Pancreatic cancer stem cell proliferation is strongly inhibited by diethyldithiocarbamate-copper complex loaded into hyaluronic acid decorated liposomes

• Published in: Biochimica et biophysica acta. General subjects Vol. 1863; no. 1; pp. 61 - 72
• Main Authors: Marengo, Alessandro, Forciniti, Stefania, Dando, Ilaria, Dalla Pozza, Elisa, Stella, Barbara, Tsapis, Nicolas, Yagoubi, Najet, Fanelli, Giuseppina, Fattal, Elias, Heeschen, Christopher, Palmieri, Marta, Arpicco, Silvia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2019; Elsevier
• Subjects: acetylcysteine; adenocarcinoma; antineoplastic activity; CD44; cell lines; cell proliferation; copper nanoparticles; cryo-electron microscopy; crystals; Diethyldithiocarbamate/copper complex; encapsulation; Galenic pharmacology; Hyaluronic acid; in vitro studies; Life Sciences; Liposomes; mechanism of action; metastasis; nanomedicine; neoplasm cells; neutralization tests; Pancreatic cancer stem cells; pancreatic neoplasms; patients; PDAC patient-derived cells; Pharmaceutical sciences; relapse; stem cells; therapeutics; transmission electron microscopy; Pancreatic cancer stem cells; Liposomes; Diethyldithiocarbamate/copper complex; Hyaluronic acid; CD44; PDAC patient-derived cells
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2018.09.018

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. 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. 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. 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. 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. [Display omitted] •Cu(DDC)2 has a stronger anti-proliferative activity than DSF, Zn(DDC)2 and Fe(DDC)2.•Cu(DDC)2 containing HA coated liposomes have a strong anti-proliferative activity on CSCs.•Cu(DDC)2 complexes precipitated inside the aqueous core of liposomes in the form of crystals.•Anti-proliferative activity of Cu(DDC)2 containing liposomes is ROS mediated.