Preparation and evaluation of a new releasable PEGylated tumor necrosis factor-α (TNF-α) conjugate for therapeutic application.
ChuanYun Dai, Ya Fu, ShaoCheng Chen, Biao Li, Bo Yao, WanHong Liu, LiQing Zhu, Nan Chen, Ji Chen, Qiang Zhang
文献索引:Sci. China Life Sci. 56(1) , 51-8, (2013)
全文:HTML全文
摘要
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.
相关化合物
相关文献:
2013-02-08
[Toxicology 304 , 13-20, (2013)]
2013-10-01
[Genes Dev. 27(19) , 2086-98, (2013)]
2014-03-01
[Toxicol. Lett. 226(2) , 228-35, (2014)]
2013-01-01
[Cell Death Dis. 4 , e507, (2013)]
2012-12-01
[Biol. Chem. 393(12) , 1405-16, (2012)]