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

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.

Development and application of hyaluronic acid in tumor targeting drug delivery

“…In vivo , the PTX-loaded HA-SLNs significantly decreased the growth of tumor, which was better than other particles and free drug. Similarly, Marengo et al 64 . loaded diethyldithiocarbamate–copper into HA-decorated liposomes for targeting pancreatic cancer stem cells.…”

Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines

“…However, this reaction was not localised to cancer tissue and insoluble crystals of DDC-Cu were still instantly formed, reducing the effective fraction [ 1 ]. Recently, Marengo et al have followed similar “split” approach but by loading copper salts to the lipid phase of PEGylated hyaluronic acid liposome encapsulating saturated solution of DDC-sodium [ 11 ]. This method might theoretically offer a slight enhancement in the solubility of DDC-Cu in liposomal dispersions; however, no long-term stability was proven.…”

Novel multifunctional triple folic acid, biotin and CD44 targeting pH-sensitive nano-actiniaes for breast cancer combinational therapy

“…An increasing number of researchers have illustrated that tumor growth, drug resistance and development are boosted by a small number of immortalized cells, known as cancer stem cells (CSCs). Consequently, completely eliminating CSCs is critical when treating tumors (Marengo et al., 2019). Breast cancer stem cells (BCSCs) have the ability to self-renew and unlimitedly proliferate, which is the main reason for tumorigenesis, metastasis, and relapse.…”