Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem

Xuexiang Han, Yiye Li (), Ying Xu, Xiao Zhao, Yinlong Zhang, Xiao Yang, Yongwei Wang, Ruifang Zhao, Gregory J. Anderson, Yuliang Zhao () and Guangjun Nie ()
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Xuexiang Han: National Center for Nanoscience and Technology
Yiye Li: National Center for Nanoscience and Technology
Ying Xu: National Center for Nanoscience and Technology
Xiao Zhao: National Center for Nanoscience and Technology
Yinlong Zhang: National Center for Nanoscience and Technology
Xiao Yang: National Center for Nanoscience and Technology
Yongwei Wang: Chinese Academy of Sciences
Ruifang Zhao: National Center for Nanoscience and Technology
Gregory J. Anderson: Royal Brisbane Hospital
Yuliang Zhao: National Center for Nanoscience and Technology
Guangjun Nie: National Center for Nanoscience and Technology

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05906-x

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