[Molecular design of polymer-conjugated cytokines and its application for drug delivery systems]

In recent years, clinical application of recombinant cytokines has been expected as a novel drug for various diseases. However, cytokines have generally poor stability in vivo, so they required of very high doses to achieve sufficient clinical effect. In addition, because cytokines have pleiotropic functions, they would cause unfavourable side-effects. Therefore an drug delivery system (DDS) is necessary for clinical use, which stabilizes the cytokines and potentiates only the expected function from other unfavorable ones in vivo. Then we performed the chemical modification of cytokines with water-soluble polymers to overcome such problems as poor stability and pleiotropic activities. This approach includes some advantages that decrease renal excretion rate of proteins and prevent the degradation by proteases. This would result in prolonging the half-lives of bioactive proteins and potentiating their clinical effects. Interestingly, we found that the polymer-conjugated cytokines, that we named hybrid-cytokines, for instance, polyethylene glycol-modified interleukin-6 (PEG-IL-6), were able to increase selectively in their function of promoting platelet production, but not in other unfavourable functions. This effects were suggested for a result of the change in the systemic distribution pattern by pegylation of proteins. In this review, we proposed that the DDS using hybrid-cytokines would be able to increase the stability and regulate the spectrum of the functions of the cytokines by controlling the pharmacokinetics and pharmacodynamics in vivo. This will provide a fundamental information enabling us to design the hybrid-proteins applicable to therapeutic use.