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Paclitaxel and Itraconazole Co‐Encapsulated Micelle Prolongs the Survival of Spontaneous LSL‐Kras G12D/+ , LSL‐Trp53 R172H/+ , Pdx‐1‐Cre Genetically Engineered Mouse Model of Pancreatic Cancer
Author(s) -
Liu Zhengsheng,
Zhang Ling,
Tian Zhou,
Kong Chao,
Liu Chun,
Liu Huiqin,
Yuan Fang,
Kong Weijian,
Qian Feng
Publication year - 2019
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.201900032
Subject(s) - cancer research , pancreatic cancer , kras , tumor microenvironment , paclitaxel , gemcitabine , cytotoxicity , chemistry , cancer , pancreas , colorectal cancer , biology , pharmacology , medicine , biochemistry , in vitro , tumor cells
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant gastrointestinal cancers with an extremely complex tumor microenvironment and a poor prognosis. The upregulation of Hedgehog (Hh) signaling pathway contributes to the abundance of stroma and barren blood vessels in the PDAC tumor microenvironment, creating a physical and biological barrier leading to strong inherent resistance to drugs. Therefore, inhibition of the Hh signaling pathway combined with chemotherapy has been explored in anti‐PDAC chemotherapy. In this study, the paclitaxel (PTX) and itraconazole (ITA) co‐encapsulated poly (ethylene glycol)‐ b ‐poly ( d , l ‐lactide) (PEG‐PLA) micelle (PIM) shows superior therapeutic outcome in PDAC. Pharmaceutically, PIM demonstrates optimized systemic pharmacokinetics and increases tumor drug accumulation due to its serum stability. Pharmacologically, through Hh inhibition and blood vessel normalization contributed by ITA and cytotoxicity contributed by PTX, PIM not only significantly inhibits the tumor growth of the human MIA PaCa‐2 cell‐derived orthotopic pancreatic cancer model but also significantly prolongs the survival of LSL‐Kras G12D/+ ; LSL‐Trp53 R172H/+ ; Pdx‐1‐Cre (KPC) genetic engineered, spontaneous PDAC mice, a clinically relevant PDAC model with high similarity as human PDAC in terms of cancer histology and biology.