title: Preparation and evaluation of a new releasable PEGylated tumor necrosis factor-α (TNF-α) conjugate for therapeutic application.
abstract: To design a releasable PEGylated TNF-α (rPEG-TNF-α), a cathepsin B-sensitive dipeptide (Val-Cit moiety) was inserted into conventional PEG-modified TNF-α (PEG-TNF-α), facilitating its clinical use for anti-tumor therapy. Comparative pharmacokinetic and pharmacodynamic studies showed that the half-lives of both PEGylated forms of TNF-α were ∼60-fold greater than that of unmodified TNF-α. In addition, the in vitro bioactivity of rPEG-TNF-α was greater than that of PEG-TNF-α with the same degree of PEG modification. Release of TNF-α from rPEG-TNF-α in vitro was dependent on the presence of cathepsin B and was inhibited by a cathepsin B inhibitor. Despite the potent cytotoxicity of unmodified TNF-α against normal cells, its PEGylated forms at higher TNF-α concentrations showed low cytotoxic activity against these cells. In contrast, both forms of PEGylated TNF-α showed potent cytotoxic activity against the B16 and L929 cell lines, with rPEG-TNF-α being 5- and 9-fold more potent, respectively, than PEG-TNF-α. Moreover, rPEG-TNF-α was a more potent in vivo antitumor agent than PEG-TNF-α.
authors: Department of Chemistry and Chemical Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China. cydai@126.com
authors: ChuanYun
authors: C
authors: Dai
authors: Ya
authors: Y
authors: Fu
authors: ShaoCheng
authors: S
authors: Chen
authors: Biao
authors: B
authors: Li
authors: Bo
authors: B
authors: Yao
authors: WanHong
authors: W
authors: Liu
authors: LiQing
authors: L
authors: Zhu
authors: Nan
authors: N
authors: Chen
authors: Ji
authors: J
authors: Chen
authors: Qiang
authors: Q
authors: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010436:Pepstatins / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D006020:Glycopeptides; D010436:Pepstatins; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D002401:Cathepsin B; D007930:Leucine; C012211:ubenimex; C008890:phosphoramidon; C031375:pepstatin