A Copper-Mediated Disulfiram-Loaded pH-Triggered PEG-Shedding TAT Peptide-Modified Lipid Nanocapsules for Use in Tumor Therapy

Abstract

Disulfiram, which exhibits marked tumor inhibition mediated by copper, was encapsulated in lipid nanocapsules modified with TAT peptide (TATp) and pH-triggered sheddable PEG to target cancer cells on the basis of tumor environmental specificity. PEG-shedding lipid nanocapsules (S-LNCs) were fabricated from LNCs by decorating short PEG chains with TATp (HS-PEG(1k)-TATp) to form TATp-LNCs and then covered by pH-sensitive graft copolymers of long PEG chains (PGA-g-PEG(2k)). The DSF-S-LNCs had sizes in the range of 60-90 nm and were stable in the presence of 50% plasma. DSF-S-LNCs exhibited higher intracellular uptake and antitumor activity at pH 6.5 than at pH 7.4. The preincubation of Cu showed that the DSF cytotoxicity was based on the accumulation of Cu in Hep G2 cells. Pharmacokinetic studies showed the markedly improved pharmacokinetic profiles of DSF-S-LNCs (AUC= 3921.391 μg/L·h, t(1/2z) = 1.294 h) compared with free DSF (AUC = 907.724 μg/L·h, t(1/2z) = 0.252 h). The in vivo distribution of S-LNCs was investigated using Cy5.5 as a fluorescent probe. In tumor-bearing mice, the delivery efficiency of S-LNCs was found to be 496.5% higher than that of free Cy5.5 and 74.5% higher than that of LNCs in tumors. In conclusion, DSF-S-LNCs increased both the stability and tumor internalization and further increased the cytotoxicity because of the higher copper content.

Time dependent of epigenetic effect of disulfiram on tumor suppressor gene of RASSF1A in Hela cancer cell line

“…The IC50 indicated biphasic effect at 2.5, 5, 12.5 µM concentrations in Hela cell line. Our results were in accordance with the studies of Wiggins, Zhang, and Jones that demonstrated the biphasic effect of DSF inMCF-7, HePG2, and ovarian cancer cell line(OVCAR-3) (20)(21)(22), while Wickstorms and Nikbakht stated the monophasic effect of DSF in ACH, H69AR, PRE and PANC-1, respectively (17,23). This controversy can be explained by different responses of various cancer cell lines and tumor cells during the exposure of DSF.…”

Anti-hepatocellular carcinoma properties of the anti-alcoholism drug disulfiram discovered to enzymatically inhibit the AMPK-related kinase SNARK in vitro

“…Again DDC, with anti-cancer effects via chelating into metal ions [20] and reported to significantly improve the overall survival in breast cancer patients [30], demonstrated unique profiles of cytotoxicity to HCC cells, and indicated the effects by DSF are to be kept even after being metabolized at least reducing SNARK expression (Figure 4G); lately further improvement in stable delivery and anti-cancer effects of DDC was reported in vivo [31]. Utilization of intact DSF, simultaneously, is being investigated for its anti-cancer properties, and such a method was recently developed by nanocapsule-protected medicine [32], achieving favorable anti-cancer effects. Still the cytotoxic efficacy could fluctuate depending on individual cell types with various genetic and pathoetiological backgrounds as was the case with PLC/PRF/5 cells positive for hepatitis B virus proteins (Figure 4B) and anti-cancer agents [33].…”

“…The utility and a newly revealed property of DSF were mechanistically suggested and in turn the significance of regulatory sites for SNARK kinase activity as validated drug target can now be comprehensively assessed using DSF as a chemical probe. Also DSF derivatives with better potencies could be examined [40] in addition to devising improved methods of delivery [32, 41]. Further chemical and biological analyses would accelerate understanding of SNARK functions and at the same time the chemical search for and development of potent SNARK inhibitors continue.…”

Repurposing disulfiram for cancer therapy via targeted nanotechnology through enhanced tumor mass penetration and disassembly

“…Cu(DDTC) 2 induces elevated reactive oxygen species (ROS) level, which exceeds the antioxidant capacity of cancer cells and subsequently results in the apoptosis of cancer cells [11]. Cu(DDTC) 2 may also regulate intracellular signaling [12, 13], enzyme activities [14] (such as acetaldehyde dehydrogenase (ALDH)) [15], and inhibit proteasome function [16]. Since many tumors have a higher copper concentration, up to 2–3 fold compared to normal tissues, the copper dependent anticancer activity of DSF makes it a great candidate for cancer therapy [17].…”