Tumor therapy by gene regulation system responding to cellular signal

For safe and efficient gene therapy, the development of gene delivery systems to specifically target tumor cells is one of the most important issues regarding present gene delivery methodologies. Recently, we have developed a novel drug or gene delivery system responding to cellular signals (D-RECS) that can activate transgenes in response to hyperactivated cellular signals. Especially, a protein kinase C (PKC)α-responsive polymeric carrier (polymer-peptide conjugate, PPC(S)) showed highly specific gene expression to tumor cells and tissues. In the present study, we have applied the PKCα-responsive polymeric carrier to tumor gene therapy. PPC(S) consists of a polyacrylamide backbone and cationic peptide side chains, which together make PPC(S) as a positive polymer, a PKCα-specific substrate. A negative control polymer, PPC(A), was also prepared by replacing a serine residue at the phosphorylation site of the peptide side chains of PPC(S) with alanine. A complex of PPC(S) with caspase-8 or the herpes simplex virus-thymidine kinase (HSV-TK) gene as therapeutic genes was transfected into certain tumor cells or tissues. The prodrug ganciclovir (GCV) was then intraperitoneally injected into PPC(S)/HSV-TK complex-transfected mice. The PPC(S)/gene complex showed significant cytotoxicity toward the tumor cells and suppression of tumor growth, compared with those of the PPC(A)/gene complex or PBS. These results indicate that the PKCα-responsive polymeric carrier is applicable for tumor-targeted gene therapy.