Ultrasensitive In Vitro and Ex Vivo Tracking of 13C-Labeled PEG–PLA Degradation Products by MALDI-TOF Mass Spectrometry

Copolymers of poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) are widely used in biomedical applications. As inactive ingredients in formulations, tracking their degradation byproducts in vivo stands as a major challenge but is a pivotal endeavor to ensure safety and further progress in clinical stages. Current bioanalytical methods used to monitor this degradation lack sensitivity and quantification precision. This study introduces a cost-effective synthetic route for 13C-labeled PEG–PLA copolymers, combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), to monitor their in vitro and ex vivo degradation. Incorporating 13C isotopes into copolymers significantly enhances MALDI-TOF sensitivity, allowing for precise detection of degradation products at exceedingly low concentrations. We demonstrate the ability to trace 13C-labeled PEG–PLA in complex biological media (urine, plasma) at concentrations 100 times lower than labeled PEG–PLA. Our results pave the way toward ultrasensitive in vivo tracking and elucidation of in vivo fate of this widely investigated polymer family.