TY - JOUR
T1 - Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem
AU - Han, Xuexiang
AU - Li, Yiye
AU - Xu, Ying
AU - Zhao, Xiao
AU - Zhang, Yinlong
AU - Yang, Xiao
AU - Wang, Yongwei
AU - Zhao, Ruifang
AU - Anderson, Gregory J.
AU - Zhao, Yuliang
AU - Nie, Guangjun
N1 - Funding Information:
This work was supported by grants from the National Basic Research Plan of China (2018YFA0208900), National Natural Science Foundation of China (31571021, 91543127, 31730032 and 31661130152), Innovation Group of the National Natural Science Foundation of China (11621505), Frontier Research Programme of the Chinese Academy of Sciences (QYZDJ-SSW-SLH022), Beijing Municipal Science and Technology Commission (Z161100000116035), National Distinguished Young Scientist Programme (31325010) and the Key Laboratory of Biomedical Effects of Nanomaterials and Nano-safety, CAS.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.
AB - Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.
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U2 - 10.1038/s41467-018-05906-x
DO - 10.1038/s41467-018-05906-x
M3 - Article
C2 - 30139933
AN - SCOPUS:85052203996
VL - 9
JO - Nat Commun
JF - Nat Commun
SN - 2041-1723
IS - 1
M1 - 3390
ER -