Enhanced antitumor potency of polyethylene glycolylated tumor necrosis factor-alpha: a novel polymer-conjugation technique with a reversible amino-protective reagent.

نویسندگان

  • S Tsunoda
  • T Ishikawa
  • Y Yamamoto
  • H Kamada
  • K Koizumi
  • J Matsui
  • Y Tsutsumi
  • T Hirano
  • T Mayumi
چکیده

We attempted to develop a novel method for the chemical modification of cytokines with synthetic polymers to increase in vivo therapeutic efficacy. A pH-reversible amino-protective reagent, dimethylmaleic anhydride (DMMAn), was used for polymer conjugation of tumor necrosis factor-alpha (TNF-alpha) with polyethylene glycol (PEG). The novel PEGylated TNF-alpha, PEG-TNF-alpha(+), which was pretreated with DMMAn before PEGylation, had 20% to 40% higher specific activity than PEG-TNF-alpha(-) (not treated with DMMAn) in vitro. Moreover, PEG-TNF-alpha(+) more potently caused tumor necrosis in Meth-A solid tumors in mice than did PEG-TNF-alpha(-). The middle fraction (M) of PEG-TNF-alpha(+), which was of the optimal degree of modification among PEG-TNF-alpha(+)s with different molecular weights, caused the highest degree of tumor hemorrhagic necrosis: 30-fold higher than native TNF-alpha and 2-fold higher than the most potent MPEG-TNF-alpha(-) that also had nearly the same molecular weight. Significantly, improvements in antitumor activity in vivo were more marked than were changes in specific activity. Furthermore, native TNF-alpha caused a dose-dependent body weight loss in mice, whereas no obvious side effects were observed in any PEG-TNF-alpha-treated mice. These results suggest that PEGylation using DMMAn is a useful for clinical cytokine delivery.

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Enhanced Antitumor Potency of Polyethylene Glycolylated Tumor Necrosis Factor-a: A Novel Polymer-Conjugation Technique with a Reversible Amino-Protective Reagent

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عنوان ژورنال:
  • The Journal of pharmacology and experimental therapeutics

دوره 290 1  شماره 

صفحات  -

تاریخ انتشار 1999