Journal Article

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

Wang, Yongwei, Li, Yiye, Nie, Guangjun, Xu, Ying, Zhao, Xiao, Zhao, Yuliang, Han, Xuexiang, Zhao, Ruifang, Zhang, Yinlong, Yang, Xiao, Anderson, Gregory J.

2018

Overview

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. Stromal-tumour interactions play an important role in pancreatic cancer progression. Here, they describe the development of a tumour microenvironment-responsive gold nanoparticle system incorporating all- trans retinoic acid (ATRA) and siRNA against heat shock protein 47 (HSP47), for use in pancreatic cancer treatment.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/51 / 14/19 / 14/34 / 14/5 / 147/143 / 639/301 / 639/925 / 64/60 / Adenocarcinoma / Animals / Anticancer properties / Cell Cycle - drug effects / Chemotherapy / Cobalt / Collagen / Drug delivery / Drug delivery systems / Endocytosis - drug effects / Extracellular matrix / Extracellular Matrix - drug effects / Extracellular Matrix - metabolism / Female / Gene Silencing - drug effects / Gold / Gold - chemistry / Heat shock proteins / Homeostasis / Humanities and Social Sciences / Humans / Hydrogen-Ion Concentration / Hyperplasia / Metal Nanoparticles - chemistry / Metal Nanoparticles - ultrastructure / Mice, Inbred BALB C / Mice, Nude / multidisciplinary / Nanoparticles / Pancreas / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - pathology / Pancreatic Stellate Cells - drug effects / Pancreatic Stellate Cells - metabolism / Pancreatic Stellate Cells - pathology / Polyethylene Glycols - chemistry / Polyethyleneimine / Polyethyleneimine - chemistry / Recovery of function / Retinoic acid / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / siRNA / Spheroids, Cellular - drug effects / Spheroids, Cellular - metabolism / Spheroids, Cellular - pathology / Stellate cells / Stromal cells / Stromal Cells - drug effects / Stromal Cells - pathology / Tissue Distribution - drug effects / Tretinoin - pharmacokinetics / Tretinoin - pharmacology / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumors / Xenograft Model Antitumor Assays