Elsevier

Journal of Controlled Release

Volume 290, 28 November 2018, Pages 1-10
Journal of Controlled Release

Nano-targeted relaxin impairs fibrosis and tumor growth in pancreatic cancer and improves the efficacy of gemcitabine in vivo

https://doi.org/10.1016/j.jconrel.2018.09.031Get rights and content
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open access

Abstract

Cancer-associated fibroblasts (CAFs), are the key effector cells in pancreatic ductal adenocarcinoma (PDAC), known to induce tumor growth and progression. Pancreatic stellate cells (PSCs) are the precursors of CAFs in PDAC that secrete abundant extracellular matrix, growth factors and cytokines. In this study, we targeted human relaxin-2 (RLX), an endogenous hormone, to PSCs to inhibit their differentiation into CAF-like myofibroblasts. RLX significantly inhibited TGF-β induced PSCs differentiation by inhibiting pSmad2 signaling pathway. In vitro in primary human PSCs (hPSCs), treatment with RLX dose-dependently inhibited the migration, contraction, and protein expression of alpha smooth muscle actin and collagen I These data demonstrate that RLX can regulate hPSCs activation in vitro. However, RLX has several drawbacks i.e. poor pharmacokinetics and systemic vasodilation, that limits its preclinical and clinical application. Thus, we designed and successfully synthesized a nanoparticle system by chemically conjugating RLX to superparamagnetic iron oxide nanoparticle (SPION) to improve its pharmacokinetics. Interestingly, we found RLX-SPION to be more efficacious compared to free RLX in vitro. Significantly, we observed RLX-SPION retarded the tumor growth by itself and also potentiated the effect of gemcitabine in a subcutaneous co-injection (Panc1 and hPSCs) tumor model. The treatment resulted in significant inhibition in tumor growth, which was attributed to reduced collagen I (ECM), desmin (hPSC marker) and CD31 (endothelial marker) expression. In contrast, free RLX showed no significant effects. Altogether, this study presents a novel therapeutic approach against tumor stroma using RLX-SPION to achieve an effective treatment against pancreatic tumor.

Keywords

Relaxin-2
Superparamagnetic iron-oxide nanoparticles
Pancreatic stellate cells
Cancer-associated fibroblasts
Pancreatic cancer
Tumor stroma

Abbreviations

hPSCs
human pancreatic stellate cells
CAFs
cancer-associated fibroblasts
PDAC
pancreatic ductal adenocarcinoma
RLX
Relaxin-2
SPION
superparamagnetic iron oxide nanoparticles
Gem
gemcitabine
TGF-β
transforming growth factor β
ECM
extracellular matrix
α-SMA
α-smooth muscle actin
Col-I
collagen-I

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1

These authors contributed equally to this work.