Effects of stability of PEGylated micelles on the accelerated blood clearance phenomenon.

Accelerated blood clearance (ABC) is a phenomenon where the blood clearance rate of the carrier system is substantially raised. It can be induced by repetitive injections of polyethylene glycol (PEG) (molecular weight 2000)-modified micelles (PM2000). To determine whether the PEG chain length and PEGylated micelle injection dose can have an effect on the ABC phenomenon, micelles were modified with PEGs of varying molecular weights; PEGs with molecular weights of 350, 550, 2000, 5000, 10,000, and 20,000 were used to generate the PEGylated micelles PM350, PM550, PM2000, PM10000, and PM20000, respectively. One special carrier, MCT-PM2000, was prepared with the original PM2000 formulation but also included extra medium-chain triglycerides. Our experimental results showed that PM2000 and PM5000 exhibit superior storage stability compared to that of PM350, PM550, PM10000, and PM20000. MCT-PM2000 demonstrated stronger dilution stability than PM2000. As expected, PM2000 and PM5000 induced the strongest enhancement in blood elimination rate compared to that of PM350, PM550, PM10000, and PM20000; MCT-PM2000 exhibited more intense ABC phenomenon compared to that of PM2000. In addition, induction of the ABC phenomenon by PM2000 and MCT-PM2000 was augmented when the injection dose was increased from 0.05 to 5 μmol phospholipid·kg. Based on our findings, we suggest that there is a positive linear relationship between stability of PEG-modified micelles and susceptibility to the ABC phenomenon. The results may be valuable for designing PEGylated micelles for multiple drug therapy.