PEGylation of bacterial cocaine esterase for protection against protease digestion and immunogenicity

JOURNAL OF CONTROLLED RELEASE

卷:142

Article

Park, Jun-Beom¹  Kwon, Young Min^1,2  Lee, Tien-Yi¹  Brim, Remy³  Ko, Mei-Chuan³  Sunahara, Roger K.³  Woods, James H.³  Yang, Victor C.¹ 

[1] Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA

[2] Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Amarillo, TX USA

[3] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA

关键词: Cocaine esterase;    PEGylation;    Protease digestion;    Immunogenicity;   

DOI  :  10.1016/j.jconrel.2009.10.015

来源: Elsevier

【 摘 要 】

Enhancing cocaine metabolism by administration of cocaine esterase (CocE) has been considered as a promising treatment strategy for cocaine overdose and addiction, as CocE is the most efficient native enzyme yet identified for metabolizing the naturally occurring cocaine. A major obstacle to the clinical application of CocE, however, lies in its thermo-instability, rapid degradation by circulating proteases, and potential immunogenicity. PEGylation. namely by modifying a protein or peptide compound via attachment of polyethylene glycol (PEG) chains, has been proven to overcome such problems and was therefore exploited in this CocE investigation. The PEG-CocE conjugates prepared in this study showed a purity of greater than 93.5%. Attachment of PEG to CocE apparently inhibited the binding of anti-CocE antibodies to the conjugate, as demonstrated by the enzyme-linked immunosorbent assay (ELISA) assay. In addition, PEGylation yielded protection to CocE against thermal degradation and protease digestion. Furthermore, preliminary in vivo results suggested that, similarly to native CocE, the PEG-CocE conjugates were able to protect animals from cocaine-induced toxic effects. Overall, this study provides evidence that the PECylation may serve as a tool to prolong CocE functionality in the circulation and reduce its potential immunogenicity. (C) 2009 Elsevier B.V. All rights reserved.

【 授权许可】

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