Salinomycin nanoparticles induce selective toxicity toward tumor cells rather than stroma in orthotopic model of pancreatic cancer

Introduction Salinomycin (SAL), a selective inhibitor of cancer stem cells (CSCs), was recently recognized for its ability to inhibit proliferation and induce apoptosis in various tumors including highly chemo-resistant ones.... [ view full abstract ]

Introduction
Salinomycin (SAL), a selective inhibitor of cancer stem cells (CSCs), was recently recognized for its ability to inhibit proliferation and induce apoptosis in various tumors including highly chemo-resistant ones. The aim of this study was to deliver SAL to orthotopic model of pancreatic cancer by the aid of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and explore some mechanistic questions regarding this treatment.
Methods
SAL-loaded NPs were prepared and investigated in terms of pharmaceutical properties. MTT assay was used to study cell proliferation in AsPC-1-luc cells. In vivo antitumor study was performed in nude mice orthotopically implanted with AsPC-1-luc cells and treated by IV administration of saline and SAL NPs for control and test groups, respectively. Tumor growth was monitored weekly through in vivo imaging of luciferase activity. The collected tumors from SAL-treated and control groups were used for protein extraction and immunofluorescent staining of different markers.
Results
Nano formulation of SAL was prepared in suitable size and loading traits. SAL (3.5 mg/kg every other day) blocked tumor growth by 52% compared to the control group after nine injections. Western blotting of tumor protein extracts indicated that SAL treatment leads to up-regulation of E-cadherin and β-catenin expressions in AsPC-1 orthotopic tumor. Noteworthy, immunofluorescence staining of adjacent tumor sections demonstrated that treatment with SAL NPs leads to considerable apoptosis in the tumor cells rather than the stroma.
Discussion
Herein, we utilized PEG-PLGA as a biocompatible and biodegradable polymer to formulate SAL into polymeric NPs, so that it could be stably solubilized for further investigations. Regarding in vivo treatments, a 52% reduction in tumor size compared to the control group highlights SAL-loaded PLGA NPs as a promising system for pancreatic cancer treatment. The results of concurrent CD31/α-SMA staining and the TUNEL assay showed that the apoptotic pancreatic cancer cells were mainly distributed in the tumor nest, which confirms efficient intratumoral extravasation and penetration of SAL-loaded NPs. Our data suggested that SAL can harness epithelial-mesenchymal transition through increased co-expression of E-cadherin and its binding protein, β-catenin. However, more mechanistic research is needed before any translation of SAL-based treatments into clinics.