rafaela Fernanda; Freire, Renato Sanches; Kubota, Lauro TatsuoElectroanalysis (2005), 17 (14), 1251-1259CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)The influence of different surface pretreatment procedures on the electrochem. response of a polycryst. Au electrode was evaluated. Mech. polishing with slurry alumina (M), chem. oxidn. with H2SO4/H2O2 (C), electrochem. polishing (potential cycling between -0.1 V and 1.2 V vs. SCE) (E), chem. redn. with EtOH, and combinations among these treatments were employed to change the surface electrode characteristics. The efficiency of the proposed pretreatments was evaluated by electrochem. responses towards the redox couple ferri(II/III)-ammonium sulfate and by the formation of a self-assembly monolayer of 3-mercaptopropionic acid (3 MPA SAM) on Au electrodes. The procedure (C) allowed important Au surfaces activation. Using procedures (C) and (E) the roughness of polycryst. Au surfaces was significantly minimized and more reproducible surfaces could be obtained. From the profile of reductive desorption of 3 MPA SAM it was possible to verify that reduced Au surfaces generated better packed monolayers than oxidized ones and a comparative study using CV and DPV techniques showed that between the two desorption peaks, the one localized at more neg. potential values corresponds to the cleavage of Au-S bond from the chemisorbed thiol. In general, the improvement in the studied electrochem. responses could not only be attributed to an increase in the real surface area of the electrode, but to the chem. surface states set off by the pretreatment procedure.
- 38Curtis, S. D.; Ploense, K. L.; Kurnik, M.; Ortega, G.; Parolo, C.; Kippin, T. E.; Plaxco, K. W.; Arroyo-Currás, N. Open source software for the real-time control, processing, and visualization of high-volume electrochemical data. Anal. Chem. 2019, 91, 12321– 12328, DOI: 10.1021/acs.analchem.9b02553Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1KksL%252FI&md5=8a2fb45b4fd84748c8c38c8754c1db12Open Source Software for the Real-Time Control, Processing, and Visualization of High-Volume Electrochemical DataCurtis, Samuel D.; Ploense, Kyle L.; Kurnik, Martin; Ortega, Gabriel; Parolo, Claudio; Kippin, Tod E.; Plaxco, Kevin W.; Arroyo-Curras, NetzahualcoyotlAnalytical Chemistry (Washington, DC, United States) (2019), 91 (19), 12321-12328CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)Electrochem. sensors are major players in the race for improved mol. diagnostics due to their convenience, temporal resoln., manufg. scalability, and their ability to support real-time measurements. This is evident in the ever-increasing no. of health-related electrochem. sensing platforms, ranging from single-measurement point-of-care devices to wearable devices supporting immediate and continuous monitoring. In support of the need for such systems to rapidly process large data vols. the authors describe here an open-source, easily customizable, multi-platform compatible program for the real-time control, processing and visualization of electrochem. data. The software's architecture is modular and fully documented, allowing the easy customization of the code to support the processing of voltammetric (e.g., square-wave and cyclic) and chronoamperometric data. The program, which the authors have called Software for the Anal. and Continuous Monitoring of Electrochem. Systems (SACMES), also includes a graphical interface allowing the user to easily change anal. parameters (e.g., signal/noise processing, baseline correction) in real-time. To demonstrate the versatility of SACMES the authors use it here to analyze the real-time data output by: (1) the electrochem., aptamer-based measurement of a specific small-mol. target, (2) a monoclonal antibody-detecting DNA-scaffold sensor, and (3) the detn. of the folding thermodn. of an electrode-attached, redox-reporter-modified protein.
- 39Xiao, Y.; Lai, R. Y.; Plaxco, K. W. Preparation of electrode-immobilized, redox-modified oligonucleotides for electrochemical DNA and aptamer-based sensing. Nat. Protoc. 2007, 2, 2875– 2880, DOI: 10.1038/nprot.2007.413Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlSlsr%252FF&md5=cbabde677e2bf0e10bf501b3d2f9df6bPreparation of electrode-immobilized, redox-modified oligonucleotides for electrochemical DNA and aptamer-based sensingXiao, Yi; Lai, Rebecca Y.; Plaxco, Kevin W.Nature Protocols (2007), 2 (11), 2875-2880CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)Recent years have seen the development of a no. of reagentless, electrochem. sensors based on the target-induced folding or unfolding of electrode-bound oligonucleotides, with examples reported to date, including sensors for the detection of specific nucleic acids, proteins, small mols. and inorg. ions. These devices, which are often termed electrochem. DNA (E-DNA) and E-AB (electrochem., aptamer-based) sensors, are comprised of an oligonucleotide probe modified with a redox reporter (in this protocol methylene blue) at one terminus and attached to a gold electrode via a thiol-gold bond at the other. Binding of an analyte to the oligonucleotide probe changes its structure and dynamics, which, in turn, influences the efficiency of electron transfer to the interrogating electrode. This class of sensors perform well even when challenged directly with blood serum, soil and other complex, multicomponent sample matrixes. This protocol describes the fabrication of E-DNA and E-AB sensors. The protocol can be completed in 12 h.
- 40Pellitero, M. A.; Curtis, S. D.; Arroyo-Currás, N. Interrogation of electrochemical aptamer-based sensors via peak-to-peak separation in cyclic voltammetry improves the temporal stability and batch-to-batch variability in biological fluids. ACS Sens. 2021, 6, 1199– 1207, DOI: 10.1021/acssensors.0c02455Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXkt1Oqu7g%253D&md5=f7ae3d9543ea0c4cfa85a2fb4396f121Interrogation of Electrochemical Aptamer-Based Sensors via Peak-to-Peak Separation in Cyclic Voltammetry Improves the Temporal Stability and Batch-to-Batch Variability in Biological FluidsPellitero, Miguel Aller; Curtis, Samuel D.; Arroyo-Curras, NetzahualcoyotlACS Sensors (2021), 6 (3), 1199-1207CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)Electrochem., aptamer-based (E-AB) sensors support continuous, real-time measurements of specific mol. targets in complex fluids such as undiluted serum. They achieve these measurements by using redox-reporter-modified, electrode-attached aptamers that undergo target binding-induced conformational changes which, in turn, change electron transfer between the reporter and the sensor surface. Traditionally, E-AB sensors are interrogated via pulse voltammetry to monitor binding-induced changes in transfer kinetics. While these pulse techniques are sensitive to changes in electron transfer, they also respond to progressive changes in the sensor surface driven by biofouling or monolayer desorption and, consequently, present a significant drift. Moreover, we have empirically obsd. that differential voltage pulsing can accelerate monolayer desorption from the sensor surface, presumably via field-induced actuation of aptamers. Here, in contrast, we demonstrate the potential advantages of employing cyclic voltammetry to measure electron-transfer changes directly. In our approach, the target concn. is reported via changes in the peak-to-peak sepn., ΔEP, of cyclic voltammograms. Because the magnitude of ΔEP is insensitive to variations in the no. of aptamer probes on the electrode, ΔEP-interrogated E-AB sensors are resistant to drift and show decreased batch-to-batch and day-to-day variability in sensor performance. Moreover, ΔEP-based measurements can also be performed in a few hundred milliseconds and are, thus, competitive with other subsecond interrogation strategies such as chronoamperometry but with the added benefit of retaining sensor capacitance information that can report on monolayer stability over time.
- 41Dauphin-Ducharme, P.; Yang, K.; Arroyo-Currás, N.; Ploense, K. L.; Zhang, Y.; Gerson, J.; Kurnik, M.; Kippin, T. E.; Stojanovic, M. N.; Plaxco, K. W. Electrochemical aptamer-based sensors for improved therapeutic drug monitoring and high-precision, feedback-controlled drug delivery. ACS Sens. 2019, 4, 2832– 2837, DOI: 10.1021/acssensors.9b01616Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVCnt7vM&md5=67cd35b6a26e364ac78a9c4339925c3bElectrochemical Aptamer-Based Sensors for Improved Therapeutic Drug Monitoring and High-Precision, Feedback-Controlled Drug DeliveryDauphin-Ducharme, Philippe; Yang, Kyungae; Arroyo-Curras, Netzahualcoyotl; Ploense, Kyle L.; Zhang, Yameng; Gerson, Julian; Kurnik, Martin; Kippin, Tod E.; Stojanovic, Milan N.; Plaxco, Kevin W.ACS Sensors (2019), 4 (10), 2832-2837CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)The Electrochem. Aptamer-Based (E-AB) sensing platform appears a convenient (rapid, single-step, calibration-free), modular approach to measure concns. of specific mols. (irresp. of their chem. reactivity) directly in blood and even in situ in the living body. Given these attributes, the platform may thus provide significant opportunities to render therapeutic drug monitoring (the clin. practice in which dosing is adjusted in response to plasma drug measurements) as frequent and convenient as the measurement of blood sugar has become for diabetics. The ability to measure arbitrary mols. in the body in real time could even enable closed-loop feedback control over plasma drug levels in a manner analogous to the recently commercialized controlled blood sugar systems. As initial exploration of this, the authors describe here the selection of an aptamer against vancomycin, a narrow therapeutic window antibiotic for which therapeutic monitoring is a crit. part of the std. of care, and its adaptation into an electrochem. aptamer-based (E-AB) sensor. Using this sensor the authors then demonstrate: (1) rapid (seconds), convenient (single-step, calibration-free) measurement of plasma vancomycin in finger-prick-scale samples of whole blood, (2) high-precision measurement of subject-specific vancomycin pharmacokinetics (in a rat animal model), and (3) high precision, closed-loop feedback control over plasma levels of the drug (in a rat animal model). The ability to not only track (with continuous-glucose-monitor-like measurement frequency and convenience), but also actively control plasma drug levels provides an unprecedented route towards improving therapeutic drug monitoring and, more generally, the personalized, high-precision delivery of pharmacol. interventions.
- 42Dilworth, T. J.; Schulz, L. T.; Rose, W. E. Vancomycin advanced therapeutic drug monitoring: Exercise in futility or virtuous endeavor to improve drug efficacy and safety?. Clin. Infect. Dis. 2021, 72, E675– E681, DOI: 10.1093/cid/ciaa1354Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtFyitrrM&md5=2f3c0a2778f415e29fe7469b17e551acVancomycin advanced therapeutic drug monitoring: exercise in futility or virtuous endeavor to improve drug efficacy and safety?Dilworth, Thomas J.; Schulz, Lucas T.; Rose, Warren E.Clinical Infectious Diseases (2021), 72 (10), e675-e681CODEN: CIDIEL; ISSN:1537-6591. (Oxford University Press)A review. Vancomycin is commonly prescribed to hospitalized patients. Decades of pharmacokinetic/pharmacodynamic research culminated in recommendations to monitor the ratio of the area under the concn.-time curve (AUC) to the min. inhibitory concn. in order to optimize vancomycin exposure and minimize toxicity in the revised 2020 guidelines. These guideline recommendations are based on limited data without high-quality evidence and limitations in strength. Despite considerable effort placed on vancomycin therapeutic drug monitoring (TDM), clinicians should recognize that the majority of vancomycin use is empiric. Most patients prescribed empiric vancomycin do not require it beyond a few days. For these patients, AUC detns. during the initial days of vancomycin exposure are futile. This added workload may detract from high-level patient care activities. Loading doses likely achieve AUC targets, so AUC monitoring after a loading dose is largely unnecessary for broad application. The excessive vancomycin TDM for decades has been propagated with limitations in evidence, and it should raise caution on contemporary vancomycin TDM recommendations.
- 43Groenewald, T. The dissolution of gold in acidic solutions of thiourea. Hydrometallurgy 1976, 1, 277– 290, DOI: 10.1016/0304-386x(76)90004-9Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE28XksV2lt74%253D&md5=e9d3db5e3b076ff2daee55970975a869The dissolution of gold in acidic solutions of thioureaGroenewald, T.Hydrometallurgy (1976), 1 (3), 277-90CODEN: HYDRDA; ISSN:0304-386X.Lab. expts. are described for the dissoln. of rotating disks of pure Au and on ground Au ores in acidic solns. of thiourea [62-56-6] contg. various oxidants including Fe(III), H2O2, O, and formamidine disulfide [3256-06-2]. The dissoln. rate of Au in these solns. approached the limiting diffusion controlled rate. Fe(III) caused the most rapid initial rate, but this rate soon decreased because of the reaction between Fe(III) and thiourea. The excessive amt. of thiourea consumed made the use of Fe(III) unattractive as the oxidant. In the leaching of crushed ore, a large proportion of the oxidant necessary for the extn. of the Au was derived from the ore. The addnl. oxidant was supplied as H2O2 during the prepn. of the leach liquor and by agitation of the slurry with air. When solns. contg. 1.2M thiourea were used, Au was extd. from the ore within 1 hr. When 0.1M thiourea was used, the complete extn. of Au required approx. 8 hr. In these cases the consumption of thiourea was 1.4 and 0.4 kg thiourea/ton, resp.
- 44Puscasu, A.; Zanchetta, M.; Posocco, B.; Bunka, D.; Tartaggia, S.; Toffoli, G. Development and validation of a selective spr aptasensor for the detection of anticancer drug irinotecan in human plasma samples. Anal. Bioanal. Chem. 2021, 413, 1225– 1236, DOI: 10.1007/s00216-020-03087-5Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXosVaqtg%253D%253D&md5=c207870dcab37e6ae2f53f33a995dd0eDevelopment and validation of a selective SPR aptasensor for the detection of anticancer drug irinotecan in human plasma samplesPuscasu, Adelina; Zanchetta, Martina; Posocco, Bianca; Bunka, David; Tartaggia, Stefano; Toffoli, GiuseppeAnalytical and Bioanalytical Chemistry (2021), 413 (4), 1225-1236CODEN: ABCNBP; ISSN:1618-2642. (Springer)In this work, a surface plasmon resonance (SPR)-based assay for the quantification of antineoplastic drug irinotecan in human plasma samples has been developed for the first time. The selective binding of irinotecan with an aptamer receptor, operating in human plasma, allowed to set-up a novel anal. methodol. to detect the drug in the anal. range of interest by using SPR as detection technique. After hybridizing the aptamer to the sensing platform and optimizing the sample prepn. procedure, a quant. assay was validated according to FDA regulatory guidelines. The anal. working range was found between 100 and 7500 ng mL-1 with negligible interferences from plasma components and co-medication assocd. with the administration of irinotecan. The utility of the new SPR assay was confirmed by analyzing plasma samples in parallel with LC-MS as ref. technique, providing a new anal. tool for the therapeutic drug monitoring of irinotecan in patients under chemotherapy regimens.
- 45Idili, A.; Arroyo-Currás, N.; Ploense, K. L.; Csordas, A. T.; Kuwahara, M.; Kippin, T. E.; Plaxco, K. W. Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living body. Chem. Sci. 2019, 10, 8164– 8170, DOI: 10.1039/c9sc01495kGoogle Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVWgsbfF&md5=ee902b2f4aed48c5f2fe348062001a38Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living bodyIdili, Andrea; Arroyo-Curras, Netzahualcoyotl; Ploense, Kyle L.; Csordas, Andrew T.; Kuwahara, Masayasu; Kippin, Tod E.; Plaxco, Kevin W.Chemical Science (2019), 10 (35), 8164-8170CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The ability to measure drugs in the body rapidly and in real time would advance both our understanding of pharmacokinetics and our ability to optimally dose and deliver pharmacol. therapies. To this end, we are developing electrochem. aptamer-based (E-AB) sensors, a seconds-resolved platform technol. that, as crit. for performing measurements in vivo, is reagentless, reversible, and selective enough to work when placed directly in bodily fluids. Here we describe the development of an E-AB sensor against irinotecan, a member of the camptothecin family of cancer chemotherapeutics, and its adaptation to in vivo sensing. To achieve this we first re-engineered (via truncation) a previously reported DNA aptamer against the camptothecins to support high-gain E-AB signaling. We then co-deposited the modified aptamer with an unstructured, redox-reporter-modified DNA sequence whose output was independent of target concn., rendering the sensor's signal gain a sufficiently strong function of square-wave frequency to support kinetic-differential-measurement drift correction. The resultant, 200 mum-diam., 3 mm-long sensor achieves 20 s-resolved, multi-hour measurements of plasma irinotecan when emplaced in the jugular veins of live rats, thus providing an unprecedentedly high-precision view into the pharmacokinetics of this class of chemotherapeutics.
- 46Chand, V. K.; Link, B. K.; Ritchie, J. M.; Shannon, M.; Wooldridge, J. E. Neutropenia and febrile neutropenia in patients with hodgkin’s lymphoma treated with doxorubicin (adriamycin), bleomycin, vinblastine and dacarbazine (abvd) chemotherapy. Leuk. Lymphoma 2006, 47, 657– 663, DOI: 10.1080/10428190500353430Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD283msF2nsw%253D%253D&md5=4f461b6aca7cfdafc0b10edde0cb9549Neutropenia and febrile neutropenia in patients with Hodgkin's lymphoma treated with doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapyChand Vikram K; Link Brian K; Ritchie Justine M; Shannon Mary; Wooldridge James ELeukemia & lymphoma (2006), 47 (4), 657-63 ISSN:1042-8194.When uncomplicated neutropenia during doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy for the treatment of Hodgkin's lymphoma is encountered, it is unclear whether or not treatment should be modified. In the present study, we determined the incidence of neutropenia, febrile neutropenia, and the relationship of febrile neutropenia to grade III/IV neutropenia and dose modification, in a large university patient population. We reviewed the charts of patients diagnosed with Hodgkin's lymphoma between 1 January 1990 and 31 December 2002 who were treated with ABVD chemotherapy, and seen at the University of Iowa with complete diagnosis, staging, and treatment dosing records. Adequate data was available on 894 treatments in 81 patients with Hodgkin's lymphoma treated with ABVD chemotherapy. Grade III/IV neutropenia was present on the scheduled day of treatment in 187 (20.9%) treatments in 64 (79%) patients. Grade III/IV neutropenia was most common at cycle 1 day 15. Febrile neutropenia developed nine times in eight patients, and eight episodes of febrile neutropenia developed when the treatment-day absolute neutrophil count (ANC) > or =1000. Dose delay of >4 days and/or dose reduction to <80% of original doxorubicin dose following grade III/IV neutropenia occurred in 29 of 187 treatments, with no episodes of febrile neutropenia. With grade III/IV neutropenia on the day of therapy, 158 treatments were administered without dose reduction or dose delay with one subsequent episode of febrile neutropenia. Neutropenia during ABVD is common, and dose modification for uncomplicated neutropenia on the day of treatment may not reduce the risk of febrile neutropenia. It may be possible to maintain dose intensity in the face of uncomplicated neutropenia during ABVD therapy.
- 47Pérez-Blanco, J. S.; Santos-Buelga, D.; Fernández de Gatta, M. d. M.; Hernández-Rivas, J. M.; Martín, A.; García, M. J. Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-hodgkin’s lymphoma. Br. J. Clin. Pharmacol. 2016, 82, 1517– 1527, DOI: 10.1111/bcp.13070Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhsl2hur%252FO&md5=8fd648e9039a502d988f0d3d9e628d69Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphomaPerez-Blanco, Jonas Samuel; Santos-Buelga, Dolores; Fernandez de Gatta, Maria del Mar; Hernandez-Rivas, Jesus Maria; Martin, Alejandro; Garcia, Maria JoseBritish Journal of Clinical Pharmacology (2016), 82 (6), 1517-1527CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Aims : The aims of the study were: (i) to characterize the pharmacokinetics (PK) of doxorubicin (DOX) and doxorubicinol (DOXol) in patients diagnosed with non-Hodgkin's lymphoma (NHL) using a population approach; (ii) to evaluate the influence of various covariates on the PK of DOX; and (iii) to evaluate the role of DOX and DOXol exposure in haematol. toxicity. Methods : Population PK modeling (using NONMEM) was performed using DOX and DOXol plasma concn.-time data from 45 NHL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The influence of drug exposure on haematol. toxicity was analyzed using the Mann-Whitney-Wilcoxon test. Results : A five-compartment model, three for DOX and two for DOXol, with first-order distribution and elimination for both entities best described the data. Population ests. for parent drug (CL) and metabolite (CLm) clearance were 62 l h-1 and 27 l h-1, resp. The fraction metabolized to DOXol (Fm) was estd. at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CLm, the objective function value decrease was not statistically significant. A trend towards an assocn. between the total area under the concn.-time curve (AUCtotal), the area under the concn.-time curve for DOX (AUC) plus the area under the concn.-time curve for DOXol (AUCm), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was obsd., according to an exponential relationship. Conclusions : The PK of DOX and DOXol were well characterized by the model developed, which could be used as a helpful tool to optimize the dosage of this drug. The results suggest that the main active metabolite of DOX, DOXol, is involved in the haematol. toxicity of the parent drug.
- 48Zhou, T.; Shen, Q.; Peng, H.; Chao, T.; Zhang, L.; Huang, L.; Yang, K.; Thapa, S.; Yu, S.; Jiang, Y. Incidence of interstitial pneumonitis in non-hodgkin’s lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab. Ann. Hematol. 2018, 97, 141– 147, DOI: 10.1007/s00277-017-3160-1Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslCmtrrP&md5=021d98c38137eac74f2c5f6404daaefaIncidence of interstitial pneumonitis in non-Hodgkin's lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximabZhou, Ting; Shen, Qian; Peng, Hui; Chao, Tengfei; Zhang, Lihong; Huang, Liu; Yang, Kaixiang; Thapa, Sudip; Yu, Shiying; Jiang, YongshengAnnals of Hematology (2018), 97 (1), 141-147CODEN: ANHEE8; ISSN:0939-5555. (Springer)Pneumonitis is a rare but severe and potentially fatal adverse effect in chemotherapy of lymphoma. This study is aimed to investigate the incidence of interstitial pneumonitis in non-Hodgkin's lymphoma (NHL) patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab. Lymphoma patients were retrospectively reviewed, and eligible patients were included in this study. According to the chemotherapy regimens, patients were classified in four groups: combination of vincristine, cyclophosphamide, doxorubicin, and prednisone (CHOP group) with rituximab (RCHOP group) and combination of vincristine, cyclophosphamide, pegylated liposomal doxorubicin and prednisone (CDOP group) with rituximab (RCDOP group). Incidence and severity of interstitial pneumonitis were compared among the four groups. Among 757 patients reviewed, 207 patients were included in final anal. Thirteen patients developed chemotherapy-induced interstitial pneumonitis, and the mean cycle of chemotherapy before the onset of pneumonitis was 4. Incidence rates of pneumonitis were 0, 1.8, 17.4, and 21.1% in CHOP, RCHOP, CDOP, and RCDOP groups, resp. (p < 0.001). The mean grades of pneumonitis were 0, 2, 2.5, and 3 in four groups, resp. (p < 0.001). After adjustment of confounders, chemotherapy regimens (OR 3.491, 95% CI 1.527-7.981, p = 0.003) and neutropenia in previous cycles (OR 2.186, 95% CI 1.281-3.731, p = 0.004) were independently assocd. with the incidence of pneumonitis. Interstitial pneumonitis should be highlighted in NHL patients who received more than 4 cycles of RCDOP chemotherapy regimen, esp. in those who had grade 4 neutropenia in the previous cycles of chemotherapy.
- 49Harris, S. M.; Mistry, P.; Freathy, C.; Brown, J. L.; Charlton, P. A. Antitumour activity of xr5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines. Br. J. Cancer 2005, 92, 722– 728, DOI: 10.1038/sj.bjc.6602403Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhsFWltLk%253D&md5=1d060067c6fe664fe87a8b9cf58d1defAntitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell linesHarris, S. M.; Mistry, P.; Freathy, C.; Brown, J. L.; Charlton, P. A.British Journal of Cancer (2005), 92 (4), 722-728CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)XR5944 (MLN944), a novel bis-phenazine, has demonstrated potent cytotoxic activity against a variety of murine and human tumor models. In the present study, the antitumor activity of XR5944 was investigated in combination with 5-fluorouracil (5-FU) or irinotecan in human colon carcinoma cell lines and xenografts. In vitro cytotoxicity of the combinations following exposure to the drugs sequentially or simultaneously was evaluated by the sulforhodamine-B assay and interactions were detd. using median-effect anal. Antagonism was obsd. (CI>1) following exposure of HT29 cells simultaneously to XR5944 and 5-FU or SN38 (active metabolite of irinotecan). In contrast, sequential exposure of either combination in either order demonstrated at least an additive response (CI ≤ 1). At least an additive response was also obsd. with these combinations in HCT116 cells regardless of schedule. Antitumor activity in HT29 xenografts in nude mice was enhanced by sequential administration of 5-FU (65 mg kg-1) or irinotecan (CPT-11) (35 mg kg-1) 48 h before XR5944 (5, 10, or 15 mg kg-1) compared to single agent treatment at the same or higher doses. Administration of irinotecan (35 mg kg-1) and XR5944 (15 mg kg-1) just 30 min apart yielded similar efficacy to sequential administration 48 h apart. All combinations were well tolerated. These data suggest that combinations of XR5944 with irinotecan or 5-FU are of significant interest in the treatment of colon cancer.
- 50Torrisi, R.; Orlando, L.; Ghisini, R.; Veronesi, P.; Intra, M.; Rocca, A.; Balduzzi, A.; Cardillo, A.; Goldhirsch, A.; Colleoni, M. A phase ii study of primary dose-dense sequential doxorubicin plus cyclophosphamide and docetaxel in ct4 breast cancer. Anticancer Res. 2006, 26, 3861– 3864Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1Gmt7jI&md5=4939ec804cea4596230dd885e9e9c45eA phase II study of primary dose-dense sequential doxorubicin plus cyclophosphamide and docetaxel in cT4 breast cancerTorrisi, R.; Orlando, L.; Ghisini, R.; Veronesi, P.; Intra, M.; Rocca, A.; Balduzzi, A.; Cardillo, A.; Goldhirsch, A.; Colleoni, M.Anticancer Research (2006), 26 (5B), 3861-3864CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)Dose-dense chemotherapy with anthracyclines and taxanes has improved either disease free survival or overall survival in high risk patients with early breast cancer. The activity and safety of a dose-dense schedule (q14 days) of adriamycin 60 mg/sqm and cyclophosphamide 600 mg/sqm (AC) × 4 cycles followed by docetaxel 75 mg/sqm for 4 cycles with hematopoietic support in patients with stage IIIB breast cancer was explored. Patients with ER ≥10% tumors received concomitant endocrine therapy with 3-mo triptorelin and letrozole. Fifteen patients with histol. proven cT4b (three patients) and cT4d (twelve patients) M0 breast cancer were enrolled. Median age was 48 years (range 25-66). Eight clin. responses including one pathol. complete remission (pCR), three stable disease (including minor responses) and four progression of disease, one during AC and three during taxotere, were obsd. Four patients had grade 3-4 non hematol. toxicities and all except one discontinued treatment. Due to the high rate of progressive disease, this schedule should not represent a std. option in cT4 breast cancer.
- 51Oakman, C.; Francis, P. A.; Crown, J.; Quinaux, E.; Buyse, M.; De Azambuja, E.; Margeli Vila, M.; Andersson, M.; Nordenskjöld, B.; Jakesz, R.; Thürlimann, B.; Gutiérrez, J.; Harvey, V.; Punzalan, L.; Dell’orto, P.; Larsimont, D.; Steinberg, I.; Gelber, R. D.; Piccart-Gebhart, M.; Viale, G.; Di Leo, A. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer-8-year results of the Breast International Group 02-98 phase III trial. Ann. Oncol. 2013, 24, 1203– 1211, DOI: 10.1093/annonc/mds627Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3ntFChtQ%253D%253D&md5=617171ca1973662d54d4f1758e09b129Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trialOakman C; Francis P A; Crown J; Quinaux E; Buyse M; De Azambuja E; Margeli Vila M; Andersson M; Nordenskjold B; Jakesz R; Thurlimann B; Gutierrez J; Harvey V; Punzalan L; Dell'orto P; Larsimont D; Steinberg I; Gelber R D; Piccart-Gebhart M; Viale G; Di Leo AAnnals of oncology : official journal of the European Society for Medical Oncology (2013), 24 (5), 1203-11 ISSN:.Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.
- 52Bailly, C. Topoisomerase i poisons and suppressors as anticancer drugs. Curr. Med. Chem. 2000, 7, 39– 58, DOI: 10.2174/0929867003375489Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXos1eqtg%253D%253D&md5=5f5d2c523f3afc63088126be99dc8435Topoisomerase I poisons and suppressors as anticancer drugsBailly, ChristianCurrent Medicinal Chemistry (2000), 7 (1), 39-58CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers)A review with 191 refs. Inhibitors of topoisomerase I constitute a novel family of antitumor agents. The camptothecin derivs. topotecan and irinotecan represent new weapons in our arsenal for battling human cancer. These two drugs act specifically at the level of the topoisomerase I-DNA complex and stimulate DNA cleavage. This mechanism of action is not restricted to the camptothecins. Numerous topoisomerase I poisons including DNA minor groove binders such as Hoechst 33258 and DNA intercalators such as benzophenanthridine alkaloids and indolocarbazole derivs. have been discovered and developed. Another important group of topoisomerase I inhibitors contains drugs which prevent or reverse topoisomerase I-DNA complex formation. Many of these topoisomerase I suppressors are natural products (β-lapachone, diospyrin, topostatin, topostin, flavonoids) which are believed to interact directly with the enzyme. This review is concerned with the different families of topoisomerase I poisons and suppressors. Their origin, chem. nature and mechanism of action are presented. The relationships between drug binding to DNA and topoisomerase I inhibition are discussed.
- 53Leung, K. K.; Downs, A. M.; Ortega, G.; Kurnik, M.; Plaxco, K. W. Elucidating the mechanisms underlying the signal drift of electrochemical aptamer-based sensors in whole blood. ACS Sens. 2021, 6, 3340– 3347, DOI: 10.1021/acssensors.1c01183Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFGhtL%252FO&md5=3f8ec70b9f33aed205bc18aaf3481c81Elucidating the Mechanisms Underlying the Signal Drift of Electrochemical Aptamer-Based Sensors in Whole BloodLeung, Kaylyn K.; Downs, Alex M.; Ortega, Gabriel; Kurnik, Martin; Plaxco, Kevin W.ACS Sensors (2021), 6 (9), 3340-3347CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)The ability to monitor drugs, metabolites, hormones, and other biomarkers in situ in the body would greatly advance both clin. practice and biomedical research. To this end, we are developing electrochem. aptamer-based (EAB) sensors, a platform technol. able to perform real-time, in vivo monitoring of specific mols. irresp. of their chem. or enzymic reactivity. An important obstacle to the deployment of EAB sensors in the challenging environments found in the living body is signal drift, whereby the sensor signal decreases over time. To date, we have demonstrated a no. of approaches by which this drift can be cor. sufficiently well to achieve good measurement precision over multihour in vivo deployments. To achieve a much longer in vivo measurement duration, however, will likely require that we understand and address the sources of this effect. In response, here, we have systematically examd. the mechanisms underlying the drift seen when EAB sensors and simpler, EAB-like devices are challenged in vitro at 37°C in whole blood as a proxy for in vivo conditions. Our results demonstrate that electrochem. driven desorption of a self-assembled monolayer and fouling by blood components are the two primary sources of signal loss under these conditions, suggesting targeted approaches to remediating this degrdn. and thus improving the stability of EAB sensors and other, similar electrochem. biosensor technologies when deployed in the body.
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Abstract
Figure 1
Figure 1. Wearable microneedle aptamer-based sensors for continuous, real-time therapeutic drug monitoring. (A) Our wearable microneedle sensor patch is designed to allow painless on-body molecular tracking in research animals. The patch consists of a microneedle sensor array integrated with electronics and a battery, all contained within a wearable case. The sensor array contains 16 gold working, 4 platinum counter, and one central reference microneedles with a form factor that allows painless penetration of the upper strata of the reticular dermis. (B) At the core of our sensing technology are electrochemical aptamer-based (E-AB) sensors, which consist of a mixed self-assembled monolayer of electrode-blocking alkanethiols with alkanethiol- and redox reporter-modified aptamers. In the presence of a target, the aptamers undergo reversible binding-induced conformational changes that affect electron transfer (eT) between the reporter and the gold needles. This sensing mechanism is reversible. (C) To enable continuous drug monitoring, the sensors are serially interrogated by square-wave voltammetry (SWV) with a time interval between 4.5 and 12 s. The sensors can be calibrated at the point of manufacture by building target titration curves, allowing correlation of current changes to changes in target concentration.
Figure 2
Figure 2. Microneedle E-AB sensor arrays support real-time molecular monitoring in vitro. (A) 3D-printed flow cell for continuous molecular monitoring. The microneedle sensor array is glued at the bottom of the cell and connected to a hand-held potentiostat to enable serial electrochemical interrogation. (B) Micrograph showing blunt microneedles used for rapid testing. The microneedle height is ∼2.3 mm, and the diameter ∼170 μm. We functionalized these using tobramycin-binding aptamers, which are modified to have covalently attached alkanethiol linkers and the redox reporter methylene blue. (C) Microneedle E-AB sensor arrays (MNs) achieve identical calibration curves relative to sensors fabricated on commercial disc macroelectrodes (MEs, 2 mm in diameter). Circles represent the average of six sensors fabricated on MEs; diamonds represent the average of three sensors fabricated on MNs; error bars represent their standard deviation. (D) Continuous, real-time monitoring of tobramycin in the flow system. Voltammetric measurements were performed every 4.5 s in 20 mM Tris, 100 mM NaCl, 5 mM MgCl2 (pH = 7.4). (E) Kinetic differential measurements (KDM) obtained after subtracting the data collected at 150 Hz (signal-off output) from data collected at 800 Hz (signal-on output).
Figure 3
Figure 3. Microneedle arrays can be reused multiple times. The newly developed chemical and electrochemical cleaning protocol reported in this work allows the reuse of microneedle devices multiple times during rapid prototyping and testing. (A) Here, for example, we show the performance of E-ABs fabricated on a single device that was reused three times. The colored data corresponds to the average of three identical measurements performed on the same device after each round of cleaning and functionalization with aptamers. Baseline peak currents at 800 Hz are ∼9 ± 0.5 mA. The shaded areas indicate the standard deviation between measurements. (B) Use of KDM for baseline correction further highlights the reproducibility achieved via the cleaning protocol. (C) For reference, untreated microneedles show lower signal output and higher baseline noise. Baseline peak currents at 800 Hz are ∼1.8 mA, 80% lower than the currents for treated microneedles.
Figure 4
Figure 4. Dual-channel microneedle E-AB devices enable simultaneous evaluation of aptamer specificity. (A) Different from Figure 2A, the 3D-printed cell was adapted to have two separate injection lines at opposite sides of the central support. By connecting these lines to the syringe pump, we could automatically inject and mix the prodrug irinotecan and its major metabolite SN-38 in the left and right chambers, respectively. (B) We functionalized the microneedles in both chambers with irinotecan-binding aptamers. In the presence of irinotecan, the E-AB sensors undergo binding-induced changes in eT between the reporter and the microneedles. However, the metabolite SN-38 induces minor conformational changes relative to irinotecan binding. (C) Microneedle E-AB sensor arrays display higher signal gain when challenged with irinotecan than with the metabolite SN-38 at square-wave frequencies of 100 Hz. (D) Demonstration of continuous, reproducible irinotecan monitoring following three boluses at a target concentration of 2 μM irinotecan in the left chamber. (E) Similarly, when challenging the right chamber with the metabolite SN-38, lower gains were obtained following three serial boluses. Voltammetric measurements were performed every 11 s in 20 mM phosphate solution containing 137 mM NaCl, 2.7 mM KCl, 2 mM MgCl2, and 1 mM CaCl2 (pH = 6.0).
Figure 5
Figure 5. Dual-channel microneedle E-AB devices enable multiplexed sensing. (A) We functionalized the microneedles in each chamber with either irinotecan-binding or doxorubicin-binding aptamers. (B) Mean calibration curves of six irinotecan-binding and doxorubicin-binding E-ABs obtained using commercial disc macroelectrodes (2 mm in diameter) demonstrate that both sensors showed high affinity when challenged with their targets. (C) When simultaneously injecting irinotecan and doxorubicin in either chamber of the microneedle device, it was possible to successfully monitor E-AB signals induced by target binding to the respective E-ABs. In the case of the irinotecan-binding sensor, irinotecan boluses of increasing concentrations produced corresponding E-AB responses. Challenging the same E-ABs with doxorubicin, a known DNA intercalator, also produced large signal changes. (D) Likewise, challenging the doxorubicin-binding E-ABs with doxorubicin boluses of increasing concentration caused proportional E-AB responses. Challenging these sensors with 4 μM irinotecan did not induce E-AB signal changes. Voltammetric measurements were performed every 12 s in 20 mM phosphate, 137 mM NaCl, 2.7 mM KCl, 2 mM MgCl2, and 1 mM CaCl2 (pH = 6.0).
Figure 6
Figure 6. Continuous molecular monitoring of tobramycin concentration in ISF. Proof-of-concept monitoring of tobramycin levels in the dermis of one rat following IV administration of the drug at a dose of 20 mg/kg. (A) We fabricated sharper microneedles that were 150 μm in diameter and 1.1 mm in length. (B) The microneedles were placed on the freshly shaved abdomen of one male rat. (C) Removal of the device from the skin revealed the expected pattern of micropunctures. (D) H&E-stained skin tissue illustrating different histological features of the rat’s skin and one penetrating track left after insertion of the microneedles. (E) Hue- and contrast-adjusted duplicate image highlighting the track mark after microneedle removal. (F) Although noisy, electrochemical interrogation of the microneedle array resulted in discernible square-wave voltammograms in ISF that strongly responded to tobramycin following an IV bolus injected into the right jugular vein of the rat (drop from blue to orange). (G) Real-time processing of the voltammograms using SACMES allowed us to visualize the sensor response, here plotted as relative signal after tobramycin dosing. SACMES uses rolling average and polynomial fit algorithms to remove noise from voltammograms, thus enabling the extraction of high signal-to-noise E-AB data. Unfortunately, progressive degradation of the sensors in ISF made it impossible to distinguish signals past t = 60 min. The red line shows a regression analysis to a two-compartment drug absorption pharmacokinetic model using the data points available.
References
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- 2Arroyo-Currás, N.; Ortega, G.; Copp, D. A.; Ploense, K. L.; Plaxco, Z. A.; Kippin, T. E.; Hespanha, J. P.; Plaxco, K. W. High-precision control of plasma drug levels using feedback-controlled dosing. ACS Pharmacol. Transl. Sci. 2018, 1, 110– 118, DOI: 10.1021/acsptsci.8b000332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVGlsrfO&md5=b35cad3fe9f053d0651e69e6ad1c9e44High-Precision Control of Plasma Drug Levels Using Feedback-Controlled DosingArroyo-Curras, Netzahualcoyotl; Ortega, Gabriel; Copp, David A.; Ploense, Kyle L.; Plaxco, Zoe A.; Kippin, Tod E.; Hespanha, Joao P.; Plaxco, Kevin W.ACS Pharmacology & Translational Science (2018), 1 (2), 110-118CODEN: APTSFN; ISSN:2575-9108. (American Chemical Society)By, in effect, rendering pharmacokinetics an exptl. adjustable parameter, the ability to perform feedback-controlled dosing informed by high-frequency in vivo drug measurements would prove a powerful tool for both pharmacol. research and clin. practice. Efforts to this end, however, have historically been thwarted by an inability to measure in vivo drug levels in real time and with sufficient convenience and temporal resoln. In response, we describe a closed-loop, feedback-controlled delivery system that uses drug level measurements provided by an in vivo electrochem. aptamer-based (E-AB) sensor to adjust dosing rates every 7 s. The resulting system supports the maintenance of either const. or predefined time-varying plasma drug concn. profiles in live rats over many hours. For researchers, the resultant high-precision control over drug plasma concns. provides an unprecedented opportunity to (1) map the relationships between pharmacokinetics and clin. outcomes, (2) eliminate inter- and intrasubject metabolic variation as a confounding exptl. variable, (3) accurately simulate human pharmacokinetics in animal models, and (4) measure minute-to-minute changes in a drug's pharmacokinetic behavior in response to changing health status, diet, drug-drug interactions, or other intrinsic and external factors. In the clinic, feedback-controlled drug delivery would improve our ability to accurately maintain therapeutic drug levels in the face of large, often unpredictable intra- and interpatient metabolic variation. This, in turn, would improve the efficacy and safety of therapeutic intervention, particularly for the most gravely ill patients, for whom metabolic variability is highest and the margin for therapeutic error is smallest.
- 3Arroyo-Currás, N.; Somerson, J.; Vieira, P. A.; Ploense, K. L.; Kippin, T. E.; Plaxco, K. W. Real-time measurement of small molecules directly in awake, ambulatory animals. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, 645– 650, DOI: 10.1073/pnas.16134581143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmslWktA%253D%253D&md5=04842755081ae2272a933ce3461cd953Real-time measurement of small molecules directly in awake, ambulatory animalsArroyo-Curras, Netzahualcoyotl; Somerson, Jacob; Vieira, Philip A.; Ploense, Kyle L.; Kippin, Tod E.; Plaxco, Kevin W.Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (4), 645-650CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The development of a technol. capable of tracking the levels of drugs, metabolites, and biomarkers in the body continuously and in real time would advance our understanding of health and our ability to detect and treat disease. It would, for example, enable therapies guided by high-resoln., patient-specific pharmacokinetics (including feedback-controlled drug delivery), opening new dimensions in personalized medicine. In response, we demonstrate here the ability of electrochem. aptamer-based (E-AB) sensors to support continuous, real-time, multihour measurements when emplaced directly in the circulatory systems of living animals. Specifically, we have used E-AB sensors to perform the multihour, real-time measurement of four drugs in the bloodstream of even awake, ambulatory rats, achieving precise mol. measurements at clin. relevant detection limits and high (3 s) temporal resoln., attributes suggesting that the approach could provide an important window into the study of physiol. and pharmacokinetics.
- 4Vieira, P. A.; Shin, C. B.; Arroyo-Currás, N.; Ortega, G.; Li, W.; Keller, A. A.; Plaxco, K. W.; Kippin, T. E. Ultra-high-precision, in-vivo pharmacokinetic measurements highlight the need for and a route toward more highly personalized medicine. Front. Mol. Biosci. 2019, 6, 69, DOI: 10.3389/fmolb.2019.000694https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXms1Wms78%253D&md5=f802c240c1a5e4f8fe4b5f718f6fbf8dUltra-high-precision, in-vivo pharmacokinetic measurements highlight the need for and a route toward more highly personalized medicineVieira, Philip A.; Shin, Christina B.; Arroyo-Curras, Netzahualcoyotl; Ortega, Gabriel; Li, Weiwei; Keller, Arturo A.; Plaxco, Kevin W.; Kippin, Tod E.Frontiers in Molecular Biosciences (2019), 6 (), 69CODEN: FMBRBS; ISSN:2296-889X. (Frontiers Media S.A.)A review. Clin. drug dosing would, ideally, be informed by high-precision, patient-specific data on drug metab. The direct detn. of patient-specific drug pharmacokinetics ("peaks and troughs"), however, currently relies on cumbersome, lab.-based approaches that require hours to days to return pharmacokinetic ests. based on only one or two plasma drug measurements. In response clinicians often base dosing on age, body mass, pharmacogenetic markers, or other indirect estimators of pharmacokinetics despite the relatively low accuracy of these approaches. Here, in contrast, we explore the use of indwelling electrochem. aptamer-based (E-AB) sensors as a means of measuring pharmacokinetics rapidly and with high precision using a rat animal model. Specifically, measuring the disposition kinetics of the drug tobramycin in Sprague-Dawley rats we demonstrate the seconds resolved, real-time measurement of plasma drug levels accompanied by measurement validation via HPLC-MS on ex vivo samples. The resultant data illustrate the significant pharmacokinetic variability of this drug even when dosing is adjusted using body wt. or body surface area, two widely used pharmacokinetic predictors for this important class of antibiotics, highlighting the need for improved methods of detg. its pharmacokinetics.
- 5Wolkowicz, K. L.; Aiello, E. M.; Vargas, E.; Teymourian, H.; Tehrani, F.; Wang, J.; Pinsker, J. E.; Doyle, F. J., 3rd; Patti, M. E.; Laffel, L. M.; Dassau, E. A review of biomarkers in the context of type 1 diabetes: Biological sensing for enhanced glucose control. Bioeng. Transl. Med. 2021, 6, e10201 DOI: 10.1002/btm2.102015https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1yrurzM&md5=9c63251fb79cdcdac7856ef612f118d8A review of biomarkers in the context of type 1 diabetes: Biological sensing for enhanced glucose controlWolkowicz, Kelilah L.; Aiello, Eleonora M.; Vargas, Eva; Teymourian, Hazhir; Tehrani, Farshad; Wang, Joseph; Pinsker, Jordan E.; Doyle, Francis J. III; Patti, Mary-Elizabeth; Laffel, Lori M.; Dassau, EyalBioengineering & Translational Medicine (2021), 6 (2), e10201CODEN: BTMIAQ; ISSN:2380-6761. (John Wiley & Sons, Inc.)A review. As wearable healthcare monitoring systems advance, there is immense potential for biol. sensing to enhance the management of type 1 diabetes (T1D). The aim of this work is to describe the ongoing development of biomarker analytes in the context of T1D. Technol. advances in transdermal biosensing offer remarkable opportunities to move from research labs. to clin. point-of-care applications. In this review, a range of analytes, including glucose, insulin, glucagon, cortisol, lactate, epinephrine, and alc., as well as ketones such as beta-hydroxybutyrate, will be evaluated to det. the current status and research direction of those analytes specifically relevant to T1D management, using both in-vitro and on-body detection. Understanding state-of-the-art developments in biosensing technologies will aid in bridging the gap from bench-to-clinic T1D analyte measurement advancement.
- 6Aiello, E. M.; Deshpande, S.; Özaslan, B.; Wolkowicz, K. L.; Dassau, E.; Pinsker, J. E.; Doyle, F. J. Review of automated insulin delivery systems for individuals with type 1 diabetes: Tailored solutions for subpopulations. Curr. Opin. Biomed. Eng. 2021, 19, 100312, DOI: 10.1016/j.cobme.2021.1003126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVGrurzN&md5=53265677f8577011c950e788f6ca0f9cReview of automated insulin delivery systems for individuals with type 1 diabetes: tailored solutions for subpopulationsAiello, Eleonora M.; Deshpande, Sunil; Ozaslan, Basak; Wolkowicz, Kelilah L.; Dassau, Eyal; Pinsker, Jordan E.; Doyle, Francis J. IIICurrent Opinion in Biomedical Engineering (2021), 19 (), 100312CODEN: COBEB4; ISSN:2468-4511. (Elsevier Inc.)A review. Automated insulin delivery (AID) systems have proven safe and effective in improving glycemic outcomes in individuals with type 1 diabetes. Clin. evaluation of this technol. has progressed to large randomized, controlled outpatient studies and recent com. approval of AID systems for children and adults. However, several challenges remain in improving these systems for different subpopulations (e.g. young children, athletes, pregnant women, seniors, and those with hypoglycemia unawareness). In this review, we highlight the requirements and challenges in AID design for selected subpopulations and discuss current advances from recent clin. studies.
- 7Li, J.; Liang, J. Y.; Laken, S. J.; Langer, R.; Traverso, G. Clinical opportunities for continuous biosensing and closed-loop therapies. Trends Chem. 2020, 2, 319– 340, DOI: 10.1016/j.trechm.2020.02.0097https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslejsL%252FJ&md5=6c2fe008aa2832b4d175f4b309fa94f1Clinical Opportunities for Continuous Biosensing and Closed-Loop TherapiesLi, Jason; Liang, Jia Y.; Laken, Steven J.; Langer, Robert; Traverso, GiovanniTrends in Chemistry (2020), 2 (4), 319-340CODEN: TCRHBQ; ISSN:2589-5974. (Cell Press)A review. Continuous glucose monitors (CGMs) and closed-loop drug delivery systems have revolutionized patient care in diabetes and anesthesia. Here, we review the current state of continuous chem. sensor development, titratable drug delivery systems, and closed-loop therapies to identify clin. meaningful trends that, if realized, can have significant impact on medical practice and patient outcome. In particular, we focus on novel wearable and implantable demonstrations that stand to redefine the patient experience. Finally, we put forth a roadmap towards identifying crit. unmet clin. opportunities to motivate future technol. development towards applications beyond glucose, to both improve patient care across diverse fields of medicine and realize the full potential of these technologies to improve therapeutic outcome.
- 8Ferguson, B. S.; Hoggarth, D. A.; Maliniak, D.; Ploense, K.; White, R. J.; Woodward, N.; Hsieh, K.; Bonham, A. J.; Eisenstein, M.; Kippin, T. E.; Plaxco, K. W.; Soh, H. T. Real-time, aptamer-based tracking of circulating therapeutic agents in living animals. Sci. Transl. Med. 2013, 5, 213ra165, DOI: 10.1126/scitranslmed.3007095There is no corresponding record for this reference.
- 9Arroyo-Currás, N.; Dauphin-Ducharme, P.; Ortega, G.; Ploense, K. L.; Kippin, T. E.; Plaxco, K. W. Subsecond-resolved molecular measurements in the living body using chronoamperometrically interrogated aptamer-based sensors. ACS Sens. 2018, 3, 360– 366, DOI: 10.1021/acssensors.7b007879https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslynu7nL&md5=71345b6d63ba81e4474706be1d55091dSubsecond-Resolved Molecular Measurements in the Living Body Using Chronoamperometrically Interrogated Aptamer-Based SensorsArroyo-Curras, Netzahualcoyotl; Dauphin-Ducharme, Philippe; Ortega, Gabriel; Ploense, Kyle L.; Kippin, Tod E.; Plaxco, Kevin W.ACS Sensors (2018), 3 (2), 360-366CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)Electrochem., aptamer-based (E-AB) sensors support the continuous, real-time measurement of specific small mols. directly in situ in the living body over the course of many hours. They achieve this by employing binding-induced conformational changes to alter electron transfer from a redox-reporter-modified, electrode-attached aptamer. Previously the authors have used voltammetry (cyclic, a.c., and square wave) to monitor this binding-induced change in transfer kinetics indirectly. Here, however, the authors demonstrate the potential advantages of employing chronoamperometry to measure the change in kinetics directly. In this approach target concn. is reported via changes in the lifetime of the exponential current decay seen when the sensor is subjected to a potential step. Because the lifetime of this decay is independent of its amplitude (e.g., insensitive to variations in the no. of aptamer probes on the electrode), chronoamperometrically interrogated E-AB sensors are calibration-free and resistant to drift. Chronoamperometric measurements can also be performed in a few hundred milliseconds, improving the previous few-second time resoln. of E-AB sensing by an order of magnitude. To illustrate the potential value of the approach the authors demonstrate here the calibration-free measurement of the drug tobramycin in situ in the living body with 300 ms time resoln. and unprecedented, few-percent precision in the detn. of its pharmacokinetic phases.
- 10Falagas, M. E.; Karageorgopoulos, D. E. Adjustment of dosing of antimicrobial agents for bodyweight in adults. Lancet 2010, 375, 248– 251, DOI: 10.1016/s0140-6736(09)60743-110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c%252FlslGitA%253D%253D&md5=2ff938785d3b73c0374b198192d1787aAdjustment of dosing of antimicrobial agents for bodyweight in adultsFalagas Matthew E; Karageorgopoulos Drosos ELancet (London, England) (2010), 375 (9710), 248-51 ISSN:.There is no expanded citation for this reference.
- 11Shuter, B.; Aslani, A. Body surface area: Du bois and du bois revisited. Eur. J. Appl. Physiol. 2000, 82, 250– 254, DOI: 10.1007/s00421005067911https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3M%252FjsFSgsg%253D%253D&md5=61b4b1fa1755f2f4aaca173630040cc8Body surface area: Du Bois and Du Bois revisitedShuter B; Aslani AEuropean journal of applied physiology (2000), 82 (3), 250-4 ISSN:1439-6319.The Du Bois and Du Bois body surface area (BSA) equation is used widely to normalise physiological parameters. However, that only nine subjects were used in its derivation does not appear to be well known and does not justify its ubiquitous application. Furthermore, the derivation appears to be hampered by a lack of modern statistical methods and the omission of a large amount of available data. We have shown that the omitted data, obtained by measurement of the length of body parts, were identical to the data obtained by encasing subjects in moulds BSA (moulds; cm2) = [1.00 (0.02)] x BSA (linear measurements) + [123 (347)] . Non-linear regression analysis of the BSA of all 42 subjects reported by Du Bois and Du Bois gave new values for the constants of the model BSA (cm2) = 94.9 x [weight (kg)0.441] x [height (cm)0.655] . Although the original equation obtained by Du Bois and Du Bois was found to be adequate in adults, we recommend that it should not be used in daily practice, owing to the low number of subjects used in its derivation. The work presented here has placed the original results of Du Bois and Du Bois on a more robust statistical footing, yielding values for the model constants that would have been obtained if Du Bois and Du Bois had had access to modern statistical methods.
- 12Neely, M. N.; Kato, L.; Youn, G.; Kraler, L.; Bayard, D.; van Guilder, M.; Schumitzky, A.; Yamada, W.; Jones, B.; Minejima, E. Prospective trial on the use of trough concentration versus area under the curve to determine therapeutic vancomycin dosing. Antimicrob. Agents Chemother. 2018, 62, e02042 DOI: 10.1128/AAC.02042-17There is no corresponding record for this reference.
- 13Zhang, T.; Cai, S.; Forrest, W. C.; Mohr, E.; Yang, Q.; Forrest, M. L. Development and validation of an inductively coupled plasma mass spectrometry (icp-ms) method for quantitative analysis of platinum in plasma, urine, and tissues. Appl. Spectrosc. 2016, 70, 1529– 1536, DOI: 10.1177/000370281666260713https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVOntrs%253D&md5=b77d346ad9611570b54ecc77fa6c4788Development and validation of an inductively coupled plasma mass spectrometry (ICP-MS) method for quantitative analysis of platinum in plasma, urine, and tissuesZhang, Ti; Cai, Shuang; Forrest, Wai Chee; Mohr, Eva; Yang, Qiuhong; Forrest, M. LairdApplied Spectroscopy (2016), 70 (9), 1529-1536CODEN: APSPA4; ISSN:0003-7028. (Sage Publications)Cisplatin, a platinum chemotherapeutic, is one of the most commonly used chemotherapeutic agents for many solid tumors. In this work, we developed and validated an inductively coupled plasma mass spectrometry (ICP-MS) method for quant. detn. of platinum levels in rat urine, plasma, and tissue matrixes including liver, brain, lungs, kidney, muscle, heart, spleen, bladder, and lymph nodes. The tissues were processed using a microwave accelerated reaction system (MARS) system prior to anal. on an Agilent 7500 ICP-MS. According to the Food and Drug Administration guidance for industry, bioanal. validation parameters of the method, such as selectivity, accuracy, precision, recovery, and stability were evaluated in rat biol. samples. Our data suggested that the method was selective for platinum without interferences caused by other presenting elements, and the lower limit of quantification was 0.5 ppb. The accuracy and precision of the method were within 15% variation and the recoveries of platinum for all tissue matrixes examd. were detd. to be 85-115% of the theor. values. The stability of the platinum-contg. solns., including calibration stds., stock solns., and processed samples in rat biol. matrixes was investigated. Results indicated that the samples were stable after three cycles of freeze-thaw and for up to three months.
- 14Zhong, X.; Tong, X.; Ju, Y.; Du, X.; Li, Y. Interpersonal factors in the pharmacokinetics and pharmacodynamics of voriconazole: Are cyp2c19 genotypes enough for us to make a clinical decision?. Curr. Drug Metab. 2018, 19, 1152– 1158, DOI: 10.2174/138920021966617122720054714https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsl2ntw%253D%253D&md5=647959d96d5eabb0a5c7ce188ca2a054Interpersonal Factors in the Pharmacokinetics and Pharmacodynamics of Voriconazole: Are CYP2C19 Genotypes Enough for Us to Make a Clinical DecisionZhong, Xuefeng; Tong, Xunliang; Ju, Yang; Du, Xiaoman; Li, YanmingCurrent Drug Metabolism (2018), 19 (14), 1152-1158CODEN: CDMUBU; ISSN:1389-2002. (Bentham Science Publishers Ltd.)A review. Objective: We reviewed studies on how genotypes affect the pharmacokinetics and pharmacodynamics of voriconazole, and attempted to det. a method to decide on dosage adjustments based on genotypes, after which, the main characteristic of voriconazole was clarified in details. The pharmacokinetics of voriconazole are influenced by various inter and intrapersonal factors, and for certain populations, such as geriatric patients and pediatric patients, these influences must be considered. CYP2C19 genotype represents the main part of the interpersonal variability related to voriconazole blood concns. Thus monitoring the concn. of voriconazole is needed in clin. scenarios to minimize the neg. influences of inter and intrapersonal factors. Several studies provided evidence on the stable trough concn. range from 1-2 to 4-6 mg/L, which was combined to consider the efficacy and toxicity. However, the therapeutic drug concn. needs to be narrowed down and evaluated by large-scale clin. trials. Conclusion: Though there is insufficient evidence on the relationship between CYP2C19 genotypes and clin. outcomes, there is a great potential for the initial voriconazole dose selection to be guided by the CYP2C19 genotype. Finally, voriconazole therapeutic drug monitoring is essential to provide patient-specific dosing recommendations, leading to more effective anti-fungal regimens to increase clin. efficacy and reduce adverse drug reactions.
- 15Payne, K. D.; Hall, R. G. Dosing of antibacterial agents in obese adults: does one size fit all?. Expert Rev. Anti-Infect. Ther. 2014, 12, 829– 854, DOI: 10.1586/14787210.2014.91294215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpsVGlsL4%253D&md5=eae045e59c32a4a92d9120088a53bcd7Dosing of antibacterial agents in obese adults: does one size fit all?Payne, Kenna D.; Hall, Ronald G, IIExpert Review of Anti-Infective Therapy (2014), 12 (7), 829-854CODEN: ERATCK; ISSN:1478-7210. (Informa Healthcare)A review. Obesity is a global pandemic affecting 33% of adults in the United States. Obese persons receiving cefazolin or fluconazole have been shown to have worse outcomes with suboptimal dosing. Studies evaluating the safety of colistin, daptomycin, and vancomycin have shown increased wt. or obesity may potentially increase toxicity. Many antimicrobials lack pharmacokinetic data to support dose individuation in obese persons, due in part to the lack of obese patients in drug development studies. A one size fits all approach to dose optimization for obese patients is not likely. Current expert opinion suggests some antimicrobials (i.e. vancomycin) be dosed according to total body wt., whereas others (i.e. aminoglycosides) require adjusted body wt. for dose calcns. Yet other antimicrobials are reported to need no dose adjustment, largely based on studies using body mass index groups. Therefore, each drug should be individually evaluated to det. the proper dose for obese persons.
- 16Tran, B. Q.; Miller, P. R.; Taylor, R. M.; Boyd, G.; Mach, P. M.; Rosenzweig, C. N.; Baca, J. T.; Polsky, R.; Glaros, T. Proteomic characterization of dermal interstitial fluid extracted using a novel microneedle-assisted technique. J. Proteome Res. 2018, 17, 479– 485, DOI: 10.1021/acs.jproteome.7b0064216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVGgtrzO&md5=d471d7ccc19eee31fad145b85b30096cProteomic Characterization of Dermal Interstitial Fluid Extracted Using a Novel Microneedle-Assisted TechniqueTran, Bao Quoc; Miller, Philip R.; Taylor, Robert M.; Boyd, Gabrielle; Mach, Phillip M.; Rosenzweig, C. Nicole; Baca, Justin T.; Polsky, Ronen; Glaros, TrevorJournal of Proteome Research (2018), 17 (1), 479-485CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)As wearable fitness devices have gained com. acceptance, interest in real-time monitoring of an individual's physiol. status using noninvasive techniques has grown. Microneedles have been proposed as a minimally invasive technique for sampling the dermal interstitial fluid (ISF) for clin. monitoring and diagnosis, but little is known about its compn. In this study, a novel microneedle array was used to collect dermal ISF from three healthy human donors and compared with matching serum and plasma samples. Using a shotgun quant. proteomic approach, 407 proteins were quantified with at least one unique peptide, and of those, 135 proteins were differently expressed at least 2-fold. Collectively, these proteins tended to originate from the cytoplasm, membrane bound vesicles, and extracellular vesicular exosomes. Proteomic anal. confirmed previously published work that indicates that ISF is highly similar to both plasma and serum. In this study, less than one percent of proteins were uniquely identified in ISF. Taken together, ISF could serve as a minimally invasive alternative for blood-derived fluids with potential for real-time monitoring applications.
- 17Samant, P. P.; Niedzwiecki, M. M.; Raviele, N.; Tran, V.; Mena-Lapaix, J.; Walker, D. I.; Felner, E. I.; Jones, D. P.; Miller, G. W.; Prausnitz, M. R. Sampling interstitial fluid from human skin using a microneedle patch. Sci. Transl. Med. 2020, 12, eaaw0285 DOI: 10.1126/scitranslmed.aaw0285There is no corresponding record for this reference.
- 18Siegmund, T.; Heinemann, L.; Kolassa, R.; Thomas, A. Discrepancies Between Blood Glucose and Interstitial Glucose-Technological Artifacts or Physiology: Implications for Selection of the Appropriate Therapeutic Target. J. Diabetes Sci. Technol. 2017, 11, 766– 772, DOI: 10.1177/193229681769963718https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czptVGqsg%253D%253D&md5=4810205e57fc783ee9b0f0016d0cf9f5Discrepancies Between Blood Glucose and Interstitial Glucose-Technological Artifacts or Physiology: Implications for Selection of the Appropriate Therapeutic TargetSiegmund Thorsten; Heinemann Lutz; Kolassa Ralf; Thomas AndreasJournal of diabetes science and technology (2017), 11 (4), 766-772 ISSN:.BACKGROUND: For decades, the major source of information used to make therapeutic decisions by patients with diabetes has been glucose measurements using capillary blood samples. Knowledge gained from clinical studies, for example, on the impact of metabolic control on diabetes-related complications, is based on such measurements. Different to traditional blood glucose measurement systems, systems for continuous glucose monitoring (CGM) measure glucose in interstitial fluid (ISF). The assumption is that glucose levels in blood and ISF are practically the same and that the information provided can be used interchangeably. Thus, therapeutic decisions, that is, the selection of insulin doses, are based on CGM system results interpreted as though they were blood glucose values. METHODS: We performed a more detailed analysis and interpretation of glucose profiles obtained with CGM in situations with high glucose dynamics to evaluate this potentially misleading assumption. RESULTS: Considering physical activity, hypoglycemic episodes, and meal-related differences between glucose levels in blood and ISF uncover clinically relevant differences that can make it risky from a therapeutic point of view to use blood glucose for therapeutic decisions. CONCLUSIONS: Further systematic and structured evaluation as to whether the use of ISF glucose is more safe and efficient when it comes to acute therapeutic decisions is necessary. These data might also have a higher prognostic relevance when it comes to long-term metabolic consequences of diabetes. In the long run, it may be reasonable to abandon blood glucose measurements as the basis for diabetes management and switch to using ISF glucose as the appropriate therapeutic target.
- 19Teymourian, H.; Tehrani, F.; Mahato, K.; Wang, J. Lab under the skin: Microneedle based wearable devices. Adv. Healthcare Mater. 2021, 10, e2002255 DOI: 10.1002/adhm.20200225519https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXltlejtrc%253D&md5=912945b4a718eb3c08bc95671feb7b90Lab under the Skin: Microneedle Based Wearable DevicesTeymourian, Hazhir; Tehrani, Farshad; Mahato, Kuldeep; Wang, JosephAdvanced Healthcare Materials (2021), 10 (17), 2002255CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)While the current smartwatches and cellphones can readily track mobility and vital signs, a new generation of wearable devices is rapidly developing to enable users to monitor their health parameters at the mol. level. Within this emerging class of wearables, microneedle-based transdermal sensors are in a prime position to play a key role in synergizing the significant advantages of dermal interstitial fluid (ISF) as a rich source of clin. indicators and painless skin pricking to allow the collection of real-time diagnostic information. While initial efforts of microneedle sensing focused on ISF extn. coupled with either on-chip anal. or off-chip instrumentation, the latest trend has been oriented toward assembling electrochem. biosensors on the tip of microneedles to allow direct continuous chem. measurements. In this context, significant advances have recently been made in exploiting microneedle-based devices for real-time monitoring of various metabolites, electrolytes, and therapeutics and toward the simultaneous multiplexed detection of key chem. markers; yet, there are several grand challenges that still exist. In this review, we outline current progress, recent trends, and new capabilities of microneedle-empowered sensors, along with the current unmet challenges and a future roadmap toward transforming the latest innovations in the field to com. products.
- 20Miller, P. R.; Taylor, R. M.; Tran, B. Q.; Boyd, G.; Glaros, T.; Chavez, V. H.; Krishnakumar, R.; Sinha, A.; Poorey, K.; Williams, K. P.; Branda, S. S.; Baca, J. T.; Polsky, R. Extraction and biomolecular analysis of dermal interstitial fluid collected with hollow microneedles. Commun. Biol. 2018, 1, 173, DOI: 10.1038/s42003-018-0170-z20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvks1CgtQ%253D%253D&md5=22fe34aba32973b987646d6e045345c2Extraction and biomolecular analysis of dermal interstitial fluid collected with hollow microneedlesMiller Philip R; Chavez Victor H; Polsky Ronen; Taylor Robert M; Baca Justin T; Tran Bao Quoc; Boyd Gabrielle; Glaros Trevor; Krishnakumar Raga; Sinha Anupama; Poorey Kunal; Williams Kelly P; Branda Steven SCommunications biology (2018), 1 (), 173 ISSN:.Dermal interstitial fluid (ISF) is an underutilized information-rich biofluid potentially useful in health status monitoring applications whose contents remain challenging to characterize. Here, we present a facile microneedle approach for dermal ISF extraction with minimal pain and no blistering for human subjects and rats. Extracted ISF volumes were sufficient for determining transcriptome, and proteome signatures. We noted similar profiles in ISF, serum, and plasma samples, suggesting that ISF can be a proxy for direct blood sampling. Dynamic changes in RNA-seq were recorded in ISF from induced hypoxia conditions. Finally, we report the first isolation and characterization, to our knowledge, of exosomes from dermal ISF. The ISF exosome concentration is 12-13 times more enriched when compared to plasma and serum and represents a previously unexplored biofluid for exosome isolation. This minimally invasive extraction approach can enable mechanistic studies of ISF and demonstrates the potential of ISF for real-time health monitoring applications.
- 21van der Maaden, K.; Jiskoot, W.; Bouwstra, J. Microneedle technologies for (trans)dermal drug and vaccine delivery. J. Controlled Release 2012, 161, 645– 655, DOI: 10.1016/j.jconrel.2012.01.04221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFWkuro%253D&md5=e8a28f652a364d28c0e460164c46ef41Microneedle technologies for (trans)dermal drug and vaccine deliveryvan der Maaden, Koen; Jiskoot, Wim; Bouwstra, JokeJournal of Controlled Release (2012), 161 (2), 645-655CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review:Microneedles have been used for the dermal and transdermal delivery of a broad range of drugs, such as small mol. wt. drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses. However, until now there are no microneedle-based (trans)dermal drug delivery systems on the market. In the past decade various types of microneedles have been developed by a no. of prodn. processes. Numerous geometries of microneedles have been designed from various materials. These microneedles have been used for different approaches of microneedle-based (trans)dermal drug delivery. Following a brief introduction about dermal and transdermal drug delivery, this review describes different prodn. methods for solid and hollow microneedles as well as conditions that influence skin penetration. Besides, the four microneedle-based (trans)dermal drug delivery approaches are discussed: "poke and flow", "poke and patch", "poke and release", and "coat and poke". A sep. section of this review is devoted to the use of microneedles for the delivery of therapeutic proteins and vaccines. Finally, we give our view on research and development that is needed to render microneedle-based (trans)dermal drug delivery technologies clin. useful in the near future.
- 22Singh, P.; Carrier, A.; Chen, Y.; Lin, S.; Wang, J.; Cui, S.; Zhang, X. Polymeric microneedles for controlled transdermal drug delivery. J. Controlled Release 2019, 315, 97– 113, DOI: 10.1016/j.jconrel.2019.10.02222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFSjtbnP&md5=75b15d588e2bfea21f978e1e1c5dd351Polymeric microneedles for controlled transdermal drug deliverySingh, Parbeen; Carrier, Andrew; Chen, Yongli; Lin, Sujing; Wang, Jinlin; Cui, Shufen; Zhang, XuJournal of Controlled Release (2019), 315 (), 97-113CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Polymeric microneedle (MN) systems are interesting transdermal drug delivery systems because of their controlled drug delivery, tunable properties, and ease of patient self-administration. They are biocompatible and can easily and painlessly penetrate the stratum corneum, delivering their contents into the dermis where they can be adsorbed into systemic circulation. Polymeric MNs can facilitate appropriate therapeutic dosing by controlling the release kinetics of pre-loaded drugs, targeting specific tissues, or responding to changing physiol. conditions. This can be accomplished by modifying the degrdn. and swelling profiles of the host polymer and the diffusion profiles of the encapsulated drugs. In this various mechanisms of controlled drug delivery using polymeric MNs, including new strategies, applications, and their future outlook are summarized and evaluated.
- 23Goud, K. Y.; Moonla, C.; Mishra, R. K.; Yu, C.; Narayan, R.; Litvan, I.; Wang, J. Wearable electrochemical microneedle sensor for continuous monitoring of levodopa: Toward parkinson management. ACS Sens. 2019, 4, 2196– 2204, DOI: 10.1021/acssensors.9b0112723https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFClsr3K&md5=c35c1f890a3f2acd6ebd10c7f0fae245Wearable Electrochemical Microneedle Sensor for Continuous Monitoring of Levodopa: Toward Parkinson ManagementGoud, K. Yugender; Moonla, Chochanon; Mishra, Rupesh K.; Yu, Chunmei; Narayan, Roger; Litvan, Irene; Wang, JosephACS Sensors (2019), 4 (8), 2196-2204CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)Levodopa is the most effective medication for treating Parkinson's disease (PD). However, because dose optimization is currently based on patients' report of symptoms, which are difficult for patients to describe, the management of PD is challenging. We report on a microneedle sensing platform for continuous minimally invasive orthogonal electrochem. monitoring of levodopa (L-Dopa). The new multimodal microneedle sensing platform relies on parallel simultaneous independent enzymic-amperometric and nonenzymic voltammetric detection of L-Dopa using different microneedles on the same sensor array patch. Such real-time orthogonal L-Dopa sensing offers a built-in redundancy and enhances the information content of the microneedle sensor arrays. This is accomplished by rapid detection of L-Dopa using square-wave voltammetry and chronoamperometry at unmodified and tyrosinase-modified carbon-paste microneedle electrodes, resp. The new wearable microneedle sensor device displays an attractive anal. performance with the enzymic and nonenzymic L-Dopa microneedle sensors offering different dimensions of information while displaying high sensitivity (with a low detection limit), high selectivity in the presence of potential interferences, and good stability in artificial interstitial fluid (ISF). The attractive anal. performance and potential wearable applications of the microneedle sensor array have been demonstrated in a skin-mimicking phantom gel as well as upon penetration through mice skin. The design and attractive anal. performance of the new orthogonal wearable microneedle sensor array hold considerable promise for reliable, continuous, minimally invasive monitoring of L-Dopa in the ISF toward optimizing the dosing regimen of the drug and effective management of Parkinson disease.
- 24Mohan, A. M. V.; Windmiller, J. R.; Mishra, R. K.; Wang, J. Continuous minimally-invasive alcohol monitoring using microneedle sensor arrays. Biosens. Bioelectron. 2017, 91, 574– 579, DOI: 10.1016/j.bios.2017.01.01624https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFKkt7Y%253D&md5=73c7edcdbcf6b5befeda34cbbff3ded9Continuous minimally-invasive alcohol monitoring using microneedle sensor arraysMohan, A. M. Vinu; Windmiller, Joshua Ray; Mishra, Rupesh K.; Wang, JosephBiosensors & Bioelectronics (2017), 91 (), 574-579CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)The present work describes an attractive skin-worn microneedle sensing device for the minimally invasive electrochem. monitoring of s.c. alc. The device consists of an assembly of pyramidal microneedle structures integrated with Pt and Ag wires, each with a microcavity opening. The microneedle aperture was modified by electropolymg. o-phenylene diamine onto the Pt wire microtransducer, followed by the immobilization of alc. oxidase (AOx) in an intermediate chitosan layer, along with an outer Nafion layer. The resulting microneedle-based enzyme electrode displays an interference-free ethanol detection in artificial interstitial fluid without compromising its sensitivity, stability and response time. The skin penetration ability and the efficaciousness of the biosensor performance towards s.c. alc. monitoring was substantiated by the ex vivo mice skin model anal. Our results reveal that the new microneedle sensor holds considerable promise for continuous non-invasive alc. monitoring in real-life situations.
- 25Mishra, R. K.; Vinu Mohan, A. M.; Soto, F.; Chrostowski, R.; Wang, J. A microneedle biosensor for minimally-invasive transdermal detection of nerve agents. Analyst 2017, 142, 918– 924, DOI: 10.1039/c6an02625g25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitlGgtL4%253D&md5=76b2c98a42d68d9f342dbdaadfe7b556A microneedle biosensor for minimally-invasive transdermal detection of nerve agentsMishra, Rupesh K.; Vinu Mohan, A. M.; Soto, Fernando; Chrostowski, Robert; Wang, JosephAnalyst (Cambridge, United Kingdom) (2017), 142 (6), 918-924CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)A microneedle electrochem. biosensor for the minimally invasive detection of organophosphate (OP) chem. agents is described. The new sensor relies on the coupling of the effective biocatalytic action of organophosphorus hydrolase (OPH) with a hollow-microneedle modified carbon-paste array electrode transducer, and involves rapid square-wave voltammetric (SWV) measurements of the p-nitrophenol product of the OPH enzymic reaction in the presence of the OP substrate. The scanning-potential SWV transduction mode offers an addnl. dimension of selectivity compared to common fixed-potential OPH-amperometric biosensors. The microneedle device offers a highly linear response for Me paraoxon (MPOx) over the range of 20-180 μM, high selectivity in the presence of excess co-existing ascorbic acid and uric acid and a high stability sensor upon exposure to the interstitial fluid (ISF). The OPH microneedle sensor was successfully tested ex vivo using mice skin samples exposed to MPOx, demonstrating its promise for minimally-invasive monitoring of OP agents and pesticides and as a wearable sensor for detecting toxic compds., in general.
- 26Windmiller, J. R.; Valdés-Ramírez, G.; Zhou, N.; Zhou, M.; Miller, P. R.; Jin, C.; Brozik, S. M.; Polsky, R.; Katz, E.; Narayan, R.; Wang, J. Bicomponent microneedle array biosensor for minimally-invasive glutamate monitoring. Electroanalysis 2011, 23, 2302– 2309, DOI: 10.1002/elan.20110036126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht12kurbK&md5=e7fbdde390eb68c0f2eb585388843be1Bicomponent Microneedle Array Biosensor for Minimally-Invasive Glutamate MonitoringWindmiller, Joshua Ray; Valdes-Ramirez, Gabriela; Zhou, Nandi; Zhou, Ming; Miller, Philip R.; Jin, Chunming; Brozik, Susan M.; Polsky, Ronen; Katz, Evgeny; Narayan, Roger; Wang, JosephElectroanalysis (2011), 23 (10), 2302-2309CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)This article describes the design of a new and attractive minimally-invasive bicomponent microneedle sensing device for the electrochem. monitoring of the excitatory neurotransmitter glutamate and glucose. The new device architecture relies on the close integration of solid and hollow microneedles into a single biosensor array device contg. multiple microcavities. Such microcavities facilitate the electropolymeric entrapment of the recognition enzyme within each microrecess. The resulting microneedle biosensor array can be employed as a minimally-invasive on-body transdermal patch, obviating the extn./sampling of the biol. fluid, thereby simplifying device requirements. The new concept is demonstrated for the electropolymeric entrapment of glutamate oxidase and glucose oxidase within a poly(o-phenylenediamine) (PPD) thin film. The PPD-based enzyme entrapment methodol. enables the effective rejection of coexisting electroactive interferents without compromising the sensitivity or response time of the device. The resulting microneedle-based glutamate and glucose biosensors thus exhibit high selectivity, sensitivity, speed, and stability in both buffer and undiluted human serum. High-fidelity glutamate measurements down to the 10 μM level were obtained in serum. The attractive recess design also serves to protect the enzyme layer upon insertion into the skin. This simple, yet robust microneedle design is well-suited for diverse biosensing applications in which real-time metabolite monitoring is a core requirement.
- 27Teymourian, H.; Moonla, C.; Tehrani, F.; Vargas, E.; Aghavali, R.; Barfidokht, A.; Tangkuaram, T.; Mercier, P. P.; Dassau, E.; Wang, J. Microneedle-based detection of ketone bodies along with glucose and lactate: Toward real-time continuous interstitial fluid monitoring of diabetic ketosis and ketoacidosis. Anal. Chem. 2020, 92, 2291– 2300, DOI: 10.1021/acs.analchem.9b0510927https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVKktbjJ&md5=3f63a4164e331b231e2b7624dce0225dMicroneedle-Based Detection of Ketone Bodies along with Glucose and Lactate: Toward Real-Time Continuous Interstitial Fluid Monitoring of Diabetic Ketosis and KetoacidosisTeymourian, Hazhir; Moonla, Chochanon; Tehrani, Farshad; Vargas, Eva; Aghavali, Reza; Barfidokht, Abbas; Tangkuaram, Tanin; Mercier, Patrick P.; Dassau, Eyal; Wang, JosephAnalytical Chemistry (Washington, DC, United States) (2020), 92 (2), 2291-2300CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)Diabetic ketoacidosis (DKA), a severe complication of diabetes mellitus with potentially fatal consequences, is characterized by hyperglycemia and metabolic acidosis due to the accumulation of ketone bodies, which requires people with diabetes to monitor both glucose and ketone bodies. However, despite major advances in diabetes management mainly since the emergence of new-generation continuous glucose monitoring (CGM) devices capable of in vivo monitoring of glucose directly in the interstitial fluid (ISF), the continuous monitoring of ketone bodies is yet to be addressed. Here, the authors present the first use of a real-time continuous ketone bodies monitoring (CKM) microneedle platform. The system is based on the electrochem. monitoring of β-hydroxybutyrate (HB) as the dominant biomarker of ketone formation. Such real-time HB detection has been realized using the β-hydroxybutyrate dehydrogenase (HBD) enzymic reaction and by addressing the major challenges assocd. with the stable confinement of the enzyme/cofactor couple (HBD/NAD+) and with a stable and selective low-potential fouling-free anodic detection of NADH. The resulting CKM microneedle device displays an attractive anal. performance, with high sensitivity (with low detection limit, 50μM), high selectivity in the presence of potential interferences, along with good stability during prolonged operation in artificial ISF. The potential applicability of this microneedle sensor toward minimally invasive monitoring of ketone bodies has been demonstrated in a phantom gel skin-mimicking model. The ability to detect HB along with glucose and lactate on a single microneedle array has been demonstrated. These findings pave the way for CKM and for the simultaneous microneedle-based monitoring of multiple diabetes-related biomarkers toward a tight glycemic control.
- 28Mishra, R. K.; Goud, K. Y.; Li, Z.; Moonla, C.; Mohamed, M. A.; Tehrani, F.; Teymourian, H.; Wang, J. Continuous opioid monitoring along with nerve agents on a wearable microneedle sensor array. J. Am. Chem. Soc. 2020, 142, 5991– 5995, DOI: 10.1021/jacs.0c0188328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltl2mt7o%253D&md5=0ea09259607b9e1d3db134f04ea9d46dContinuous Opioid Monitoring along with Nerve Agents on a Wearable Microneedle Sensor ArrayMishra, Rupesh K.; Goud, K. Yugender; Li, Zhanhong; Moonla, Chochanon; Mohamed, Mona A.; Tehrani, Farshad; Teymourian, Hazhir; Wang, JosephJournal of the American Chemical Society (2020), 142 (13), 5991-5995CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)There are urgent needs for sensing devices capable of distinguishing between episodes of opioid overdose and nerve agent poisoning. This work presents a wearable microneedle sensor array for minimally invasive continuous electrochem. detection of opioid (OPi) and organophosphate (OP) nerve agents on a single patch platform. The new multimodal microneedle sensor array relies on unmodified and organophosphorus hydrolase (OPH) enzyme-modified carbon paste (CP) microneedle electrodes for square wave voltammetric (SWV) detection of the fentanyl and nerve agent targets, resp. Such real-time simultaneous sensing provides distinct unique information, along with attractive anal. performance, including high sensitivity, selectivity, and stability, for real-time on-body OPi-OP anal. The patch represents the first sensing device capable of continuously monitoring fentanyl down to the nanomolar level through a nanomaterial-based multilayered surface architecture. Applicability of the sensor array toward opioids screening is demonstrated for morphine and norfentanyl. Successful OPi-OP detection conducted in a skin-mimicking phantom gel demonstrates the suitability of the device for rapid on-body sensing. Such progress toward continuous minimally invasive transdermal anal. of drugs of abuse and nerve agents holds promise for rapid countermeasures for protecting soldiers, civilians, and healthcare personnel.
- 29Xiao, Y.; Lubin, A. A.; Heeger, A. J.; Plaxco, K. W. Label-free electronic detection of thrombin in blood serum by using an aptamer-based sensor. Angew. Chem., Int. Ed. 2005, 44, 5456– 5459, DOI: 10.1002/anie.20050098929https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpvF2ksLg%253D&md5=03fba0f9b28e0c7c8375e8fef4a5446fLabel-free electronic detection of thrombin in blood serum by using an aptamer-based sensorXiao, Yi; Lubin, Arica A.; Heeger, Alan J.; Plaxco, Kevin W.Angewandte Chemie, International Edition (2005), 44 (34), 5456-5459CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A methylene blue (MB) tagged, thrombin-binding DNA aptamer immobilized on a gold surface undergoes a large conformational change upon target binding and inhibits electron transfer. This folding produces a large, readily measurable change in redox current and allows the electrochem. detection of thrombin in blood serum.
- 30Tuerk, C.; Gold, L. Systematic evolution of ligands by exponential enrichment: Rna ligands to bacteriophage t4 DNA polymerase. Science 1990, 249, 505– 510, DOI: 10.1126/science.220012130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXlt1OltLY%253D&md5=a40a28db9df4a5da4c1b1652a34aa715Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymeraseTuerk, Craig; Gold, LarryScience (Washington, DC, United States) (1990), 249 (4968), 505-10CODEN: SCIEAS; ISSN:0036-8075.A novel method was developed for rapidly selecting preferred binding sequences from a population of random sequences. The method is designated systematic evolution of ligands by exponential enrichment (SELEX). High-affinity nucleic acid ligands for a protein were isolated by a procedure that depends on alternate cycles of ligand selection from pools of variant sequences and amplification of the bound species. Multiple rounds exponentially enrich the population for the highest affinity species that can be clonally isolated and characterized. In particular one eight-base region of an RNA that interacts with the T4 DNA polymerase was chosen and randomized. Two different sequences were selected by this procedure from the calcd. pool of 65,536 species. One is the wild-type sequence found in the bacteriophage mRNA; one is varied from wild type at four positions. The binding consts. of these two RNA's to T4 DNA polymerase are equiv. These protocols with minimal modification can yield high-affinity ligands for any protein that binds nucleic acids as part of its function; high affinity ligands could conceivably be developed for any target mol.
- 31Ellington, A. D.; Szostak, J. W. In vitro selection of rna molecules that bind specific ligands. Nature 1990, 346, 818– 822, DOI: 10.1038/346818a031https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXitVGgsw%253D%253D&md5=522ad1b4f0284ee88173b02035f9e9c5In vitro selection of RNA molecules that bind specific ligandsEllington, Andrew D.; Szostak, Jack W.Nature (London, United Kingdom) (1990), 346 (6287), 818-22CODEN: NATUAS; ISSN:0028-0836.Subpopulations of RNA mols. that bind specifically to a variety of org. dyes have been isolated from a population of random sequence RNA mols. Roughly one in 1010 random sequence RNA mols. folds in such a way as to create a specific binding site for small ligands.
- 32Wu, Y.; Belmonte, I.; Sykes, K. S.; Xiao, Y.; White, R. J. Perspective on the future role of aptamers in analytical chemistry. Anal. Chem. 2019, 91, 15335– 15344, DOI: 10.1021/acs.analchem.9b0385332https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFCns7jE&md5=da66671382b5e90ffd90a9ebc3ad7a46Perspective on the Future Role of Aptamers in Analytical ChemistryWu, Yao; Belmonte, Israel; Sykes, Kiana S.; Xiao, Yi; White, Ryan J.Analytical Chemistry (Washington, DC, United States) (2019), 91 (24), 15335-15344CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)A review. It has been almost 30 years since the invention of SELEX (Systematic Evolution of Ligands by Exponential Enrichment) methodol. and the description of the first aptamers. In retrospect over the past 30 years, advances in aptamer development and application have demonstrated that aptamers are potentially useful reagents that can be employed in diverse areas within anal. chem., biotechnol., biomedicine, and mol. biol. While often touted as artificial antibodies with an ability to be selected for any target, aptamer development, unfortunately, lags behind development of anal. methodologies that employ aptamers, hindering deeper integration into the application of anal. tool development. This perspective covers recent advances in SELEX methodol. coupled with post-selection procedures all aimed at enhancing affinity and specificity of the selected aptamers - what we view as a crit. barrier in the future role of aptamers in anal. chem. We discuss post-selection modifications that can be used for enhancing performance of the selected aptamers in anal. device by including understanding intermol. interaction forces in the binding domain. While highlighting promising properties of aptamers that enable several anal. advances, we provide discussion on the challenges of penetration of aptamers in the anal. field.
- 33Yi, K.; Wang, Y.; Shi, K.; Chi, J.; Lyu, J.; Zhao, Y. Aptamer-decorated porous microneedles arrays for extraction and detection of skin interstitial fluid biomarkers. Biosens. Bioelectron. 2021, 190, 113404, DOI: 10.1016/j.bios.2021.11340433https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVWgsr%252FF&md5=a13387a1f4051515f0ce0639ab3f9d98Aptamer-decorated porous microneedles arrays for extraction and detection of skin interstitial fluid biomarkersYi, Kexin; Wang, Yuetong; Shi, Keqing; Chi, Junjie; Lyu, Jianxin; Zhao, YuanjinBiosensors & Bioelectronics (2021), 190 (), 113404CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)The detection of biomarkers in body fluids plays a great role in the diagnosis, treatment, and prognosis of diseases. Here, we present novel aptamer-decorated porous microneedles (MNs) arrays to realize the extn. and detection of biomarkers in skin interstitial fluid (ISF) in situ. The porous MNs arrays are fabricated by replicating the neg. molds comprising glass microspheres with a UV-curable ethoxylated trimethylolpropane triacrylate (ETPTA). As the MNs arrays combine the superiorities of porous structure and aptamers, their sp. surface area increased significantly to 6.694 m2/g, thus vast of stable aptamer probes with a concn. of 0.9459μM could be immobilized. In addn., the MNs arrays could ext. skin ISF into their porous structure on the basis of the capillarity principle, and subsequently capture and detect skin ISF biomarkers without sample post-process. Taking advantage of these features, we further demonstrated a highly sensitive and rapid detection of ISF endotoxin in the concn. ranges of 0.0342 EU/mL to 8.2082 EU/mL from rats model injected with endotoxin via tail vein by using such aptamer-decorated porous MNs arrays, with the limit of detection (LOD) of 0.0064 EU/mL. These results indicated that the aptamer-decorated porous MNs arrays possess great potential for non-invasive extn. and detection of biomarkers in clin. applications.
- 34Shaver, A.; Curtis, S. D.; Arroyo-Currás, N. Alkanethiol monolayer end groups affect the long-term operational stability and signaling of electrochemical, aptamer-based sensors in biological fluids. ACS Appl. Mater. Interfaces 2020, 12, 11214– 11223, DOI: 10.1021/acsami.9b2238534https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFKqsro%253D&md5=5f10c2efa8960f892202a6184bf9d63aAlkanethiol Monolayer End Groups Affect the Long-Term Operational Stability and Signaling of Electrochemical, Aptamer-Based Sensors in Biological FluidsShaver, Alexander; Curtis, Samuel D.; Arroyo-Curras, NetzahualcoyotlACS Applied Materials & Interfaces (2020), 12 (9), 11214-11223CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)Electrochem. aptamer-based (E-AB) sensors achieve highly precise measurements of specific mol. targets in untreated biol. fluids. This unique ability, together with their measurement frequency of seconds or faster, has enabled the real-time monitoring of drug pharmacokinetics in live animals with unprecedented temporal resoln. However, one important weakness of E-AB sensors is that their bioelectronic interface degrades upon continuous electrochem. interrogation-a process typically seen as a drop in faradaic and an increase in charging currents over time. This progressive degrdn. limits their in vivo operational life to 12 h at best, a period that is much shorter than the elimination half-life of the vast majority of drugs in humans. Thus, there is a crit. need to develop novel E-AB interfaces that resist continuous electrochem. interrogation in biol. fluids for prolonged periods. In response, our group is pursuing the development of better packed, more stable self-assembled monolayers (SAMs) to improve the signaling and extend the operational life of in vivo E-AB sensors from hours to days. By invoking hydrophobicity arguments, we have created SAMs that do not desorb from the electrode surface in aq. physiol. solns. and biol. fluids. These SAMs, formed from 1-hexanethiol solns., decrease the voltammetric charging currents of E-AB sensors by 3-fold relative to std. monolayers of 6-mercapto-1-hexanol, increase the total faradaic current, and alter the electron transfer kinetics of the platform. Moreover, the stability of our new SAMs enables uninterrupted, continuous E-AB interrogation for several days in biol. fluids, like undiluted serum, at a physiol. temp. of 37°C.
- 35Arroyo-Currás, N.; Dauphin-Ducharme, P.; Scida, K.; Chávez, J. L. From the beaker to the body: Translational challenges for electrochemical, aptamer-based sensors. Anal. Methods 2020, 12, 1288– 1310, DOI: 10.1039/d0ay00026dThere is no corresponding record for this reference.
- 36Dauphin-Ducharme, P.; Ploense, K. L.; Arroyo-Currás, N.; Kippin, T. E.; Plaxco, K. W. Electrochemical aptamer-based sensors: A platform approach to high-frequency molecular monitoring in situ in the living body. Biomedical Engineering Technologies; Methods in Molecular Biology; Ossandon, M. R., Baker, H., Rasooly, A., Eds.; Springer US: Humana, New York, NY, 2022; Vol. 2393, pp 479– 492.There is no corresponding record for this reference.
- 37Carvalhal, R. F.; Sanches Freire, R.; Kubota, L. T. Polycrystalline gold electrodes: A comparative study of pretreatment procedures used for cleaning and thiol self-assembly monolayer formation. Electroanalysis 2005, 17, 1251– 1259, DOI: 10.1002/elan.20040322437https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXntlCmt7g%253D&md5=b11109b738ba7cc3c2a8d1d123dcc166Polycrystalline gold electrodes: A comparative study of pretreatment procedures used for cleaning and thiol self-assembly monolayer formationCarvalhal, Rafaela Fernanda; Freire, Renato Sanches; Kubota, Lauro TatsuoElectroanalysis (2005), 17 (14), 1251-1259CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)The influence of different surface pretreatment procedures on the electrochem. response of a polycryst. Au electrode was evaluated. Mech. polishing with slurry alumina (M), chem. oxidn. with H2SO4/H2O2 (C), electrochem. polishing (potential cycling between -0.1 V and 1.2 V vs. SCE) (E), chem. redn. with EtOH, and combinations among these treatments were employed to change the surface electrode characteristics. The efficiency of the proposed pretreatments was evaluated by electrochem. responses towards the redox couple ferri(II/III)-ammonium sulfate and by the formation of a self-assembly monolayer of 3-mercaptopropionic acid (3 MPA SAM) on Au electrodes. The procedure (C) allowed important Au surfaces activation. Using procedures (C) and (E) the roughness of polycryst. Au surfaces was significantly minimized and more reproducible surfaces could be obtained. From the profile of reductive desorption of 3 MPA SAM it was possible to verify that reduced Au surfaces generated better packed monolayers than oxidized ones and a comparative study using CV and DPV techniques showed that between the two desorption peaks, the one localized at more neg. potential values corresponds to the cleavage of Au-S bond from the chemisorbed thiol. In general, the improvement in the studied electrochem. responses could not only be attributed to an increase in the real surface area of the electrode, but to the chem. surface states set off by the pretreatment procedure.
- 38Curtis, S. D.; Ploense, K. L.; Kurnik, M.; Ortega, G.; Parolo, C.; Kippin, T. E.; Plaxco, K. W.; Arroyo-Currás, N. Open source software for the real-time control, processing, and visualization of high-volume electrochemical data. Anal. Chem. 2019, 91, 12321– 12328, DOI: 10.1021/acs.analchem.9b0255338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1KksL%252FI&md5=8a2fb45b4fd84748c8c38c8754c1db12Open Source Software for the Real-Time Control, Processing, and Visualization of High-Volume Electrochemical DataCurtis, Samuel D.; Ploense, Kyle L.; Kurnik, Martin; Ortega, Gabriel; Parolo, Claudio; Kippin, Tod E.; Plaxco, Kevin W.; Arroyo-Curras, NetzahualcoyotlAnalytical Chemistry (Washington, DC, United States) (2019), 91 (19), 12321-12328CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)Electrochem. sensors are major players in the race for improved mol. diagnostics due to their convenience, temporal resoln., manufg. scalability, and their ability to support real-time measurements. This is evident in the ever-increasing no. of health-related electrochem. sensing platforms, ranging from single-measurement point-of-care devices to wearable devices supporting immediate and continuous monitoring. In support of the need for such systems to rapidly process large data vols. the authors describe here an open-source, easily customizable, multi-platform compatible program for the real-time control, processing and visualization of electrochem. data. The software's architecture is modular and fully documented, allowing the easy customization of the code to support the processing of voltammetric (e.g., square-wave and cyclic) and chronoamperometric data. The program, which the authors have called Software for the Anal. and Continuous Monitoring of Electrochem. Systems (SACMES), also includes a graphical interface allowing the user to easily change anal. parameters (e.g., signal/noise processing, baseline correction) in real-time. To demonstrate the versatility of SACMES the authors use it here to analyze the real-time data output by: (1) the electrochem., aptamer-based measurement of a specific small-mol. target, (2) a monoclonal antibody-detecting DNA-scaffold sensor, and (3) the detn. of the folding thermodn. of an electrode-attached, redox-reporter-modified protein.
- 39Xiao, Y.; Lai, R. Y.; Plaxco, K. W. Preparation of electrode-immobilized, redox-modified oligonucleotides for electrochemical DNA and aptamer-based sensing. Nat. Protoc. 2007, 2, 2875– 2880, DOI: 10.1038/nprot.2007.41339https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlSlsr%252FF&md5=cbabde677e2bf0e10bf501b3d2f9df6bPreparation of electrode-immobilized, redox-modified oligonucleotides for electrochemical DNA and aptamer-based sensingXiao, Yi; Lai, Rebecca Y.; Plaxco, Kevin W.Nature Protocols (2007), 2 (11), 2875-2880CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)Recent years have seen the development of a no. of reagentless, electrochem. sensors based on the target-induced folding or unfolding of electrode-bound oligonucleotides, with examples reported to date, including sensors for the detection of specific nucleic acids, proteins, small mols. and inorg. ions. These devices, which are often termed electrochem. DNA (E-DNA) and E-AB (electrochem., aptamer-based) sensors, are comprised of an oligonucleotide probe modified with a redox reporter (in this protocol methylene blue) at one terminus and attached to a gold electrode via a thiol-gold bond at the other. Binding of an analyte to the oligonucleotide probe changes its structure and dynamics, which, in turn, influences the efficiency of electron transfer to the interrogating electrode. This class of sensors perform well even when challenged directly with blood serum, soil and other complex, multicomponent sample matrixes. This protocol describes the fabrication of E-DNA and E-AB sensors. The protocol can be completed in 12 h.
- 40Pellitero, M. A.; Curtis, S. D.; Arroyo-Currás, N. Interrogation of electrochemical aptamer-based sensors via peak-to-peak separation in cyclic voltammetry improves the temporal stability and batch-to-batch variability in biological fluids. ACS Sens. 2021, 6, 1199– 1207, DOI: 10.1021/acssensors.0c0245540https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXkt1Oqu7g%253D&md5=f7ae3d9543ea0c4cfa85a2fb4396f121Interrogation of Electrochemical Aptamer-Based Sensors via Peak-to-Peak Separation in Cyclic Voltammetry Improves the Temporal Stability and Batch-to-Batch Variability in Biological FluidsPellitero, Miguel Aller; Curtis, Samuel D.; Arroyo-Curras, NetzahualcoyotlACS Sensors (2021), 6 (3), 1199-1207CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)Electrochem., aptamer-based (E-AB) sensors support continuous, real-time measurements of specific mol. targets in complex fluids such as undiluted serum. They achieve these measurements by using redox-reporter-modified, electrode-attached aptamers that undergo target binding-induced conformational changes which, in turn, change electron transfer between the reporter and the sensor surface. Traditionally, E-AB sensors are interrogated via pulse voltammetry to monitor binding-induced changes in transfer kinetics. While these pulse techniques are sensitive to changes in electron transfer, they also respond to progressive changes in the sensor surface driven by biofouling or monolayer desorption and, consequently, present a significant drift. Moreover, we have empirically obsd. that differential voltage pulsing can accelerate monolayer desorption from the sensor surface, presumably via field-induced actuation of aptamers. Here, in contrast, we demonstrate the potential advantages of employing cyclic voltammetry to measure electron-transfer changes directly. In our approach, the target concn. is reported via changes in the peak-to-peak sepn., ΔEP, of cyclic voltammograms. Because the magnitude of ΔEP is insensitive to variations in the no. of aptamer probes on the electrode, ΔEP-interrogated E-AB sensors are resistant to drift and show decreased batch-to-batch and day-to-day variability in sensor performance. Moreover, ΔEP-based measurements can also be performed in a few hundred milliseconds and are, thus, competitive with other subsecond interrogation strategies such as chronoamperometry but with the added benefit of retaining sensor capacitance information that can report on monolayer stability over time.
- 41Dauphin-Ducharme, P.; Yang, K.; Arroyo-Currás, N.; Ploense, K. L.; Zhang, Y.; Gerson, J.; Kurnik, M.; Kippin, T. E.; Stojanovic, M. N.; Plaxco, K. W. Electrochemical aptamer-based sensors for improved therapeutic drug monitoring and high-precision, feedback-controlled drug delivery. ACS Sens. 2019, 4, 2832– 2837, DOI: 10.1021/acssensors.9b0161641https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVCnt7vM&md5=67cd35b6a26e364ac78a9c4339925c3bElectrochemical Aptamer-Based Sensors for Improved Therapeutic Drug Monitoring and High-Precision, Feedback-Controlled Drug DeliveryDauphin-Ducharme, Philippe; Yang, Kyungae; Arroyo-Curras, Netzahualcoyotl; Ploense, Kyle L.; Zhang, Yameng; Gerson, Julian; Kurnik, Martin; Kippin, Tod E.; Stojanovic, Milan N.; Plaxco, Kevin W.ACS Sensors (2019), 4 (10), 2832-2837CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)The Electrochem. Aptamer-Based (E-AB) sensing platform appears a convenient (rapid, single-step, calibration-free), modular approach to measure concns. of specific mols. (irresp. of their chem. reactivity) directly in blood and even in situ in the living body. Given these attributes, the platform may thus provide significant opportunities to render therapeutic drug monitoring (the clin. practice in which dosing is adjusted in response to plasma drug measurements) as frequent and convenient as the measurement of blood sugar has become for diabetics. The ability to measure arbitrary mols. in the body in real time could even enable closed-loop feedback control over plasma drug levels in a manner analogous to the recently commercialized controlled blood sugar systems. As initial exploration of this, the authors describe here the selection of an aptamer against vancomycin, a narrow therapeutic window antibiotic for which therapeutic monitoring is a crit. part of the std. of care, and its adaptation into an electrochem. aptamer-based (E-AB) sensor. Using this sensor the authors then demonstrate: (1) rapid (seconds), convenient (single-step, calibration-free) measurement of plasma vancomycin in finger-prick-scale samples of whole blood, (2) high-precision measurement of subject-specific vancomycin pharmacokinetics (in a rat animal model), and (3) high precision, closed-loop feedback control over plasma levels of the drug (in a rat animal model). The ability to not only track (with continuous-glucose-monitor-like measurement frequency and convenience), but also actively control plasma drug levels provides an unprecedented route towards improving therapeutic drug monitoring and, more generally, the personalized, high-precision delivery of pharmacol. interventions.
- 42Dilworth, T. J.; Schulz, L. T.; Rose, W. E. Vancomycin advanced therapeutic drug monitoring: Exercise in futility or virtuous endeavor to improve drug efficacy and safety?. Clin. Infect. Dis. 2021, 72, E675– E681, DOI: 10.1093/cid/ciaa135442https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtFyitrrM&md5=2f3c0a2778f415e29fe7469b17e551acVancomycin advanced therapeutic drug monitoring: exercise in futility or virtuous endeavor to improve drug efficacy and safety?Dilworth, Thomas J.; Schulz, Lucas T.; Rose, Warren E.Clinical Infectious Diseases (2021), 72 (10), e675-e681CODEN: CIDIEL; ISSN:1537-6591. (Oxford University Press)A review. Vancomycin is commonly prescribed to hospitalized patients. Decades of pharmacokinetic/pharmacodynamic research culminated in recommendations to monitor the ratio of the area under the concn.-time curve (AUC) to the min. inhibitory concn. in order to optimize vancomycin exposure and minimize toxicity in the revised 2020 guidelines. These guideline recommendations are based on limited data without high-quality evidence and limitations in strength. Despite considerable effort placed on vancomycin therapeutic drug monitoring (TDM), clinicians should recognize that the majority of vancomycin use is empiric. Most patients prescribed empiric vancomycin do not require it beyond a few days. For these patients, AUC detns. during the initial days of vancomycin exposure are futile. This added workload may detract from high-level patient care activities. Loading doses likely achieve AUC targets, so AUC monitoring after a loading dose is largely unnecessary for broad application. The excessive vancomycin TDM for decades has been propagated with limitations in evidence, and it should raise caution on contemporary vancomycin TDM recommendations.
- 43Groenewald, T. The dissolution of gold in acidic solutions of thiourea. Hydrometallurgy 1976, 1, 277– 290, DOI: 10.1016/0304-386x(76)90004-943https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE28XksV2lt74%253D&md5=e9d3db5e3b076ff2daee55970975a869The dissolution of gold in acidic solutions of thioureaGroenewald, T.Hydrometallurgy (1976), 1 (3), 277-90CODEN: HYDRDA; ISSN:0304-386X.Lab. expts. are described for the dissoln. of rotating disks of pure Au and on ground Au ores in acidic solns. of thiourea [62-56-6] contg. various oxidants including Fe(III), H2O2, O, and formamidine disulfide [3256-06-2]. The dissoln. rate of Au in these solns. approached the limiting diffusion controlled rate. Fe(III) caused the most rapid initial rate, but this rate soon decreased because of the reaction between Fe(III) and thiourea. The excessive amt. of thiourea consumed made the use of Fe(III) unattractive as the oxidant. In the leaching of crushed ore, a large proportion of the oxidant necessary for the extn. of the Au was derived from the ore. The addnl. oxidant was supplied as H2O2 during the prepn. of the leach liquor and by agitation of the slurry with air. When solns. contg. 1.2M thiourea were used, Au was extd. from the ore within 1 hr. When 0.1M thiourea was used, the complete extn. of Au required approx. 8 hr. In these cases the consumption of thiourea was 1.4 and 0.4 kg thiourea/ton, resp.
- 44Puscasu, A.; Zanchetta, M.; Posocco, B.; Bunka, D.; Tartaggia, S.; Toffoli, G. Development and validation of a selective spr aptasensor for the detection of anticancer drug irinotecan in human plasma samples. Anal. Bioanal. Chem. 2021, 413, 1225– 1236, DOI: 10.1007/s00216-020-03087-544https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXosVaqtg%253D%253D&md5=c207870dcab37e6ae2f53f33a995dd0eDevelopment and validation of a selective SPR aptasensor for the detection of anticancer drug irinotecan in human plasma samplesPuscasu, Adelina; Zanchetta, Martina; Posocco, Bianca; Bunka, David; Tartaggia, Stefano; Toffoli, GiuseppeAnalytical and Bioanalytical Chemistry (2021), 413 (4), 1225-1236CODEN: ABCNBP; ISSN:1618-2642. (Springer)In this work, a surface plasmon resonance (SPR)-based assay for the quantification of antineoplastic drug irinotecan in human plasma samples has been developed for the first time. The selective binding of irinotecan with an aptamer receptor, operating in human plasma, allowed to set-up a novel anal. methodol. to detect the drug in the anal. range of interest by using SPR as detection technique. After hybridizing the aptamer to the sensing platform and optimizing the sample prepn. procedure, a quant. assay was validated according to FDA regulatory guidelines. The anal. working range was found between 100 and 7500 ng mL-1 with negligible interferences from plasma components and co-medication assocd. with the administration of irinotecan. The utility of the new SPR assay was confirmed by analyzing plasma samples in parallel with LC-MS as ref. technique, providing a new anal. tool for the therapeutic drug monitoring of irinotecan in patients under chemotherapy regimens.
- 45Idili, A.; Arroyo-Currás, N.; Ploense, K. L.; Csordas, A. T.; Kuwahara, M.; Kippin, T. E.; Plaxco, K. W. Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living body. Chem. Sci. 2019, 10, 8164– 8170, DOI: 10.1039/c9sc01495k45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVWgsbfF&md5=ee902b2f4aed48c5f2fe348062001a38Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living bodyIdili, Andrea; Arroyo-Curras, Netzahualcoyotl; Ploense, Kyle L.; Csordas, Andrew T.; Kuwahara, Masayasu; Kippin, Tod E.; Plaxco, Kevin W.Chemical Science (2019), 10 (35), 8164-8170CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The ability to measure drugs in the body rapidly and in real time would advance both our understanding of pharmacokinetics and our ability to optimally dose and deliver pharmacol. therapies. To this end, we are developing electrochem. aptamer-based (E-AB) sensors, a seconds-resolved platform technol. that, as crit. for performing measurements in vivo, is reagentless, reversible, and selective enough to work when placed directly in bodily fluids. Here we describe the development of an E-AB sensor against irinotecan, a member of the camptothecin family of cancer chemotherapeutics, and its adaptation to in vivo sensing. To achieve this we first re-engineered (via truncation) a previously reported DNA aptamer against the camptothecins to support high-gain E-AB signaling. We then co-deposited the modified aptamer with an unstructured, redox-reporter-modified DNA sequence whose output was independent of target concn., rendering the sensor's signal gain a sufficiently strong function of square-wave frequency to support kinetic-differential-measurement drift correction. The resultant, 200 mum-diam., 3 mm-long sensor achieves 20 s-resolved, multi-hour measurements of plasma irinotecan when emplaced in the jugular veins of live rats, thus providing an unprecedentedly high-precision view into the pharmacokinetics of this class of chemotherapeutics.
- 46Chand, V. K.; Link, B. K.; Ritchie, J. M.; Shannon, M.; Wooldridge, J. E. Neutropenia and febrile neutropenia in patients with hodgkin’s lymphoma treated with doxorubicin (adriamycin), bleomycin, vinblastine and dacarbazine (abvd) chemotherapy. Leuk. Lymphoma 2006, 47, 657– 663, DOI: 10.1080/1042819050035343046https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD283msF2nsw%253D%253D&md5=4f461b6aca7cfdafc0b10edde0cb9549Neutropenia and febrile neutropenia in patients with Hodgkin's lymphoma treated with doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapyChand Vikram K; Link Brian K; Ritchie Justine M; Shannon Mary; Wooldridge James ELeukemia & lymphoma (2006), 47 (4), 657-63 ISSN:1042-8194.When uncomplicated neutropenia during doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy for the treatment of Hodgkin's lymphoma is encountered, it is unclear whether or not treatment should be modified. In the present study, we determined the incidence of neutropenia, febrile neutropenia, and the relationship of febrile neutropenia to grade III/IV neutropenia and dose modification, in a large university patient population. We reviewed the charts of patients diagnosed with Hodgkin's lymphoma between 1 January 1990 and 31 December 2002 who were treated with ABVD chemotherapy, and seen at the University of Iowa with complete diagnosis, staging, and treatment dosing records. Adequate data was available on 894 treatments in 81 patients with Hodgkin's lymphoma treated with ABVD chemotherapy. Grade III/IV neutropenia was present on the scheduled day of treatment in 187 (20.9%) treatments in 64 (79%) patients. Grade III/IV neutropenia was most common at cycle 1 day 15. Febrile neutropenia developed nine times in eight patients, and eight episodes of febrile neutropenia developed when the treatment-day absolute neutrophil count (ANC) > or =1000. Dose delay of >4 days and/or dose reduction to <80% of original doxorubicin dose following grade III/IV neutropenia occurred in 29 of 187 treatments, with no episodes of febrile neutropenia. With grade III/IV neutropenia on the day of therapy, 158 treatments were administered without dose reduction or dose delay with one subsequent episode of febrile neutropenia. Neutropenia during ABVD is common, and dose modification for uncomplicated neutropenia on the day of treatment may not reduce the risk of febrile neutropenia. It may be possible to maintain dose intensity in the face of uncomplicated neutropenia during ABVD therapy.
- 47Pérez-Blanco, J. S.; Santos-Buelga, D.; Fernández de Gatta, M. d. M.; Hernández-Rivas, J. M.; Martín, A.; García, M. J. Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-hodgkin’s lymphoma. Br. J. Clin. Pharmacol. 2016, 82, 1517– 1527, DOI: 10.1111/bcp.1307047https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhsl2hur%252FO&md5=8fd648e9039a502d988f0d3d9e628d69Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphomaPerez-Blanco, Jonas Samuel; Santos-Buelga, Dolores; Fernandez de Gatta, Maria del Mar; Hernandez-Rivas, Jesus Maria; Martin, Alejandro; Garcia, Maria JoseBritish Journal of Clinical Pharmacology (2016), 82 (6), 1517-1527CODEN: BCPHBM; ISSN:1365-2125. (Wiley-Blackwell)Aims : The aims of the study were: (i) to characterize the pharmacokinetics (PK) of doxorubicin (DOX) and doxorubicinol (DOXol) in patients diagnosed with non-Hodgkin's lymphoma (NHL) using a population approach; (ii) to evaluate the influence of various covariates on the PK of DOX; and (iii) to evaluate the role of DOX and DOXol exposure in haematol. toxicity. Methods : Population PK modeling (using NONMEM) was performed using DOX and DOXol plasma concn.-time data from 45 NHL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The influence of drug exposure on haematol. toxicity was analyzed using the Mann-Whitney-Wilcoxon test. Results : A five-compartment model, three for DOX and two for DOXol, with first-order distribution and elimination for both entities best described the data. Population ests. for parent drug (CL) and metabolite (CLm) clearance were 62 l h-1 and 27 l h-1, resp. The fraction metabolized to DOXol (Fm) was estd. at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CLm, the objective function value decrease was not statistically significant. A trend towards an assocn. between the total area under the concn.-time curve (AUCtotal), the area under the concn.-time curve for DOX (AUC) plus the area under the concn.-time curve for DOXol (AUCm), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was obsd., according to an exponential relationship. Conclusions : The PK of DOX and DOXol were well characterized by the model developed, which could be used as a helpful tool to optimize the dosage of this drug. The results suggest that the main active metabolite of DOX, DOXol, is involved in the haematol. toxicity of the parent drug.
- 48Zhou, T.; Shen, Q.; Peng, H.; Chao, T.; Zhang, L.; Huang, L.; Yang, K.; Thapa, S.; Yu, S.; Jiang, Y. Incidence of interstitial pneumonitis in non-hodgkin’s lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab. Ann. Hematol. 2018, 97, 141– 147, DOI: 10.1007/s00277-017-3160-148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslCmtrrP&md5=021d98c38137eac74f2c5f6404daaefaIncidence of interstitial pneumonitis in non-Hodgkin's lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximabZhou, Ting; Shen, Qian; Peng, Hui; Chao, Tengfei; Zhang, Lihong; Huang, Liu; Yang, Kaixiang; Thapa, Sudip; Yu, Shiying; Jiang, YongshengAnnals of Hematology (2018), 97 (1), 141-147CODEN: ANHEE8; ISSN:0939-5555. (Springer)Pneumonitis is a rare but severe and potentially fatal adverse effect in chemotherapy of lymphoma. This study is aimed to investigate the incidence of interstitial pneumonitis in non-Hodgkin's lymphoma (NHL) patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab. Lymphoma patients were retrospectively reviewed, and eligible patients were included in this study. According to the chemotherapy regimens, patients were classified in four groups: combination of vincristine, cyclophosphamide, doxorubicin, and prednisone (CHOP group) with rituximab (RCHOP group) and combination of vincristine, cyclophosphamide, pegylated liposomal doxorubicin and prednisone (CDOP group) with rituximab (RCDOP group). Incidence and severity of interstitial pneumonitis were compared among the four groups. Among 757 patients reviewed, 207 patients were included in final anal. Thirteen patients developed chemotherapy-induced interstitial pneumonitis, and the mean cycle of chemotherapy before the onset of pneumonitis was 4. Incidence rates of pneumonitis were 0, 1.8, 17.4, and 21.1% in CHOP, RCHOP, CDOP, and RCDOP groups, resp. (p < 0.001). The mean grades of pneumonitis were 0, 2, 2.5, and 3 in four groups, resp. (p < 0.001). After adjustment of confounders, chemotherapy regimens (OR 3.491, 95% CI 1.527-7.981, p = 0.003) and neutropenia in previous cycles (OR 2.186, 95% CI 1.281-3.731, p = 0.004) were independently assocd. with the incidence of pneumonitis. Interstitial pneumonitis should be highlighted in NHL patients who received more than 4 cycles of RCDOP chemotherapy regimen, esp. in those who had grade 4 neutropenia in the previous cycles of chemotherapy.
- 49Harris, S. M.; Mistry, P.; Freathy, C.; Brown, J. L.; Charlton, P. A. Antitumour activity of xr5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines. Br. J. Cancer 2005, 92, 722– 728, DOI: 10.1038/sj.bjc.660240349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhsFWltLk%253D&md5=1d060067c6fe664fe87a8b9cf58d1defAntitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell linesHarris, S. M.; Mistry, P.; Freathy, C.; Brown, J. L.; Charlton, P. A.British Journal of Cancer (2005), 92 (4), 722-728CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)XR5944 (MLN944), a novel bis-phenazine, has demonstrated potent cytotoxic activity against a variety of murine and human tumor models. In the present study, the antitumor activity of XR5944 was investigated in combination with 5-fluorouracil (5-FU) or irinotecan in human colon carcinoma cell lines and xenografts. In vitro cytotoxicity of the combinations following exposure to the drugs sequentially or simultaneously was evaluated by the sulforhodamine-B assay and interactions were detd. using median-effect anal. Antagonism was obsd. (CI>1) following exposure of HT29 cells simultaneously to XR5944 and 5-FU or SN38 (active metabolite of irinotecan). In contrast, sequential exposure of either combination in either order demonstrated at least an additive response (CI ≤ 1). At least an additive response was also obsd. with these combinations in HCT116 cells regardless of schedule. Antitumor activity in HT29 xenografts in nude mice was enhanced by sequential administration of 5-FU (65 mg kg-1) or irinotecan (CPT-11) (35 mg kg-1) 48 h before XR5944 (5, 10, or 15 mg kg-1) compared to single agent treatment at the same or higher doses. Administration of irinotecan (35 mg kg-1) and XR5944 (15 mg kg-1) just 30 min apart yielded similar efficacy to sequential administration 48 h apart. All combinations were well tolerated. These data suggest that combinations of XR5944 with irinotecan or 5-FU are of significant interest in the treatment of colon cancer.
- 50Torrisi, R.; Orlando, L.; Ghisini, R.; Veronesi, P.; Intra, M.; Rocca, A.; Balduzzi, A.; Cardillo, A.; Goldhirsch, A.; Colleoni, M. A phase ii study of primary dose-dense sequential doxorubicin plus cyclophosphamide and docetaxel in ct4 breast cancer. Anticancer Res. 2006, 26, 3861– 386450https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1Gmt7jI&md5=4939ec804cea4596230dd885e9e9c45eA phase II study of primary dose-dense sequential doxorubicin plus cyclophosphamide and docetaxel in cT4 breast cancerTorrisi, R.; Orlando, L.; Ghisini, R.; Veronesi, P.; Intra, M.; Rocca, A.; Balduzzi, A.; Cardillo, A.; Goldhirsch, A.; Colleoni, M.Anticancer Research (2006), 26 (5B), 3861-3864CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)Dose-dense chemotherapy with anthracyclines and taxanes has improved either disease free survival or overall survival in high risk patients with early breast cancer. The activity and safety of a dose-dense schedule (q14 days) of adriamycin 60 mg/sqm and cyclophosphamide 600 mg/sqm (AC) × 4 cycles followed by docetaxel 75 mg/sqm for 4 cycles with hematopoietic support in patients with stage IIIB breast cancer was explored. Patients with ER ≥10% tumors received concomitant endocrine therapy with 3-mo triptorelin and letrozole. Fifteen patients with histol. proven cT4b (three patients) and cT4d (twelve patients) M0 breast cancer were enrolled. Median age was 48 years (range 25-66). Eight clin. responses including one pathol. complete remission (pCR), three stable disease (including minor responses) and four progression of disease, one during AC and three during taxotere, were obsd. Four patients had grade 3-4 non hematol. toxicities and all except one discontinued treatment. Due to the high rate of progressive disease, this schedule should not represent a std. option in cT4 breast cancer.
- 51Oakman, C.; Francis, P. A.; Crown, J.; Quinaux, E.; Buyse, M.; De Azambuja, E.; Margeli Vila, M.; Andersson, M.; Nordenskjöld, B.; Jakesz, R.; Thürlimann, B.; Gutiérrez, J.; Harvey, V.; Punzalan, L.; Dell’orto, P.; Larsimont, D.; Steinberg, I.; Gelber, R. D.; Piccart-Gebhart, M.; Viale, G.; Di Leo, A. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer-8-year results of the Breast International Group 02-98 phase III trial. Ann. Oncol. 2013, 24, 1203– 1211, DOI: 10.1093/annonc/mds62751https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s3ntFChtQ%253D%253D&md5=617171ca1973662d54d4f1758e09b129Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trialOakman C; Francis P A; Crown J; Quinaux E; Buyse M; De Azambuja E; Margeli Vila M; Andersson M; Nordenskjold B; Jakesz R; Thurlimann B; Gutierrez J; Harvey V; Punzalan L; Dell'orto P; Larsimont D; Steinberg I; Gelber R D; Piccart-Gebhart M; Viale G; Di Leo AAnnals of oncology : official journal of the European Society for Medical Oncology (2013), 24 (5), 1203-11 ISSN:.Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.
- 52Bailly, C. Topoisomerase i poisons and suppressors as anticancer drugs. Curr. Med. Chem. 2000, 7, 39– 58, DOI: 10.2174/092986700337548952https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXos1eqtg%253D%253D&md5=5f5d2c523f3afc63088126be99dc8435Topoisomerase I poisons and suppressors as anticancer drugsBailly, ChristianCurrent Medicinal Chemistry (2000), 7 (1), 39-58CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers)A review with 191 refs. Inhibitors of topoisomerase I constitute a novel family of antitumor agents. The camptothecin derivs. topotecan and irinotecan represent new weapons in our arsenal for battling human cancer. These two drugs act specifically at the level of the topoisomerase I-DNA complex and stimulate DNA cleavage. This mechanism of action is not restricted to the camptothecins. Numerous topoisomerase I poisons including DNA minor groove binders such as Hoechst 33258 and DNA intercalators such as benzophenanthridine alkaloids and indolocarbazole derivs. have been discovered and developed. Another important group of topoisomerase I inhibitors contains drugs which prevent or reverse topoisomerase I-DNA complex formation. Many of these topoisomerase I suppressors are natural products (β-lapachone, diospyrin, topostatin, topostin, flavonoids) which are believed to interact directly with the enzyme. This review is concerned with the different families of topoisomerase I poisons and suppressors. Their origin, chem. nature and mechanism of action are presented. The relationships between drug binding to DNA and topoisomerase I inhibition are discussed.
- 53Leung, K. K.; Downs, A. M.; Ortega, G.; Kurnik, M.; Plaxco, K. W. Elucidating the mechanisms underlying the signal drift of electrochemical aptamer-based sensors in whole blood. ACS Sens. 2021, 6, 3340– 3347, DOI: 10.1021/acssensors.1c0118353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFGhtL%252FO&md5=3f8ec70b9f33aed205bc18aaf3481c81Elucidating the Mechanisms Underlying the Signal Drift of Electrochemical Aptamer-Based Sensors in Whole BloodLeung, Kaylyn K.; Downs, Alex M.; Ortega, Gabriel; Kurnik, Martin; Plaxco, Kevin W.ACS Sensors (2021), 6 (9), 3340-3347CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)The ability to monitor drugs, metabolites, hormones, and other biomarkers in situ in the body would greatly advance both clin. practice and biomedical research. To this end, we are developing electrochem. aptamer-based (EAB) sensors, a platform technol. able to perform real-time, in vivo monitoring of specific mols. irresp. of their chem. or enzymic reactivity. An important obstacle to the deployment of EAB sensors in the challenging environments found in the living body is signal drift, whereby the sensor signal decreases over time. To date, we have demonstrated a no. of approaches by which this drift can be cor. sufficiently well to achieve good measurement precision over multihour in vivo deployments. To achieve a much longer in vivo measurement duration, however, will likely require that we understand and address the sources of this effect. In response, here, we have systematically examd. the mechanisms underlying the drift seen when EAB sensors and simpler, EAB-like devices are challenged in vitro at 37°C in whole blood as a proxy for in vivo conditions. Our results demonstrate that electrochem. driven desorption of a self-assembled monolayer and fouling by blood components are the two primary sources of signal loss under these conditions, suggesting targeted approaches to remediating this degrdn. and thus improving the stability of EAB sensors and other, similar electrochem. biosensor technologies when deployed in the body.
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