title: PEGylation and pharmacological characterization of a potential anti-tumor drug, an engineered arginine deiminase originated from Pseudomonas plecoglossicida.
abstract: Arginine deiminase (ADI) has been studied as a potential anti-cancer agent for arginine-auxotrophic tumors. PEGylation is one of the best methods to formulate a bioconjugated protein with extended physical stability and reduced immunogenicity. Here, PEGylation and pharmacological properties of an engineered ADI originated from Pseudomonas plecoglossicida were studied. Among polyethylene glycol (PEG) reagents with succinimidyl ester groups varying in size and linkers, three PEGylated products with high yield and catalytic activity were further characterized, named ADI-SS(20 kDa), ADI-SC(20 kDa), and ADI-SPA(20 kDa). In the pharmacodynamic/pharmacokinetic (PD/PK) studies with ADI-SPA(20 kDa), a remarkable improvement in circulating half-life compared with native ADI was observed. ADI-SPA(20 kDa) injections via intravenous, intramuscular and subcutaneous routes all exhibited superior efficacy than native ADI on depleting serum arginine. Additionally, our results demonstrated that single ADI-SPA(20 kDa) administration of 5 U/mouse via intravenous injection could maintain serum arginine at an undetectable level for 5 days with a half-life of 53.2 h, representing 11-fold improvement in half-life than that of the native ADI. In a mice H22 hepatocarcinoma model, ADI-SPA(20 kDa) dosage of 5 U per 5 days showed an inhibition rate of 95.02% on tumor growth during 15-day treatments.
authors.affiliation: The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China.
authors.forename: Menghan
authors.initials: M
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China.
authors.forename: Serwanja
authors.initials: S
authors.lastname: Jamil
authors.affiliation: The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Han
authors.affiliation: The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China.
authors.forename: Guochao
authors.initials: G
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, Jiangsu, China. Electronic address: yni@jiangnan.edu.cn.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D006867:Hydrolases / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D015202:Protein Engineering; D011549:Pseudomonas / Q000201:enzymology* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D006867:Hydrolases; C019723:arginine deiminase
keywords: Arginine deiminase; Cancer; Mice model; PEGylation; Pharmacodynamic/pharmacokinetic