Youn, YS Na, DH Yoo, SD Song, SC Lee, KC 2024-01-21T04:41:30Z 2024-01-21T04:41:30Z 2021-09-01 2005-07 1357-2725 https://pubs.kist.re.kr/handle/201004/136342 Ricin A-chain, which exhibits excellent cytotoxicity to tumor cells, has been widely used as an inummotoxin source. However, it has the fatal shortcoming of poor pharmacokinetics due to the tremendous liver uptake via carbohydrate-mediated recognition. Modification of proteins with polyethylene glycol, PEGylation, has the advantages of shielding the specific sites and prolonging the biological half-life. In this study, the carbohydrate-specific PEGylation of ricin A-chain was considered to be a novel approach to overcome this limitation. The carbohydrate group of ricin A-chain was oxidized by sodium m-periodate and further specifically conjugated with hydrazide-derivatized PEG. For a comparative study, the PEGylated ricin A-chain at amino groups was prepared using the hydroxysuccinimide ester-derivatized PEG. The carbohydrate-specifically PEGylated ricin A-chain showed a markedly lower liver uptake and systemic clearance compared with the amine-directly PEGylated ricin A-chain as well as the unmodified ricin A-chain. Furthermore, carbohydrate-specifically PEGylated ricin A-chain showed a significantly higher in vitro ribosome-inactivating activity than the amine-directly PEGylated ricin A-chain. These findings clearly demonstrate that the carbohydrate-specificity as well as PEGylation plays an important role in improving the in vivo pharmacokinetic properties and in vitro bioactivity. Therefore, these results suggest that the therapeutic use of immunotoxins constructed using this carbohydrate-specifically PEGylated ricin A-chain has potential as a cancer therapy. (c) 2005 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD SITE-SPECIFIC PEGYLATION SEPHAROSE-UNBINDING RICIN FLIGHT MASS-SPECTROMETRY CHEMICAL DEGLYCOSYLATION DIRECTED PEGYLATION TUMOR-LOCALIZATION SALMON CALCITONINS ANTITUMOR POTENCY FACTOR-ALPHA INVIVO FATE Carbohydrate-specifically polyethylene glycol-modified ricin A-chain with improved therapeutic potential Article 10.1016/j.biocel.2005.01.014 1 INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, v.37, no.7, pp.1525 - 1533 INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 37 7 1525 1533 scie scopus 000229161600018 2-s2.0-17044429357 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article SITE-SPECIFIC PEGYLATION SEPHAROSE-UNBINDING RICIN FLIGHT MASS-SPECTROMETRY CHEMICAL DEGLYCOSYLATION DIRECTED PEGYLATION TUMOR-LOCALIZATION SALMON CALCITONINS ANTITUMOR POTENCY FACTOR-ALPHA INVIVO FATE ricin A chain PEGylation liver uptake cytotoxicity