Coating liposomes with ring-like PEG: the synthesis and stealth effect of cholesterol–PEG–cholesterol

Abstract

Escaping from the immune system to achieve a long circulation time is an essential prerequisite for targeting liposomes. Monomethoxy-poly(ethylene glycol)–distearoylphosphatidylethanolamine (mPEG–DSPE) is the most commonly used stealth polymer for long circulating liposomes. With its monomethoxy end moving freely on the liposomal surface, the linear PEG chains of mPEG–DSPE construct a hydration layer to repel complement proteins and thus evade immune clearance. We describe in this work a new kind of PEG derivative whose two ends were grafted with cholesterol (cholesterol–PEG–cholesterol, CPC). According to the in vitro and in vivo results, the presence of CPC in liposomes was shown to reduce the uptake by phagocyte cells while extending the circulation time. The stealth performance of CPC liposomes is closely related to the molecular weight of PEG moieties. CPC_6k performed better than CPC_2k, CPC_4k and the commonly used mPEG_2k–DSPE. CPC on the liposomal surface would not let the free end of PEG act as the immune recognition site, meanwhile, the PEG chain of CPC tends to adopt a twisted ring-like conformation rather than a linear conformation, which is considered to be associated with the stealth effect. This finding adds to the range of stealth liposomes and may be valuable for developing new drug carriers.