Evasion of the accelerated blood clearance phenomenon by branched PEG lipid derivative coating of nanoemulsions

PEGylation increases the circulation time of the nanocarrier, but also triggers accelerated blood clearance (ABC) phenomenon. It is well-known that the ABC phenomenon results in shortened blood circulation and aberrant increase in liver and spleen accumulation, which greatly limits the application of PEGylated nano-preparations. For many years, researchers have been working hard to find ways to reduce or eliminate the ABC phenomenon. Previous studies have focused on PEG molecular weight and PEG alternative materials, but there has never been any research on the effect of different PEG chain types on the ABC phenomenon. Therefore, 40 kDa molecular weight of linear PEG lipid derivatives (DSPE-mPEG40k) and branched PEG lipid derivatives (DSPE-mPEG2,40k) were selected to modify nanoemulsions to explore the influence of distinct PEG chain types on avoiding the ABC phenomenon for the first time. We pioneer the use of linear and branched PEG lipid derivatives (DSPE-mPEG40k and DSPE-mPEG2,40k) to modify nanoemulsions (PE40k and PE2,40k). Upon characterization, PE40k and PE2,40k showed good physicochemical properties in the aspect of size, polydispersity index (PDI value), and zeta potential. Surprisingly, the pharmacokinetics study indicated that repeated injection of PE40k and PE2,40k did not trigger the ABC phenomenon. More importantly, PE2,40k possessed a long circulation time and did not cause ABC phenomenon after repeated injection. This may be attributed to the fact that PE2,40k induced noticeably lower anti-PEG IgM levels compared to linear PEG-modified nanocarriers and did not activate the complement system. Therefore, we speculate that DSPE-mPEG2,40k-modified nanocarriers possess promising prospects in avoiding the ABC phenomenon, which may improve the possibility of wide application of nanoformulations.