Taishi Higashi
Kumamoto University, Japan
Title: Self-assembly PEGylation Retaining Activity (SPRA) technology via an interaction between cyclodextrin and adamantane: Application for insulin, lysozyme and bromelain
Biography
Biography: Taishi Higashi
Abstract
Polyethylene glycol (PEG) modification (PEGylation) is one of the best approaches to improve the stabilities and blood half-lives of protein drugs; however, PEGylation dramatically reduces the bioactivities of protein drugs. Here, we present “self-assembly PEGylation retaining activity” (SPRA) technology via a host–guest interaction between PEGylated b-cyclodextrin (PEG-b-CyD) and adamantane-appended (Ad)-proteins. Firstly, we prepared SPRA-insulin and SPRA-lysozyme. Both SPRA-proteins showed high stability against heat and trypsin digest, comparable with that of covalently PEGylated protein equivalents. Importantly, the SPRA-lysozyme possessed ca. 100% lytic activity, whereas the activity of the covalently PEGylated lysozyme was ca. 23%. Additionally, SPRA-insulin provided a prolonged and peak-less blood glucose profile when compared with insulin glargine. It also showed no loss of activity. In contrast, the covalently PEGylated insulin showed a negligible hypoglycemic effect. Next, we prepared SPRA-bromelain, because bromelain is known to degrade the extracellular matrix (ECM) in pancreatic cancer and increase the penetration of antitumor agents, although the blood half-life of bromelain is short. SPRA-bromelain showed high in vitro ECM-degrading activity, and enhanced not only the accumulation of FITC-dextran (2 MDa) in the tumor, but also the in vivo antitumor activities of doxorubicin and DOXIL. These findings indicate that SPRA technology has the potential as a generic method, surpassing conventional PEGylation methods for proteins.