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Abstract
Zwitterionic polycarboxybetaines (PCBs) have gained attention as alternative stealth polymers whose
liposomal formulation and protein conjugates were reported not to elicit anti-polymer antibodies. Here, we
studied the blood retention and antigenicity of liposomes modified with PCBs focusing on their chemical
structures and doses. We compared PCBs with either 1 or 3 (PCB1 or PCB3) spacer carbons between the
carboxylate and ammonium groups. PCB3-modified liposomes had a short blood retention, whereas PCB1-
modified liposomes demonstrated extended blood retention that was somewhat superior to PEGylated liposome.
This confirmed the excellent non-fouling nature of PCB1 reported previously. Interestingly, PCB1-liposome as
well as PCB3-liposome elicited specific IgMs toward each PCB. The dose-dependent production of specific
IgMs to PCB-liposomes was similar to that of PEGylated liposome, i.e., high doses of PCB-liposomes reduced
the production of specific IgMs, termed immunological tolerance. These results indicate the importance of
investigating the effect of dose to clarify the existence of antigenicity of stealth polymers
