Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidone on solid tumors in mice

We attempted the development of a novel polymer conjugation to further impr ove the therapeutic potency of antitumor cytokines compared with PEGylation fur clinical application, Compared with native tumor necrosis factor (TNF) -alpha in vitro, specific bioactivities of polyvinyl-pyrrolidone (WP)modifi ed TNF-alphaa (PVP-TNF-os) were decreased by increasing the degree of WP at tachment. PVP-TNF-alpha fraction 3, M-r, 101,000, had the most effective an titumor activity of the various PVP-TNF-alphas in vivo. PVP-TNF-alpha fract ion 3 had >200-fold higher antitumor effect than native TNF-a; and the anti tumor activity of PVP-TNF-ol fraction 3 was >2fold higher than that of MPEG -TNF-alpha (M-r 108,000), which had the highest antitumor activity among th e polyethylene glycol (PEG)-conjugatcul TNF-alphas. Additionally, a high do se of native TNF-alpha induced toxic side effects such as body weight reduc tion, piloerection. and tissue inflammation, whereas no side effects were o bserved after i.v. administration of PVP-TNF-alpha fraction 3. The plasma h alf-life of PVP-TNF-alpha fraction 3 (360 min) was about 80- and 3-fold lon ger than those of native TNF-alpha (4.6 min) and MPEG-TNF-alpha (122 min), respectively. The mechanism of increased antitumor effect in vivo caused th e prolongation of plasma half-life and increase in stability. These results suggested that PVP is a useful polymeric modifier for bioconjugation of TN F-alpha to increase its antitumor potency, and multifunctionally bioconjuga ted TNF-alpha may be a potentiated antitumor agent for clinical use.