Deciphering the in vivo fate and biomacromolecular interactions of DSPE-PEG2000

  • J Control Release. 2025 Dec 22:390:114571. doi: 10.1016/j.jconrel.2025.114571.
Deqi Cai  1 ,  Chong Su  2 ,  Mingyang Zhao  3 ,  Huan Yang  3 ,  Zhe Zhang  2 ,  Yingze Liu  2 ,  Jingkai Gu  4
Affiliations
  • 1. State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, PR China; Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, PR China.
  • 2. Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, PR China.
  • 3. Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, PR China; Beijing Institute of Drug Metabolism, Beijing 102209, PR China.
  • 4. State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, PR China; Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, PR China; Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, PR China; Beijing Institute of Drug Metabolism, Beijing 102209, PR China. Electronic address: [email protected].
PMID: 41443353 DOI: 10.1016/j.jconrel.2025.114571
Abstract

DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-2000), a key excipient of stealth nano-formulations like Doxil®, prolongs nano-carrier blood residence by forming steric hydrophilic barriers. However, its assumed biological inertness faces challenges from emerging PEG-related risks. Limited by analytical methods, its in vivo fate and biomacromolecular interactions remain uncharacterized. Here, Liquid Chromatography-Quadrupole/Time-of-Flight Mass Spectrometry (LC-Q-TOF MS) and anti-PEG single-chain variable fragment (PEG-scFv) strategy were innovatively employed to decode DSPE-PEG2000's biological properties post-intravenous administration. Results reveal a short plasma half-life, tissue-specific distribution in lung, liver, and spleen, complement activation without adaptive antibody response, cleavage to DSPE/PEG2000 with renal excretion/degradation of PEG2000, and a plasma protein binding rate (PPB) of 63.2 ± 7.11 % that competitively displaces 50 % of doxorubicin binding. These findings establish its non-inert profile of tissue-specific distribution, innate immune activation, complex metabolism, and plasma protein-based excipient-drug interactions, highlighting DSPE-PEG2000's potential safety risks. The innovative methodology developed herein provides a paradigm for polymer tracking and offers critical insights to guide excipient safety assessments and optimization.

Keywords
DSPE-PEG2000; Drug-excipient interaction; LC-MS/MS; LC-Q-TOF MS; Pharmacokinetics; Single-chain variable fragment(scFv).
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