Branched PEG-modification: A new strategy for nanocarriers to evade of the accelerated blood clearance phenomenon and enhance anti-tumor efficacy.

Abstract

PEGylation is one of the most successful technologies for reducing immunogenicity, improving the stability and circulation time of nanocarriers, and has been applied in the clinic for over three decades. However, linear PEG-modified nanocarriers have been found to induce anti-PEG IgM at the first injection, which triggers the accelerated blood clearance (ABC) phenomenon upon repeated injections. Furthermore, clinical and research evidence has revealed that anti-PEG antibodies also cause serious complement activation-related pseudoallergies (CARPA), which greatly reduce the safety of linear PEGylated nanocarriers. In this study, as an alternative to linear PEG, branched PEG was selected owing to its low antigenicity. We pioneer the use of branched PEG lipid derivatives [DSPE-mPEG_2,n (n = 2, 10, and 20 kDa)] to modify nanoemulsions (PE_2,n) and liposomes (PL_2,n). Upon characterization, PE_2,n and PL_2,n showed similar physicochemical properties to linear DSPE-mPEG₂₀₀₀-modified nanocarriers in terms of size, polydispersity index (PDI), and zeta potential. However, our pharmacokinetics study surprisingly indicated that PE_2,n and PL_2,n did not induce the ABC phenomenon after repeated injection. This may be attributed to the fact that PE_2,n and PL_2,n induced noticeably lower levels of anti-PEG IgM than linear PEG-modified nanocarriers and did not activate the complement system. Furthermore, we are the first to investigate the anti-tumor efficacy of DSPE-mPEG_2,n-modified liposomal doxorubicin (DOX). The pharmacodynamic experiments showed that DSPE-mPEG_2,n-m-modified liposomal DOX had better in vivo anti-tumor effects than linear DSPE-mPEG₂₀₀₀-modified liposomes. Therefore, we speculate that DSPE-mPEG_2,n-modified nanocarriers possess promising prospects in avoiding the ABC phenomenon, reducing CARPA, and improving the anti-tumor efficacy of encapsulated drugs.