Size-dependent Induction of Accelerated Blood Clearance Phenomenon by Repeated Injections of Polymeric Micelles

An accelerated blood clearance (ABC) phenomenon is induced by repeated injections of poly(ethylene glycol)-modified (PEGylated) liposomes. We previously indicated that the phenomenon was induced by polymeric micelles possessing PEG chains like as liposomes, although, the induction mechanism of the ABC phenomenon is not fully elucidated. In the present study, we investigate whether repeat-injection of the polymeric micelles having PEG chains trigger the phenomenon or not. Two polymeric micelles, PM-30 (polymeric micelles with 33.6nm in diameter) and PM-75 (76.2nm), were prepared with PEG-poly[Asp(pentyl)] and PEG-poly[Asp(nonyl)], respectively. We firstly examined the ABC-triggering effect of these micelles, and observed that both polymeric micelles, especially PM-75, induced the production of anti-PEG IgM antibody in treated mice. Then, PM-30 or PM-75 was preadministered into mice as a preconditioning. Seven days later, AlexaFluor594-labeled PM-30 or PM-75 was administered to determine the susceptibility of the phenomenon. As a result, rapid clearance of AlexaFluor594-labeled PM-75 from the bloodstream and accumulation in the liver were observed in PM-75 pretreated mice. Although, the ABC phenomenon of AlexaFluor594-labeled PM-30 was less obvious in PM-30 pretreated mice. Our present results indicated that the repeated injections of polymeric micelles caused the ABC phenomenon in a size-dependent manner.