Molecular design of polyvinylpyrrolidone-conjugated interleukin-6 for enhancement of in vivo thrombopoietic activity in mice.
Functional polyvinylpyrrolidone (PVP) was synthesized as a novel polymeric modifier for polymer-conjugated cytokines, and its efficiency and applicability as a drug delivery system (DDS) were evaluated. PVP with a carboxyl group at one end of the main chain was prepared by radical polymerization (M(n): 6000, M(w)/M(n): 1.14) with the aid of 4,4'-azobis(4-cyanovaleric acid) as a radical initiator and 3-mercaptopropionic acid as a transfer agent. Interleukin-6 (IL-6) was covalently conjugated via the formation of amino bonds between the lysine amino groups of IL-6 and PVP. PVP-conjugated IL-6, in which 60% of the fourteen lysine amino groups of IL-6 were estimated to be coupled with PVP (M-PVP-IL-6), showed more than 50-fold greater thrombopoietic potency in vivo than native IL-6. No side effects, such as body weight loss, were observed in the M-PVP-IL-6 treated mice. These results indicate that PVP as a polymeric modifier is a promising DDS for clinical application of cytokines and other therapeutic agents.
Tsunoda
S
S
Department of Biopharmaceutics, School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, 565-0871, Osaka, Japan.
Kamada
H
H
Yamamoto
Y
Y
Ishikawa
T
T
Matsui
J
J
Koizumi
K
K
Kaneda
Y
Y
Tsutsumi
Y
Y
Ohsugi
Y
Y
Hirano
T
T
Mayumi
T
T
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008970:Molecular Weight; D010592:Pharmaceutic Aids / Q000737:chemistry*; D010976:Platelet Count; D011205:Povidone / Q000737:chemistry*; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
D015850:Interleukin-6; D010592:Pharmaceutic Aids; D011205:Povidone