Chemically and biologically synthesized CPP-modified gelonin for enhanced anti-tumor activity

JOURNAL OF CONTROLLED RELEASE

卷:172

Article

Shin, Meong Cheol^1,2  Zhang, Jian^1,2  David, Allan E.³  Trommer, Wolfgang E.⁴  Kwon, Young Min⁵  Min, Kyoung Ah²  Kim, Jin H.²  Yang, Victor C.^1,2 

[1] Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therape, Tianjin 300070, Peoples R China

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

[3] Auburn Univ, Dept Chem Engn, Auburn, AL 36849 USA

[4] TU Kaiserslautern, Dept Chem, D-67653 Kaiserslautern, Germany

[5] Nova SE Univ, Coll Pharm, Dept Pharmaceut Sci, Ft Lauderdale, FL 33328 USA

关键词: Gelonin;    LMWP;    Cell penetrating peptide;    Cancer;    Ribosome-inactivating protein;    Toxin;   

DOI  :  10.1016/j.jconrel.2013.08.016

来源: Elsevier

【 摘 要 】

The ineffectiveness of small molecule drugs against cancer has generated significant interest in more potent macromolecular agents. Gelonin, a plant-derived toxin that inhibits protein translation, has attracted much attention in this regard. Due to its inability to internalize into cells, however, gelonin exerts only limited tumoricidal effect. To overcome this cell membrane barrier, we modified gelonin, via both chemical conjugation and genetic recombination methods, with low molecular weight protamine (LMWP), a cell-penetrating peptide (CPP) which was shown to efficiently ferry various cargos into cells. Results confirmed that gelonin-LMWP chemical conjugate (cG-L) and recombinant gelonin-LMWP chimera (rG-L) possessed N-glycosidase activity equivalent to that of unmodified recombinant gelonin (rGel); however, unlike rGel, both gelonin-LMWPs were able to internalize into cells. Cytotoxicity studies further demonstrated that cG-L and rG-L exhibited significantly improved tumoricidal effects, with IC50 values being 120-fold lower than that of rGel. Moreover, when tested against a CT26 s.c. xenograft tumor mouse model, significant inhibition of tumor growth was observed with rG-L doses as low as 2 mu g/tumor, while no detectable therapeutic effects were seen with rGel at 10-fold higher doses. Overall, this study demonstrated the potential of utilizing CPP-modified gelonin as a highly potent anticancer drug to overcome limitations of current chemotherapeutic agents. (C) 2013 Elsevier B.V. All rights reserved.

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