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Antitumor Activity of Tumor Necrosis Factor- Conjugated with Polyvinylpyrrolidone on Solid Tumors in Mice¹

Faculty of Pharmaceutical Sciences, Osaka University, Osaka 565-0871 [H. Ka., Y. T., Y. Y., T. K., Y. K., Y. M., H. Ko., S. N., T. M.] and National Institute of Bioscience and Human Technology, Ibaraki 305-8566 [S-i. T.], Japan

We attempted the development of a novel polymer conjugation to further improve the therapeutic potency of antitumor cytokines compared with PEGylation for clinical application. Compared with native tumor necrosis factor (TNF)- in vitro, specific bioactivities of polyvinyl-pyrrolidone (PVP)-modified TNF-s (PVP-TNF-s) were decreased by increasing the degree of PVP attachment. PVP-TNF- fraction 3, M_r 101,000, had the most effective antitumor activity of the various PVP-TNF-s in vivo.

PVP-TNF- fraction 3 had >200-fold higher antitumor effect than native TNF-, and the antitumor activity of PVP-TNF- fraction 3 was >2-fold higher than that of MPEG-TNF- (M_r 108,000), which had the highest antitumor activity among the polyethylene glycol (PEG)-conjugated TNF-s. Additionally, a high dose of native TNF- induced toxic side effects such as body weight reduction, piloerection, and tissue inflammation, whereas no side effects were observed after i.v. administration of PVP-TNF- fraction 3. The plasma half-life of PVP-TNF- fraction 3 (360 min) was about 80- and 3-fold longer than those of native TNF- (4.6 min) and MPEG-TNF- (122 min), respectively. The mechanism of increased antitumor effect in vivo caused the prolongation of plasma half-life and increase in stability. These results suggested that PVP is a useful polymeric modifier for bioconjugation of TNF- to increase its antitumor potency, and multifunctionally bioconjugated TNF- may be a potentiated antitumor agent for clinical use.

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