Personalized monitoring of therapeutic salicylic acid in dried blood spots using a three-layer setup and desorption electrospray ionization mass spectrometry

Abstract

Desorption electrospray ionization (DESI) mass spectrometry is an emerging technology for direct therapeutic drug monitoring in dried blood spots (DBS). Current DBS methods require manual application of small molecules as internal standards for absolute drug quantification. With industrial standardization in mind, we superseded the manual addition of standard and built a three-layer setup for robust quantification of salicylic acid directly from DBS. We combined a dioctyl sodium sulfosuccinate weave facilitating sample spreading with a cellulose layer for addition of isotope-labeled salicylic acid as internal standard and a filter paper for analysis of the standard-containing sample by DESI-MS. Using this setup, we developed a quantification method for salicylic acid from whole blood with a validated linear curve range from 10 to 2000 mg/L, a relative standard deviation (RSD%) ≤14%, and determination coefficients of 0.997. The limit of detection (LOD) was 8 mg/L and the lower limit of quantification (LLOQ) was 10 mg/L. Recovery rates in method verification by LC-MS/MS were 97 to 101% for blinded samples. Most importantly, a study in healthy volunteers after administration of a single dose of Aspirin provides evidence to suggest that the three-layer setup may enable individual pharmacokinetic and endpoint testing following blood collection by finger pricking by patients at home. Taken together, our data suggests that DBS-based quantification of drugs by DESI-MS on pre-manufactured three-layer cartridges may be a promising approach for future near-patient therapeutic drug monitoring.

Rapid drug detection in whole blood droplets using a desorption electrospray ionization static profiling approach – a proof‐of‐concept

“…In contrast, methods for DESI analysis of DBS necessitate relatively high solvent spray volumes (up to 15 μL/min). Using DBS also necessitates relatively high volumes of blood (6–15 μL), thus preventing the deposition of a large number of blood spots in a limited surface. The concept of DESI static profiling of blood droplets also opens a large field for high‐throughput analytics.…”

“…However, it was not possible to obtain a satisfactory sensitivity using dried plasma spots without LLE . Whole blood was also analyzed by DESI using dried blood spots (DBS) and could be used for drug quantification purposes …”

Ambient ionization and miniature mass spectrometry system for chemical and biological analysis

“…While semi-quantitation can be simply performed by ambient ionization, the use of internal standards (IS) can significantly improve the limit of quantitation (LOQ), linear dynamic range, and RSD for the analysis. Using salicylic acid isotopologue as the IS, DESI-MS was utilized for the quantitation of therapeutic salicylic acid in rat DBS using a three-layer setup for sampling [44]. Good correlation was observed between quantitative results by DESI-MS and LC-MS/MS (Fig.…”

“…Quantitative analysis by ambient ionization-MS. (a) Good correlation between DESI-MS and LC-MS/MS quantitative results of SA in rat DBS using the three-layer setup (Reprinted with permission from [44], Elsevier) (b) Calibration curve of sitamaquine in rat blood (10–10, 000 ng/ml) using 570 ng/ml sitamaquine- d 10 as the IS. (Reprinted with permission from [45], Wiley) (c) Calibration curve for the analysis of sitamaquine in rat blood by liquid extraction-based surface sampling and ionization using sitamaquine- d 10 as the IS.…”

In-capillary microextraction for direct mass spectrometry analysis of biological samples

“…These achievements suggest a promising direction in technical development for direct MS analysis of complex samples. Although several works have been done by DESI[17] and paper spray[18,19], direct MS analysis of biofluid is still inefficient and remains challenging.…”