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Effects of Uncleavable and Cleavable PEG-Lipids with Different Molecular Weights on Accelerated Blood Clearance of PEGylated Emulsions in Beagle Dogs

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Abstract

To investigate the effect of polyethylene glycol (PEG) molecular weights on circulation time of PEGylated emulsions and the second injection of injected PEGylated emulsions, we studied the effect of molecular weights on the pharmacokinetic behavior of PEG-DSPE (modified emulsions with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethyleneglycol)]) and PEG-CHMC (modified emulsions with poly(ethyleneglycol)-cholesteryl carbonate) emulsions in beagle dogs. The “accelerated blood clearance” (ABC) phenomenon was induced. Through this study, the contribution of PEG molecular weights on the ABC phenomenon was further clarified, and the results provided guidance for lessening or eliminating the ABC phenomenon. We injected different PEG-modified emulsions with 10% PEG-modified density into beagle dogs at 2 μmol phospholipids kg−1 and the blood samples were drawn after 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 60 min, 120 min, 240 min, 360 min, 600 min, and 24 h. Then, concentrations of the drug were assayed using high-performance liquid chromatography (HPLC). The results showed that the circulation times of PEG-DSPE–modified emulsions were significantly different because of the difference in molecular weights, whereas those of the PEG-CHMC modified emulsions were not. The spatial conformation of PEG with small molecular weights (PEG400, PEG600, and PEG800) was more likely to induce a strong ABC phenomenon. The results of our work suggest the interaction of circulation time and PEG molecular weights on the ABC phenomenon, implying that the spatial conformation of PEG has advantages that alleviate the ABC phenomenon. Importantly, the results have implications for the choice of molecular weights of PEG for PEGylated formulations.

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Acknowledgments

This study was supported by the Scientific Research Project of Yuncheng University (Grant CY-2017013) and the National Natural Science Foundation of China (Grant Nos. 81573375).

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Authors and Affiliations

  1. College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China

    Jiao Jiao, Xiang Luo, Chunling Wang, Mengyang Liu, Xinrong Liu, Yihui Deng & Yanzhi Song

  2. Department of Applied Chemistry, Yuncheng University, Yuncheng, 044000, Shanxi, China

    Jiao Jiao & Liting Wei

  3. College of Chemistry and Chemical Engineering, Shaoxing University, Zhejiang, 312000, China

    Xiang Luo

  4. Department of Politics and Public Administration, Yuncheng Advanced Normal College, Yuncheng, 044000, Shanxi, China

    Xiaoqin Jiao

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  1. Jiao Jiao
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Correspondence to Yihui Deng or Yanzhi Song.

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Experiments applied on all animals were all carried out consistent with the procedures approved by local Animal Welfare Committee.

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Jiao, J., Luo, X., Wang, C. et al. Effects of Uncleavable and Cleavable PEG-Lipids with Different Molecular Weights on Accelerated Blood Clearance of PEGylated Emulsions in Beagle Dogs. AAPS PharmSciTech 21, 106 (2020). https://doi.org/10.1208/s12249-020-1640-4

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