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

Biochim Biophys Acta Gen Subj. 2019 Jan;1863(1):61-72. doi: 10.1016/j.bbagen.2018.09.018. Epub 2018 Sep 26.


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.

Keywords: CD44; Diethyldithiocarbamate/copper complex; Hyaluronic acid; Liposomes; PDAC patient-derived cells; Pancreatic cancer stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / chemistry
  • Calorimetry, Differential Scanning
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Copper / chemistry*
  • Cryoelectron Microscopy
  • Ditiocarb / chemistry*
  • Drug Screening Assays, Antitumor
  • Humans
  • Hyaluronan Receptors / metabolism
  • Hyaluronic Acid / chemistry*
  • Liposomes / chemistry*
  • Microscopy, Electron, Transmission
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / drug effects
  • Pancreas / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Phospholipids / chemistry
  • Reactive Oxygen Species / metabolism


  • CD44 protein, human
  • Hyaluronan Receptors
  • Liposomes
  • Phospholipids
  • Reactive Oxygen Species
  • Copper
  • Hyaluronic Acid
  • Ditiocarb
  • Acetylcysteine