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,
State Key Laboratory of Natural and Biomimetic Drugs, and School of Pharmaceutical Sciences, Peking University, Xueyuan Road 38, Beijing 100191, China
Received 26 January 2011
Accepted 10 April 2011
Available online 7 May 2011
Mitochondrial targeting resveratrol
Mitochondria signaling pathway
Intrinsic multidrug resistance
Intrinsic multidrug resistance (MDR) of cancers remains a major obstacle to successful chemotherapy. A
dequalinium polyethylene glycol-distearoylphosphatidylethanolamine (DQA-PEG
was synthesized as a mitochondriotropic molecule, and mitochondrial targeting resveratrol liposomes
were developed by modifying DQA-PEG
-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
-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.
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 .
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 .
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 .
Cancer cell mitochondria are structurally and functionally different
from their normal counterparts . They exhibit an extensive
metabolic and are more susceptible to mitochondrial perturbation
than normal cell mitochondria .
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 . Both
Corresponding author. Tel./fax: þ8610 8280 2683.
E-mail address: email@example.com (W.-L. Lu).
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0142-9612/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
Biomaterials 32 (2011) 5673e5687