PEG length effect of peptide-functional liposome for blood brain barrier (BBB) penetration and brain targeting

Nanoparticles, in particular PEGylated, show great potential for in vivo brain targeted drug delivery. Nevertheless, how polyethylene glycol (PEG) length of nanoparticles affects their blood brain barrier (BBB) penetration or brain targeting is still unclear. In this study, we investigated the power of PEG chain-lengths (2, 3.4, 5, 10 kDa) in BBB penetration and brain targeting using Angiopep-2 peptide decorated liposomes. We found that PEG chain-length is critical, where the shorter PEG enabled the Angiopep-2 decorated liposomes to display more potent in vitro cell uptake via endocytosis. In contrast, their in vitro BBB penetration via transcytosis was much weaker relative to the liposomes with longer PEG chains, which result from their ineffective BBB exocytosis. Interestingly, the in vivo brain targeting aligns with the in vitro BBB penetration, as the long chain PEG-modified liposomes exerted superior brain accumulation both in normal or orthotropic glioblastoma (GBM) bearing mice, which could be ascribed to the combinational effect of prolonged circulation and enhanced BBB penetration of long chain PEG attached liposomes. These results demonstrate the crucial role of PEG length of nanoparticles for BBB penetration and brain targeting, providing guidance for PEG length selection in the design of nanocarrier for brain diseases treatment.