Accelerated blood clearance of nanoemulsions modified with PEG-cholesterol and PEG-phospholipid derivatives in rats: The effect of PEG-lipid linkage and PEG molecular weight.
Accelerated blood clearance of nanoemulsions modified with PEG-cholesterol and PEG-phospholipid derivatives in rats: The effect of PEG-lipid linkage and PEG molecular weight.
复制标题
DOI：
10.1021/acs.molpharmaceut.9b00770
复制
发表时间：
2019-12
影响因子：
4.9
通讯作者：
Mengyang Liu;Yanyi Chu;Huan Liu;Yuqing Su;Qi Zhang;Jiao Jiao-Jiao;Mingqi Liu;Junqiang Ding;Min Liu;Yawei Hu;Yueying Dai;Rongping Zhang;Xinrong Liu;Yihui Deng;Yanzhi Song
中科院分区：
文献类型：
--
作者：
Mengyang Liu;Yanyi Chu;Huan Liu;Yuqing Su;Qi Zhang;Jiao Jiao-Jiao;Mingqi Liu;Junqiang Ding;Min Liu;Yawei Hu;Yueying Dai;Rongping Zhang;Xinrong Liu;Yihui Deng;Yanzhi Song
用聚乙二醇（PEG）修饰的各种类型的纳米载体表现出加速血液清除（ABC）现象，导致循环时间缩短和肝脏和脾脏蓄积异常增加。基于大鼠血清中酯酶的丰度，我们在纳米乳液（分别为CHMCE和PE）的表面上开发了具有碳酸酯键的可裂解甲氧基聚（乙二醇）-胆固醇碳酸甲酯（mPEG-CHMC）和具有氨基甲酸酯键的不可裂解N-（羰基-甲氧基聚乙二醇-n）-1，2-二硬脂酰基-sn-甘油基-3-羟基-乙醇胺（mPEG-DSPE）。两种PEG衍生物均具有六种不同分子量的PEG（n = 350、550、750、1000、2000和5000）。通过单次和重复注射两种聚乙二醇化纳米乳的药代动力学行为和生物分布，研究可裂解键和PEG分子量对ABC现象的影响，试图找到消除ABC现象的潜在策略。CHMCEn（n = 1000、2000和5000）表现出与PE 550和PE 750相同的药代动力学行为，并且仅在一定程度上以缩短循环时间为代价减轻ABC现象，表明可裂解的碳酸酯键不是消除ABC现象的理想策略。随着PEG分子量的增加，ABC现象变得更加严重。令人惊讶的是，与PE 2000相比，PE 5000诱导较低的抗PEG IgM水平和较弱的ABC现象，同时具有相似的长循环时间。结果表明，增加PEG衍生物中PEG的分子量可能是消除ABC现象同时保证更长循环时间的潜在策略。
Various types of nanocarriers modified with polyethylene 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 poly(ethylene glycol)-cholesteryl methyl carbonate (mPEG-CHMC) with a carbonate linkage and non-cleavable N-(Carbonyl-methoxy polyethyleneglycol-n)-1,2-distearoyl-sn-glycero-3-phos-phoethanolamine (mPEG-DSPE) with an 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 linkage and PEG molecular weight 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 cleavable carbonate linkage was not an ideal strategy to eliminate the ABC phenomenon. As the molecular weights of PEG increased, ABC phenomenon became more severe. Surprisingly, PE5000 induced lower anti-PEG IgM level and weaker ABC phenomenon compared with PE2000, while possessing 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.