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


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.

SUBMITTER: Han X 

PROVIDER: S-EPMC6107580 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Han Xuexiang X   Li Yiye Y   Xu Ying Y   Zhao Xiao X   Zhang Yinlong Y   Yang Xiao X   Wang Yongwei Y   Zhao Ruifang R   Anderson Gregory J GJ   Zhao Yuliang Y   Nie Guangjun G  

Nature communications 20180823 1


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,  ...[more]

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