Journal
CANCER LETTERS
Volume 357, Issue 1, Pages 346-354Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.11.042
Keywords
Arginine deiminase; PEGylation; Cancer; Pharmacodynamic/pharmacokinetic; Mice model
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Funding
- Natural Science Foundation of China [30900030, 21276112]
- National Basic Research and Development Program of China [2011CB710800]
- New Century Excellent Talents in University [NCET-11-0658]
- Fundamental Research Funds for the Central Universities [JUSRP51409B]
- Program of Introducing Talents of Discipline to Universities [111-2-06]
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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-SS20 (kDa), ADI-SC20 (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 H-22 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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