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Nat Commun. 2018 Aug 23;9(1):3390. doi: 10.1038/s41467-018-05906-x.

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

Han X1,2,3, Li Y4,5, Xu Y1,2, Zhao X1,2, Zhang Y1,2, Yang X1,2, Wang Y6, Zhao R1,2, Anderson GJ7, Zhao Y8,9, Nie G10,11.

Author information

1
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China.
2
University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
3
Department of Chemistry, Tsinghua University, Beijing, 100084, P.R. China.
4
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China. liyy@nanoctr.cn.
5
University of Chinese Academy of Sciences, Beijing, 100049, P.R. China. liyy@nanoctr.cn.
6
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P.R. China.
7
QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia.
8
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China. zhaoyl@nanoctr.cn.
9
University of Chinese Academy of Sciences, Beijing, 100049, P.R. China. zhaoyl@nanoctr.cn.
10
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China. niegj@nanoctr.cn.
11
University of Chinese Academy of Sciences, Beijing, 100049, P.R. China. niegj@nanoctr.cn.

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.

PMID:
30139933
PMCID:
PMC6107580
DOI:
10.1038/s41467-018-05906-x
[Indexed for MEDLINE]
Free PMC Article

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