Using polyethylene glycol (PEG) to functionalize liposomes improves their stealth properties and stability in blood. However, PEG is known to induce the accelerated blood clearance (ABC) phenomenon, which occurs for multiple doses owing to anti-PEG IgM being produced after the initial injection. In this study, as an alternative to PEG, polysarcosine (PSar) was selected owing to its low antigenicity and its highly dense chains with controllable lengths, similar to PEG. Furthermore, we directly evaluate the potential of PSar for avoiding the ABC phenomenon by comparing PSar with PEG on the same liposome platform, which has similar physicochemical properties such as hydrophobic region, membrane fluidity, and size. PEG- and PSar-liposomes were prepared and characterized for comparison. PSar-liposomes showed similar physicochemical properties to PEG-liposomes in terms of size control, zeta potential, membrane polarity, and fluidity; however, ELISA results showed noticeably lower levels and faster production speeds of both IgM and IgG for PSar-liposomes than for PEG-liposomes. In addition, a pharmacokinetics experiment with multiple injections showed that PSar-PE coating of liposomes may help to circumvent the ABC phenomenon.
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