Efficient Targeted Therapy for Pancreatic Cancer Using Nanosystem and Focusing on the Suppression of Pancreatic Stellate Cell Activation

Abstract

Introduction: Pancreatic cancer is characterized by remarkable desmoplasia which causes poor drug delivery and resistance to anticancer therapy. Pancreatic stellate cells (PSCs) play a key role in construction of such tumor environment and enhance the malignancy of pancreatic cancer cells. We have previously reported PSC activation was suppressed by inhibiting autophagy of PSC using a lysosomal inhibitor, chloroquine (CQ). However, CQ requires high dosage to be effective in vivo. In this study, we developed nanoparticle-based drug delivery system (DDS) and evaluated its availability in the tumor-bearing mouse model. Methods: Poly lactic-co-glycolic acid (PLGA) was used as a DDS carrier. The PLGA nanoparticles were loaded with ICG (Nano-ICG) or CQ (Nano-CQ). The accumulation of Nano-ICG in pancreatic tumor was evaluated by in vivoimaging system (IVIS). The effects of CQ, Nano-CQ, or the combination of these agents and gemcitabine (GEM) on the activation of PSC and tumor growth were investigated in the orthotopic xenograft mouse model. Results: Nano-ICG showed pancreatic tumor-specific accumulation and persisted for more than one week after administration. No obvious accumulation was observed in other major organs including liver, kidney, and normal pancreatic tissue. The fraction of activated PSC was significantly decreased in Nano-CQ group compared to the control group. The combination of Nano-CQ and GEM showed the best ability to restrain tumor progression among all the groups. Conclusion: Our PLGA-based nanosystem was considered to be a promising DDS for the treatment of pancreatic cancer and nano-CQ could enhance the efficacy of anticancer drugs.