The PEGylation strategy of covalently modifying small molecule drugs, peptides and protein drugs with polyethylene glycol (PEG) to improve their pharmacokinetics and efficacy has become one of the most widely used drug modification technologies. However, the immunogenicity and antigenicity of PEG severely limit the clinical efficacy of PEGylated drugs and preparations. Because polymerdisper PEG is a homologous mixture, it has certain obstacles to the study of drug mechanism. Here we use a special end-group capping strategy to separate PEGs with different degrees of polymerization, which minimizes side reactions during the reaction and avoids complicated separation and purification steps. A series of single molecular weight PEGs with a degree of polymerization of 8-192 were successfully synthesized, and the maximum molecular weight was as high as 8848 Da (8848 meters above sea level of Mount Everest). Subsequently, we prepared single-molecule PEGylated probes and liposomes with a single molecular weight, preliminary studies found that they have longer blood half-life and less total protein corona. In further comparison of the empty liposomes without DOX loading, it was found that the amount of anti-PEG antibodies produced by monodisperse PEG-DSPE liposomes after intravenous injection into mice was much smaller than that of polydisperse PEG. These materials will have a major impact on the research and innovation of PEGylated drugs in the future.

Study on biological effects of single molecular weight accurate polyethylene glycol

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