Alessandro Marengo1, Stefania Forciniti2, Ilaria Dando2, Elisa Dalla Pozza2, Barbara Stella1, Nicolas Tsapis3, Najet Yagoubi4, Giuseppina Fanelli5, Elias Fattal3, Christopher Heeschen6, Marta Palmieri7, Silvia Arpicco8. 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. 7. Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy. Electronic address: marta.palmieri@univr.it. 8. Department of Drug Science and Technology, University of Torino, Italy. Electronic address: silvia.arpicco@unito.it.
Abstract
BACKGROUND: Pancreatic 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. METHODS: Hyaluronic 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. RESULTS: Liposomes 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. CONCLUSIONS: The 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 SIGNIFICANCE: This 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.
BACKGROUND:Pancreatic 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. METHODS:Hyaluronic 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. RESULTS: Liposomes 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. CONCLUSIONS: The 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 SIGNIFICANCE: This 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.
Authors: Julian Palzer; Benedikt Mues; Richard Goerg; Merel Aberle; Sander S Rensen; Steven W M Olde Damink; Rianne D W Vaes; Thorsten Cramer; Thomas Schmitz-Rode; Ulf P Neumann; Ioana Slabu; Anjali A Roeth Journal: Int J Nanomedicine Date: 2021-04-23
Authors: Radu A Paun; Daciana C Dumut; Amanda Centorame; Thusanth Thuraisingam; Marian Hajduch; Martin Mistrik; Petr Dzubak; Juan B De Sanctis; Danuta Radzioch; Maryam Tabrizian Journal: Pharmaceutics Date: 2022-03-14 Impact factor: 6.321