title: Molecular design of hybrid tumor necrosis factor-alpha III: polyethylene glycol-modified tumor necrosis factor-alpha has markedly enhanced antitumor potency due to longer plasma half-life and higher tumor accumulation.
abstract: We have reported that chemical modification of tumor necrosis factor-alpha (TNF-alpha) with polyethylene glycol (PEG) markedly increases its antitumor potency without any adverse side effects. MPEG-TNF-alpha, especially, in which 56% of the lysine amino groups of TNF-alpha are coupled with PEG, exhibits 100-fold more antitumor activity in vivo than native TNF-alpha in the Meth-A murine sarcoma model. In this study, we investigated the pharmacokinetics of PEG-modified TNF-alpha with various molecular sizes to clarify the mechanisms of the enhanced antitumor potency of MPEG-TNF-alpha. The plasma half-lives of modified TNF-alpha increased with increasing molecular size. The decreased plasma clearance of modified TNF-alpha was partially caused by the shielding effect of the proteolytic sites in TNF-alpha by the attached PEG and the decreased transport from blood to various tissues. Almost all native TNF-alpha was uniformly distributed to the kidney and reticuloendothelial system within 1 hr of an intravenous administration, and rapidly disappeared from these tissues at 3 hr. However, very little native TNF-alpha was transported into the tumor. The absolute distributed amount and distribution profile of modified TNF-alpha to tissues other than the tumor were the same as those of native TNF-alpha, whereas the plasma levels of the modified TNF-alpha were higher than plasma levels of the native TNF-alpha. The tumor distribution of modified TNF-alpha was markedly enhanced compared with native TNF-alpha and gradually increased over time. About 9-fold more MPEG-TNF-alpha was distributed to the tumor than native TNF-alpha. Thus, we found that the marked increase in the antitumor potency of PEG-modified TNF-alpha resulted from the enhanced blood residency and tumor accumulation. The antitumor effect of MPEG-TNF-alpha against sarcoma-180 other than Meth-A fibrosarcoma was also about 100 times greater than that of native TNF-alpha when systemically administered. The optimal PEGylation of TNF-alpha facilitated its antitumor potency and MPEG-TNF-alpha may be useful systemic antitumor therapeutic drug.
authors.affiliation: Faculty of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: T
authors.initials: T
authors.lastname: Kihira
authors.forename: S
authors.initials: S
authors.lastname: Tsunoda
authors.forename: H
authors.initials: H
authors.lastname: Kamada
authors.forename: S
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Kaneda
authors.forename: T
authors.initials: T
authors.lastname: Kanamori
authors.forename: T
authors.initials: T
authors.lastname: Mayumi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D010450:Endopeptidases