Accelerated Blood Clearance of Nanoemulsions Modified
with PEG-Cholesterol and PEG-Phospholipid Derivatives in Rats: The
Effect of PEG-Lipid Linkages and PEG Molecular Weights
posted on 2020-03-09, 14:40authored byMengyang Liu, Yanyi Chu, Huan Liu, Yuqing Su, Qi Zhang, Jiao Jiao, Mingqi Liu, Junqiang Ding, Min Liu, Yawei Hu, Yueying Dai, Rongping Zhang, Xinrong Liu, Yihui Deng, Yanzhi Song
Various types of nanocarriers modified
with poly(ethylene glycol)
(PEG) exhibit the accelerated blood clearance (ABC) phenomenon, resulting
in reduced circulation time and abnormal increase in hepatic and splenic
accumulations. Based on the abundance of esterases in the serum of
rats, we developed cleavable methoxy PEG-cholesteryl methyl carbonate
(mPEG-CHMC) with a carbonate linkage and noncleavable N-(carbonyl-methoxy PEG-n)-1,2-distearoyl-sn-glycero-3-phos-phoethanolamine (mPEG-DSPE) with a carbamate
linkage on the surface of the nanoemulsions (CHMCE and PE, respectively).
Both PEG derivatives possessed PEG with six different molecular weights
(n = 350, 550, 750, 1000, 2000, and 5000). The pharmacokinetic
behaviors and biodistributions of single and repeated injection of
the two types of PEGylated nanoemulsions were determined to investigate
the influence of cleavable linkages and PEG molecular weights on the
ABC phenomenon in an attempt to find a potential strategy to eliminate
the ABC phenomenon. CHMCEns (n =
1000, 2000, and 5000) exhibited the same pharmacokinetic behaviors
as PE550 and PE750 and only alleviated the ABC phenomenon to a certain
extent at the expense of shortened cycle time, indicating that the
cleavable carbonate linkage was not an ideal strategy to eliminate
the ABC phenomenon. As the molecular weights of PEG increased, the
ABC phenomenon became more severe. Surprisingly, PE5000 induced a
lower anti-PEG IgM level and a weaker ABC phenomenon compared with
PE2000 while possessing a similar long circulation time. The results
suggested that increasing the molecular weight of PEG in the PEG derivatives
could be a potential strategy for eliminating the ABC phenomenon while
simultaneously guaranteeing longer circulation time.