We have reported a disease-cell specific gene expression system that is responsive to intracellular signaling proteins (e.g., protein kinases and proteases) hyperactivated in diseased cells. For this system, cationic peptide-grafted polymers were synthesized for polyplex formation with genes. Here, we modified poly(ethylene glycol) (PEG) to a protein kinase A (PKA)-responsive polymer to improve polyplex stability. PEG modification neutralized the surface charge of the polyplex and successfully increased polyplex stability at physiological conditions. However, PEG modification (PEG contents, 0.6 and 3.3 mol %) showed almost negligible effects on the reactivity of grafted peptides to PKA and the promotion of gene expression responding to PKA activity. Excessive modification of PEG (PEG contents, 6.8 mol %) inhibited polyplex formation. These results indicate that moderate modification of PEG to the enzyme-responsive polymer improves polyplex stability without inhibiting the reaction with enzymes.
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