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<p>Individual polyethylene glycol (PEG) oligomers’ in vivo fate is crucial for evaluating polymer-based therapeutic safety. Herein, a high-throughput UPC<sup>2</sup>-MS/MS method was developed for the oligomer-resolved excretion kinetics of PEG600 (<i>n</i> = 10–17) in rats. By optimizing supercritical CO<sub>2</sub> chromatography and utilizing ammonium adducts ([M+NH<sub>4</sub>]<sup>+</sup>), baseline separation of eight oligomers was achieved within 2.4 min, significantly enhancing efficiency for bioanalysis. This platform significantly enhances analytical capacity, enabling the efficient processing of large-scale biological sample sets required for mass balance studies. Application of this method revealed distinct molecular-weight-dependent elimination. Specifically, 72-h urinary recovery showed a complex non-linear relationship, peaking at <i>n</i> = 10 (71.9%) and <i>n</i> = 16 (72.7%). Simultaneously, total cumulative recovery (urine and feces) decreased progressively from &gt;95% (<i>n</i> = 10, 11) to 75.3% (<i>n</i> = 17). This reduction suggests enhanced tissue sequestration or metabolic biotransformation for larger oligomers. This high-resolution profiling uncovers subtle elimination differences obscured in bulk analysis, providing critical pharmacokinetic insights for PEG excipients.</p> Graphical abstract <p></p>

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High-throughput UPC2-MS/MS for elucidating the molecular-weight-dependent excretion kinetics of PEG polymers with 10–17 subunits

  • 期刊论文

  • 发表日期：

    2026年3月12日

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  • Jiarui Zhang,
  • Jiale Liu,
  • Jintian Lai,
  • Yue Deng,
  • Shuang Feng,
  • Xinyue Zhou,
  • Meiyun Shi,
  • Lei Yin

摘要

Individual polyethylene glycol (PEG) oligomers’ in vivo fate is crucial for evaluating polymer-based therapeutic safety. Herein, a high-throughput UPC2-MS/MS method was developed for the oligomer-resolved excretion kinetics of PEG600 (n = 10–17) in rats. By optimizing supercritical CO2 chromatography and utilizing ammonium adducts ([M+NH4]+), baseline separation of eight oligomers was achieved within 2.4 min, significantly enhancing efficiency for bioanalysis. This platform significantly enhances analytical capacity, enabling the efficient processing of large-scale biological sample sets required for mass balance studies. Application of this method revealed distinct molecular-weight-dependent elimination. Specifically, 72-h urinary recovery showed a complex non-linear relationship, peaking at n = 10 (71.9%) and n = 16 (72.7%). Simultaneously, total cumulative recovery (urine and feces) decreased progressively from >95% (n = 10, 11) to 75.3% (n = 17). This reduction suggests enhanced tissue sequestration or metabolic biotransformation for larger oligomers. This high-resolution profiling uncovers subtle elimination differences obscured in bulk analysis, providing critical pharmacokinetic insights for PEG excipients.

Graphical abstract