A noticeable phenomenon: Thiol terminal PEG enhances the immunogenicity of PEGylated emulsions injected intravenously or subcutaneously into rats

Repeated intravenous injection of long-circulating methoxy-polyethylene glycol (PEG)-liposomes alters the pharmacokinetics and biodistribution of the second administration, regarded as the “accelerated blood clearance (ABC) phenomenon.” Nevertheless, the effect of terminal groups of distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) on the induction of the ABC phenomenon had not been reported previously. In this study, rats were injected intravenously or subcutaneously with PEG coated emulsions (DE) which were prepared using PEG terminated with either the methoxyl (OCH3), hydroxyl (OH), amino (NH2), carboxyl (COOH), or thiol (SH) group. DE-OCH3 demonstrated the longest prolonged half-life in vivo after a single intravenous injection, followed by DE-SH and DE-COOH. In contrast, DE-OH was rapidly removed from the blood circulation, as was DE-NH2. Moreover, we observed a strong positive relationship between the circulation time of initially injected PEGylated emulsions and the extent to which the ABC phenomenon was induced, but a exception of DE-SH increasing the ABC effect. Furthermore, the present study suggested that thiols might stimulate the proliferation and differentiation of B cells to induce the fastest clearance of the second intravenous administration by inducing the synthesis of the cell membrane and cytosolic proteins or reacting with follicular dendritic cells. The results strongly suggested that thiol groups played a stimulatory role in the immune response and provided a considerable implication for multiple drug therapy of thiol groups.

Graphical abstractDSPE-PEG-SH-modified emulsions induced a significant ABC phenomenon and produced high levels anti-PEG IgM, regardless of the administration route (intravenous or subcutaneous).Figure optionsDownload full-size imageDownload high-quality image (91 K)Download as PowerPoint slide