Abstract
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-α (TNF-α) with polyethylene glycol (PEG). The novel PEGylated TNF-α, PEG-TNF-α(+), which was pretreated with DMMAn before PEGylation, had 20% to 40% higher specific activity than PEG-TNF-α(−) (not treated with DMMAn) in vitro. Moreover, PEG-TNF-α(+) more potently caused tumor necrosis in Meth-A solid tumors in mice than did PEG-TNF-α(−). The middle fraction (M) of PEG-TNF-α(+), which was of the optimal degree of modification among PEG-TNF-α(+)s with different molecular weights, caused the highest degree of tumor hemorrhagic necrosis: 30-fold higher than native TNF-α and 2-fold higher than the most potent MPEG-TNF-α(−) 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-α caused a dose-dependent body weight loss in mice, whereas no obvious side effects were observed in any PEG-TNF-α-treated mice. These results suggest that PEGylation using DMMAn is a useful for clinical cytokine delivery.
Footnotes
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Send reprint requests to: Dr. Tadanori Mayumi, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail:mayumi{at}phs.osaka-u.ac.jp
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↵1 This study was supported in part by grants-in-aid for Cancer Research and for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, by Health Sciences Research Grants for Research on Health Sciences from the Ministry of Health and Welfare, and by Research Fellowships of Japan Society for the Promotion of Science for Young Scientists. S. T. is a Research Fellow of Japan Society for the Promotion of Science.
- Abbreviations:
- TNF-α
- tumor necrosis factor-α
- PEG
- polyethylene glycol
- DMMAn
- dimethylmaleic anhydride
- Received December 31, 1998.
- Accepted March 4, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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