A Copper-Mediated Disulfiram-Loaded pH-Triggered PEG-Shedding 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 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.
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Ling
L
Zhang
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Bin
B
Tian
Department of Pharmacology, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Yi
Y
Li
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Tian
T
Lei
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Jia
J
Meng
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Liu
L
Yang
Normal College, Shenyang University , Shenyang, Liaoning, PR China.
Yan
Y
Zhang
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.|Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine , Shenyang, Liaoning, PR China.
Fen
F
Chen
Department of Pharmacology, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Haotian
H
Zhang
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Hui
H
Xu
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Yu
Y
Zhang
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University , Shenyang, Liaoning, PR China.
Xing
X
Tang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry*; D004221:Disulfiram / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D065546:Drug Liberation; D004705:Endocytosis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000737:chemistry*; D013058:Mass Spectrometry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D019265:Spectroscopy, Near-Infrared; D055672:Static Electricity; D014018:Tissue Distribution / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry*
D008055:Lipids; D053769:Nanocapsules; D011136:Polysorbates; D054322:tat Gene Products, Human Immunodeficiency Virus; D011092:Polyethylene Glycols; D003300:Copper; D004221:Disulfiram
TAT peptide; copper; disulfiram; lipid nanocapsules; pH sensitive; sheddable