Pancreatic ductal
adenocarcinoma (PDA) is a highly fatal disease with 5-year survival of ∼8.5%. Nanoplatforms such as
nab-paclitaxel and nanoliposomal
irinotecan demonstrate superiority and utility in treating different progressions of PDA by prolonging the median overall survival by only a few months. Due to the dense surrounding stroma and the high autophagy in
pancreatic cancer,
integrin ɑvβ3 targeting,
acid environmental sensitive, TR
peptide-modified liposomal platforms loaded with combined autophagy inhibiting
hydroxychloroquine (HCQ), and cytotoxic
paclitaxel (PTX) were designed (TR-PTX/HCQ-Lip) to accomplish the aim of synergistically killing
tumor cells while inhibiting stroma
fibrosis. The results showed that TR
peptide-modified
liposomes (TR-Lip) have superior targeting and penetrating effects both in vitro and in vivo. TR-PTX/HCQ-Lip efficiently inhibited autophagy in pancreatic cells and surrounding cancer-associated fibroblasts. The synergistic anti-
fibrosis roles were also confirmed both in vitro and in vivo, all of which contributes to the enhanced curative effects of TR-PTX/HCQ-Lip in both heterogenetic and orthotopic
pancreatic cancer models. STATEMENT OF SIGNIFICANCE: Autophagy plays a significant role in pancreatic ductal
adenocarcinoma, especially in activating cancer associated fibroblasts which is also related to
collagen generation that promotes the formation of dense stroma, which hinder the cytotoxic drugs to target and kill
cancer cells. In this study, we designed
integrin ɑvβ3 targeting,
acid environmental sensitive liposomal platforms to co-loaded
paclitaxel and the autophagy inhibitor
hydroxychloroquine. The results showed that the muti-functional
liposomes can target to the pancreatic
tumor and efficiently kill
tumor cells and inhibit stroma
fibrosis, thus improve the
therapeutic effect in orthotopic
pancreatic cancer models.