Self-assembly PEGylation Retaining Activity (SPRA) technology via an interaction between cyclodextrin and adamantane: Application for insulin, lysozyme and bromelain

15^th Annual European Pharma Congress

May 07-09, 2018 | Frankfurt, Germany

Taishi Higashi, Keiichi Motoyama and Hidetoshi Arima

Kumamoto University, Japan

Scientific Tracks Abstracts: Pharmaceut Reg Affairs

Abstract :

Polyethylene glycol (PEG) modification (PEGylation) is one of the best approaches to improve the stabilities and blood halflives of protein drugs; however, PEGylation dramatically reduces the bioactivities of protein drugs. Here, we present â�?�?selfassembly PEGylation retaining activityâ�? (SPRA) technology via a hostâ�?�?guest interaction between PEGylated �?²-cyclodextrin (PEG-�?²-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 FITCdextran (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. Recent Publications 1. Higashi T, Hirayama F, Misumi S, Arima H, Uekama K (2008) Design and evaluation of polypseudorotaxanes of PEGylated insulin with cyclodextrins as sustained release system. Biomaterials 29:3866-3871. 2. Higashi T, Li J, Song X, Zhu J, Taniyoshi M, Hirayama F, Iohara D, Motoyama K, Arima H (2016) Thermoresponsive formation of dimethyl cyclodextrin polypseudorotaxanes and subsequent one-pot synthesis of polyrotaxanes. ACS Macro Lett. 5:158-162. 3. Hirotsu T, Higashi T, Abu Hashim II, Misumi S, Wada K, Motoyama K, Arima H (2017) Self-assembly PEGylation Retaining Activity (SPRA) technology via a host-guest interaction surpassing conventional PEGylation methods of proteins. Mol. Pharm. 14:368-376. 4. Hirotsu T, Higashi T, Motoyama K, Arima H (2017) Cyclodextrin-based sustained and controllable release system of insulin utilizing the combination system of self-assembly PEGylation and polypseudorotaxane formation. Carbohydr. Polym. 15:42-48.

Biography :

Taishi Higashi took part in a half-year internship of Evonik Röhm GmbH & Co., Darmstadt, Germany in 2008. Then, he obtained PhD (Pharmaceutical Sciences) at Kumamoto University, Japan in 2009. In 2009-2011, he became a Research Scientist of Taisho Pharmaceutical Co., Ltd, Japan, and engaged self-medication business such as oral solid formulation. From 2011, he works as a Research Associate in the Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences at Kumamoto University, Japan. In 2013-2014, he became a Guest Researcher at Faculty of Engineering, National University of Singapore. From 2016, he holds the additional post as a Technical Adviser in CyDing Co., Ltd. His research topic is “supramolecular pharmaceutical sciences” which combines Pharmaceutical Sciences and Supramolecular Chemistry.
Email:higashit@kumamoto-u.ac.jp