The use of mitochondrial targeting resveratrol liposomes modified with a
dequalinium polyethylene glycol-distearoylphosphatidyl ethanolamine
conjugate to induce apoptosis in resistant lung cancer cells
Xiao-Xing Wang, Yang-Bing Li, Hong-Juan Yao, Rui-Jun Ju, Yan Zhang, Ruo-Jing Li, Yang Yu, Liang Zhang,
Wan-Liang Lu
*
State Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Xueyuan Road 38, Beijing 100191, China
article info
Article history:
Received 26 January 2011
Accepted 10 April 2011
Available online 7 May 2011
Keywords:
DQA-PEG
2000
-DSPE conjugate
Mitochondrial targeting resveratrol
liposomes
Mitochondria signaling pathway
Intrinsic multidrug resistance
Lung cancer
abstract
Intrinsic multidrug resistance (MDR) of cancers remains a major obstacle to successful chemotherapy. A
dequalinium polyethylene glycol-distearoylphosphatidylethanolamine (DQA-PEG
2000
-DSPE) conjugate
was synthesized as a mitochondriotropic molecule, and mitochondrial targeting resveratrol liposomes
were developed by modifying DQA-PEG
2000
-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-PEG
2000
-DSPE conjugate synthesized was about 87% and the
particle size of mitochondrial targeting resveratrol liposomes was approximately 70 nm. The mito-
chondrial 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.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The multidrug resistance (MDR) of cancers is a major obstacle to
successful cancer chemotherapy, and it results in incomplete
therapeutic response, recurrent and metastasis of cancers [1].
Intrinsic MDR plays a crucial role in the drug resistance and is
caused by genetic and epigenetic changes of cancer cells through
altering function of pro-apoptotic or apoptotic genes encoded
proteins such as Bcl-2 family proteins [2,3] and capase proteins
involved in the apoptosis signaling pathway [4,5].
There are two basic ways to eliminate cancer cells in the
chemotherapy. One approach is to kill cancer cells by direct expo-
sure of cancer cells to toxic chemicals. The other one is to induce the
suicide of cancer cells, namely, induction of apoptosis which has
been regarded as a very important strategy for thoroughly elimi-
nating tumors [6].
Mitochondria are membrane-enclosed organelles found in most
eukaryotic cells, and are described as "cellular power plants".
Besides supplying cellular energy, mitochondria are involved in
a range of other processes, such as cellular differentiation, cell
death, as well as the control of the cell cycle and cell growth [7].
Cancer cell mitochondria are structurally and functionally different
from their normal counterparts [8]. They exhibit an extensive
metabolic and are more susceptible to mitochondrial perturbation
than normal cell mitochondria [9].
Cancer cell apoptosis induced by anticancer drugs may involve
two independent initiator pathways that lie in upstream of all these
effector events: activation of upstream caspase by cross-linking
with death receptors on their ligands, and the release of apopto-
genic factors by triggering various forms of cellular stress [10]. Both
*
Corresponding author. Tel./fax: þ8610 8280 2683.
E-mail address: luwl@bjmu.edu.cn (W.-L. Lu).
Contents lists available at ScienceDirect
Biomaterials
journal homepage: www.elsevier.com/locate/biomaterials
0142-9612/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biomaterials.2011.04.029
Biomaterials 32 (2011) 5673e5687