Molecular design of conjugated tumor necrosis factor-alpha: synthesis and characteristics of polyvinyl pyrrolidone modified tumor necrosis factor-alpha.
We conjugated tumor necrosis factor-alpha (TNF-alpha) with the synthetic polymeric modifier polyvinyl pyrrolidone (PVP) to facilitate its clinical use for anti-tumor therapy. TNF-alpha was chemically conjugated with the terminal carboxyl-bearing PVP at one end of its main chain, which was radically polymerized via the formation of an amide bond between the lysine amino groups of TNF-alpha and carboxyl group of PVP. In vitro specific bioactivity of PVP-conjugated TNF-alpha (PVP-TNF-alpha) relative to that of native TNF-alpha gradually decreased with increases in the degree of PVP attachment. In contrast, PVP-TNF-alpha in which 40% of TNF-alpha lysine residues were coupled with PVP (MPVP-TNF-alpha) exhibited the highest anti-tumor activity among the conjugated derivatives examined. MPVP-TNF-alpha had more than 200-fold higher anti-tumor efficacy than native TNF-alpha, and the anti-tumor activity of MPVP- TNF-alpha was more than 5-fold stronger than that MPEG- TNF-alpha which had the highest anti-tumor activity among PEG-conjugated TNF-alphas examined. Additionally, a high dose of native TNF-alpha induced toxic side-effects such as body weight reduction, piloerection and tissue inflammation, while no side effects were observed following i.v. administration of MPVP-TNF-alpha. The plasma half-life of MPVP-TNF-alpha (360 min) was about 80 and 3-fold longer than those of native TNF-alpha (4.6 min) and MPEG-TNF-alpha (122 min), respectively. These results suggested that PVP is a useful polymeric modifier for increasing the anti-tumor activity of PVP.
Kamada
H
H
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Tsutsumi
Y
Y
Tsunoda
S
S
Kihira
T
T
Kaneda
Y
Y
Yamamoto
Y
Y
Nakagawa
S
S
Horisawa
Y
Y
Mayumi
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006207:Half-Life; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D009336:Necrosis; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011108:Polymers; D011205:Povidone / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011108:Polymers; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D011205:Povidone; D008239:Lysine