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.

Targeting Pancreatic Stellate Cells in Cancer

“…Currently, a phase Ib study is underway investigating ATRA along with gemcitabine and nab-paclitaxel in PDAC [113]. More recently, ATRA has been combined with heat shock protein 47 (HSP47) targeting siRNA, capable of reprogramming hPSCs, and delivered using a pHresponsive polyethylene glycol (PEG) grafted polythylamine (PEI)-coated gold nanoparticles [114]. This nanoparticle formulation reprogrammed PSCs and inhibited ECM hyperplasia, causing enhanced drug delivery to orthotopic (hPSC + Panc-1) pancreatic tumors, thereby increasing the efficacy of gemcitabine [114].…”

“…More recently, ATRA has been combined with heat shock protein 47 (HSP47) targeting siRNA, capable of reprogramming hPSCs, and delivered using a pHresponsive polyethylene glycol (PEG) grafted polythylamine (PEI)-coated gold nanoparticles [114]. This nanoparticle formulation reprogrammed PSCs and inhibited ECM hyperplasia, causing enhanced drug delivery to orthotopic (hPSC + Panc-1) pancreatic tumors, thereby increasing the efficacy of gemcitabine [114]. Additionally, the vitamin D receptor (VDR) has been shown to be a master transcriptional regulator to regain the quiescent state of PSCs [98].…”

Modifying the Tumour Microenvironment: Challenges and Future Perspectives for Anticancer Plasma Treatments

“…The desmoplastic reaction induced by plasma suggests an increased deposition of collagen [159,160], a response often associated with impaired drug delivery and penetration of anticancer treatments [161]. However, it is possible to re-educate stromal cells to reduce desmoplasia, as shown for pancreatic stellate cells [162].…”

Modulating the tumor microenvironment with new therapeutic nanoparticles: A promising paradigm for tumor treatment

“…Upon systemic administration into pancreatic tumor‐bearing mice, these nanoparticles efficiently inhibited collagen production by releasing the drug in response to MMP2 cleavage, improving ECM structure and thus enhancing gemcitabine perfusion in the tumors. More recently, a pH‐responsive PEGylated polyethylenimine‐coated gold nanoparticle was designed to codeliver all‐ trans retinoic acid (an inducer of pancreatic stellate cell [PSC] quiescence) and siRNA targeting heat shock protein 47 (a collagen‐specific molecular chaperone) to pancreatic tumors (Figure A and B) . The nanosystem effectively restored homoeostasis of tumor ECM by inducing PSC quiescence and decreasing collagen deposition after intravenous administration, thereby promoting gemcitabine delivery to pancreatic tumors and improving the antitumor efficacy of chemotherapeutics (Figure C and D).…”

“…Scale bar, 1 cm. Reproduced with permission . Copyright 2018, Nature [Color figure can be viewed at wileyonlinelibrary.com]…”