Development and Application of an MS^ALL-Based Approach for the Quantitative Analysis of Linear Polyethylene Glycols in Rat Plasma by Liquid Chromatography Triple-Quadrupole/Time-of-Flight Mass Spectrometry

Abstract

Polyethylene glycols (PEGs) are synthetic polymers composed of repeating ethylene oxide subunits. They display excellent biocompatibility and are widely used as pharmaceutical excipients. To fully understand the biological fate of PEGs requires accurate and sensitive analytical methods for their quantitation. Application of conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) is difficult because PEGs have polydisperse molecular weights (MWs) and tend to produce multicharged ions in-source resulting in innumerable precursor ions. As a result, multiple reaction monitoring (MRM) fails to scan all ion pairs so that information on the fate of unselected ions is missed. This Article addresses this problem by application of liquid chromatography-triple-quadrupole/time-of-flight mass spectrometry (LC-Q-TOF MS) based on the MS technique. This technique performs information-independent acquisition by allowing all PEG precursor ions to enter the collision cell (Q2). In-quadrupole collision-induced dissociation (CID) in Q2 then effectively generates several fragments from all PEGs due to the high collision energy (CE). A particular PEG product ion (m/z 133.08592) was found to be common to all linear PEGs and allowed their total quantitation in rat plasma with high sensitivity, excellent linearity and reproducibility. Assay validation showed the method was linear for all linear PEGs over the concentration range 0.05-5.0 μg/mL. The assay was successfully applied to the pharmacokinetic study in rat involving intravenous administration of linear PEG 600, PEG 4000, and PEG 20000. It is anticipated the method will have wide ranging applications and stimulate the development of assays for other pharmaceutical polymers in the future.

Recent advances in the bioanalytical methods of polyethylene glycols and PEGylated pharmaceuticals

“…Zhou et al. applied this technique to analyze the PEGs in rat plasma, the triethylene glycol fragment was identified as an optimal product ion for the quantification of PEG, due to its high sensitivity and minimal endogenous interferences (Figure 6III) [219]. Combined with appropriate sample preparation procedure and chromatographic separation, PEG 400, PEG 600, PEG 750, PEG 2000, PEG 4000, PEG 5000, PEG 6000, PEG 10 kDa, and PEG 20 kDa were analyzed by this technique.…”

Cargo-Free Nanomedicine with pH Sensitivity for Codelivery of DOX Conjugated Prodrug with SN38 To Synergistically Eradicate Breast Cancer Stem Cells

“…As shown in Table S2, in the free PEG−DOX+SN38 group, there were 20 metabolites significantly altered in plasma compared to in the normal group, including a decrease in pyruvic acid, lactic acid, 3-phosphoglycerate, malic acid, and amino acids and an increase in palmitoleic acid, which indicated an abnormality in energy metabolism and amino acid metabolism. 40,41 In contrast, only seven significantly altered plasma metabolites in PEG−DOX/SN38 NPs vs the normal group were distinguished (Table S3). Moreover, as shown in Table S4, 21 significantly altered liver metabolites in free PEG−DOX +SN38 vs the normal group were identified, such as an increase in malic acid, fumaric acid, and so on, while there were only 4 significantly altered liver metabolites in PEG−DOX/ SN38 NPs vs the normal group (Table S5).…”

Ultra‐high‐performance liquid chromatography coupled with quadrupole time of flight mass spectrometry method for quantifying polymer poloxamer 124 and its application to pharmacokinetic study

“…Therefore, it is urgent to develop a sensitive and accurate method. In this study, quantitative study was conducted on a UHPLC-Q-TOF MS with high resolution as well as strong qualitative and quantitative capabilities, which combined UHPLC coupled with Q-TOF-MS. Highmolecular polymer PEG has been successfully quantified in a way that provides a good theoretical basis for quantifying PL124 [19][20][21]. To the best of our knowledge, there is no study about the pharmacokinetics of PL124.…”