Copper-mediated disulfiram-loaded pH-triggered PEG sheddable TAT peptide-modified lipid nanocapsules for use in tumor therapy.

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 based on tumor environmental specificity. PEG sheddable lipid nanocapsules (S-LNCs) were fabricated from LNCs by decorating short PEG chains with TATp (HS-PEG1k-TATp) to form TATp-LNCs, and then covered by pH-sensitive graft copolymers of long PEG chains (PGA-g-PEG2k). The DSF-S-LNCs had sizes in the range 60-90 nm and were stable in the presence of 50% plasma. DSF-S-LNCs exhibited higher intracellular uptake and anti-tumor activity at pH 6.5 than pH 7.4. The pre-incubation 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 mg/L·h, t1/2z=1.294 h) compared with free DSF (AUC=907.724 mg/L·h, t1/2z=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 free Cy5.5 and 74.5% higher than 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.