Pancreatic cancer is highly aggressive, malignant, and notoriously difficult to cure using conventional
cancer therapies. These conventional
therapies have significant limitations due to excessive extracellular matrix (ECM) of
pancreatic cancer and poor
cancer specificity. The excess ECM prevents infiltration of drugs into the inner layer of the solid
tumor. Therefore, novel treatment modalities that can specifically target the
tumor and degrade the ECM are required for effective
therapy. In the present study, we used ECM-degrading and Wnt signal-disrupting oncolytic adenovirus (oAd/DCN/LRP) to achieve a desirable therapeutic outcome against
pancreatic cancer. In addition, to overcome the limitations in systemic delivery of oncolytic Ad (oAd) and to specifically target
pancreatic cancer,
neurotensin peptide (NT)-conjugated
polyethylene glycol (PEG) was chemically crosslinked to the surface of Ad, generating a systemically
injectable hybrid system, oAd/DCN/LRP-PEG-NT. We tested the targeting and therapeutic efficacy of oAd/DCN/LRP-PEG-NT toward
neurotensin receptor 1 (NTR)-overexpressing
pancreatic cancer cells, both in vitro and in vivo. The oAd/DCN/LRP-PEG-NT elicited increased NTR-selective
cancer cell killing and transduction efficiency when compared with a cognate control lacking NT (oAd/DCN/LRP-PEG). Furthermore, systemic administration of oAd/DCN/LRP-PEG-NT significantly decreased induction of innate and adaptive immune responses against Ad, and blood retention time was markedly prolonged by PEGylation. Moreover, NTR-targeting oAd elicited greater in vivo
tumor growth suppression when compared with naked oAd and 9.5 × 10(6)-fold increased
tumor-to-liver ratio. This significantly enhanced antitumor effect of oAd/DCN/LRP-PEG-NT was mediated by active viral replication and viral spreading, which was facilitated by ECM degradation and inhibition of Wnt signaling-related factors (Wnt, β-
catenin, and/or
vimentin) in the
tumor tissues. Taken together, these results demonstrate that oAd/DCN/LRP-PEG-NT has strong therapeutic potential for systemic treatment of NTR-overexpressing
pancreatic cancer due to its NTR-targeting ability, enhanced therapeutic efficacy, and safety.