The use of mitochondrial targeting resveratrol liposomes modified with a dequalinium polyethylene glycol-distearoylphosphatidyl ethanolamine conjugate to induce apoptosis in resistant lung cancer cells

Abstract Intrinsic multidrug resistance (MDR) of cancers remains a major obstacle to successful chemotherapy. A dequalinium polyethylene glycol-distearoylphosphatidylethanolamine (DQA-PEG2000 -DSPE) conjugate was synthesized as a mitochondriotropic molecule, and mitochondrial targeting resveratrol l...

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Bibliographic Details
Published in:Biomaterials 2011-08, Vol.32 (24), p.5673-5687
Main Authors: Wang, Xiao-Xing, Li, Yang-Bing, Yao, Hong-Juan, Ju, Rui-Jun, Zhang, Yan, Li, Ruo-Jing, Yu, Yang, Zhang, Liang, Lu, Wan-Liang
Format: Article
Language:English
Subjects:
Advanced Basic Science
Animals
Apoptosis - drug effects
Cell Line, Tumor
Cytochromes c - metabolism
Dentistry
Dequalinium - chemistry
Dequalinium - therapeutic use
DQA-PEG 2000-DSPE conjugate
Female
Humans
Intrinsic multidrug resistance
Liposomes - chemistry
Liposomes - therapeutic use
Lung cancer
Lung Neoplasms - metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Mitochondria - metabolism
Mitochondria signaling pathway
Mitochondrial targeting resveratrol liposomes
Phosphatidylethanolamines - chemistry
Polyethylene Glycols - chemistry
Stilbenes - chemistry
Stilbenes - therapeutic use
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Summary:Abstract Intrinsic multidrug resistance (MDR) of cancers remains a major obstacle to successful chemotherapy. A dequalinium polyethylene glycol-distearoylphosphatidylethanolamine (DQA-PEG2000 -DSPE) conjugate was synthesized as a mitochondriotropic molecule, and mitochondrial targeting resveratrol liposomes were developed by modifying DQA-PEG2000 -DSPE on the surface of liposomes for overcoming the resistance. Evaluations were performed on the human lung adenocarcinoma A549 cells and resistant A549/cDDP cells, A549 and A549/cDDP tumor spheroids as well as the xenografted resistant A549/cDDP cancers in nude mice. The yield of DQA-PEG2000 -DSPE conjugate synthesized was about 87% and the particle size of mitochondrial targeting resveratrol liposomes was approximately 70 nm. The mitochondrial targeting liposomes significantly enhanced the cellular uptake, and selectively accumulated into mitochondria when encapsulating coumarin as the fluorescent probe. Furthermore, mitochondrial targeting resveratrol liposomes induced apoptosis of both non-resistant and resistant cancer cells by dissipating mitochondria membrane potential, releasing cytochrome c and increasing the activities of caspase 9 and 3. They also exhibited significant antitumor efficacy in two kinds of cancer cells, in tumor spheroids by penetrating deeply into the core, and in xenografted resistant A549/cDDP cancers in nude mice. Mitochondrial targeting resveratrol liposomes co-treating with vinorelbine liposomes significantly enhanced the anticancer efficacy against the resistant A549/cDDP cells. In conclusion, mitochondrial targeting resveratrol liposomes would provide a potential strategy to treat the intrinsic resistant lung cancers by inducing apoptosis via mitochondria signaling pathway.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2011.04.029