Tumor vascular targeted delivery of polymer-conjugated adenovirus vector for cancer gene therapy.

Previously, we generated a cancer-specific gene therapy system using adenovirus vectors (Adv) conjugated to polyethylene glycol (Adv-PEG). Here, we developed a novel Adv that targets both tumor tissues and tumor vasculatures after systemic administration by conjugating CGKRK tumor vasculature homing peptide to the end of a 20-kDa PEG chain (Adv-PEG(CGKRK)). In a primary tumor model, systemic administration of Adv-PEG(CGKRK) resulted in ~500- and 100-fold higher transgene expression in tumor than that of unmodified Adv and Adv-PEG, respectively. In contrast, the transgene expression of Adv-PEG(CGKRK) in liver was about 400-fold lower than that of unmodified Adv, and was almost the same as that of Adv-PEG. We also demonstrated that transgene expression with Adv-PEG(CGKRK) was enhanced in tumor vessels. Systemic administration of Adv-PEG(CGKRK) expressing the herpes simplex virus thymidine kinase (HSVtk) gene (Adv-PEG(CGKRK)-HSVtk) showed superior antitumor effects against primary tumors and metastases with negligible side effects by both direct cytotoxic effects and inhibition of tumor angiogenesis. These results indicate that Adv-PEG(CGKRK) has potential as a prototype Adv with suitable efficacy and safety for systemic cancer gene therapy against both primary tumors and metastases.