Pancreatic cancer stem cell proliferation is strongly inhibited by diethyldithiocarbamate-copper complex loaded into hyaluronic acid decorated liposomes |
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Authors: | Alessandro Marengo Stefania Forciniti Ilaria Dando Elisa Dalla Pozza Barbara Stella Nicolas Tsapis Najet Yagoubi Giuseppina Fanelli Elias Fattal Christopher Heeschen Marta Palmieri Silvia Arpicco |
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Affiliation: | 1. Department of Drug Science and Technology, University of Torino, Italy;2. Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy;3. Institut Galien Paris-Sud, CNRS, Université Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France;4. EA 401, Matériaux et Santé, Université Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France;5. Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy;6. Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, UK |
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Abstract: | BackgroundPancreatic cancer stem cells (CSCs) are responsible for resistance to standard therapy, metastatic potential, and disease relapse following treatments. The current therapy for pancreatic ductal adenocarcinoma (PDAC) preferentially targets the more differentiated cancer cell population, leaving CSCs as a cell source for tumor mass formation and recurrence. For this reason, there is an urgent need to improve current therapies and develop novel CSC-targeted therapeutic approaches.MethodsHyaluronic acid (HA) decorated liposomes, containing diethyldithiocarbamate?copper (Cu(DDC)2), able to target the specific CSC marker CD44 receptor were prepared by ion gradient technique and fully characterized. Their antiproliferative effect was evaluated on pancreatic CSCs derived from PDAC cell lines or patients. To clarify the mechanism of action of Cu(DDC)2 liposomes, ROS level neutralization assay in the presence of N-acetyl-L-cysteine was performed.ResultsLiposomes showed high encapsulation efficiency and Cryo-TEM analysis revealed the presence of Cu(DDC)2 crystals in the aqueous core of liposomes. In vitro test on pancreatic CSCs derived from PDAC cell lines or patients showed high ROS mediated anticancer activity of HA decorated liposomes. The sphere formation capability of CSCs obtained from patients was drastically reduced by liposomal formulations containing Cu(DDC)2.ConclusionsThe obtained results show that the encapsulation of Cu(DDC)2 complex in HA decorated liposomes strongly increases its anti-proliferative activity on pancreatic CSCs.General significanceThis paper describes for the first time the use of HA decorated liposomes containing Cu(DDC)2 against pancreatic CSCs and opens the way to the development of nanomedicine based CSC-targeted therapeutic approaches. |
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Keywords: | Liposomes Hyaluronic acid Diethyldithiocarbamate/copper complex CD44 Pancreatic cancer stem cells PDAC patient-derived cells |
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