2
2
D. Chen et al. / Carbohydrate Polymers 94 (2013) 17–23
cell viability of free Cur, Cur-LM, Cur-LM-G and PBS alone were
modified liposome carried the model drugs and promoted the
stability, prevented their premature release, the microbubble
enhanced the drug release, and the temperature-sensitive gel
maintained both particles in body temperature could be affected
by US (Epstein-Barash et al., 2010).
7
2.8 ± 3.1, 85.2 ± 3.4, 90.3 ± 4.3, and 96 ± 2.3, respectively. The
results indicated that encapsulated Cur in Cur-LM or Cur-LM-G was
less toxic than the free Cur. It is clear that curcumin encapsulated
to Cur-LM and Cur-LM-G could enhance the viability.
5. Conclusions
3.7. In vivo assay
In this work, we have prepared a novel curcumin-loaded
The anti-tumor efficacy of dual-sensitive curcumin-loaded lipo-
liposome microbubble gel based on N-cholesteryl hemisuccinate-
O-sulfate chitosan (NCHOSC). The liposomal microbubble based
on NCHOSC with a high encapsulation efficiency of curcumin was
formed and improved the solubility of curcumin. The chemical
structure of NCHOSC was characterized by FTIR, 1H NMR. As ultra-
sound guided drug delivery carrier, liposome-loaded microbubble
and gels were characterized, containing in vitro studies, cell assay
and in vivo assay using curcumin as a model drug. The diameter of
most liposomal microbubble is about 950 nm. The temperature-
sensitive CS/GP gel containing liposomal microbubble can be
formulated at room temperature and would form a gel at body tem-
perature. Simultaneously, the ultrasound-sensitive induced release
of curcumin was 85% applying ultrasound. The results of cyto-
toxicity assay indicated that encapsulated curcumin in Cur-LM or
Cur-LM-G was less toxic than the free curcumin. The anti-tumor
efficacy in vivo suggested that Cur-LM-G by ultrasound suppressed
tumor growth most efficiently. These results indicated that dual-
sensitive curcumin-loaded liposomal microbubble gel could be a
potential temperature and ultrasound dual-sensitive drug carrier
in local drug delivery system.
somal microbubble gel in vivo was evaluated in tumor-bearing
BALB/c mice. As shown in Fig. 5, there was no difference between
the groups with or without ultrasound irradiation in 1 week, how-
ever, after the next week, there was different. This could be the
reason of slow-release of Cur from the liposome-loaded microbub-
ble gel in vivo under the body temperature and ultrasound. The
tumor volume of the saline control group was excessively enlarged
3
(
>1000 mm ), while the other groups were much smaller. The ultra-
sound group suppressed tumor growth most efficiently, followed
by the non-ultrasound group (P < 0.05). This enhanced anti-tumor
activity could be explained by the increased local concentration of
Cur near the tumor by ultrasound.
4
. Discussion
In this work, we have prepared a novel curcumin-loaded
liposomal microbubble gel based on N-cholesteryl hemisuccinate-
O-sulfate chitosan (NCHOSC) which is interesting. In our previous
study, the novel water-soluble chitosan derivative NCHOSC was
synthesized. Its anticoagulation activity in vitro was determined by
an activated partial thromboplastin time (APTT) assay, a thrombin
time (TT) assay and a prothrombin time (PT) assay. Results of anti-
coagulation assays showed NCHOSC significantly prolonged APTT
and TT (Fan et al., 2012).
Conflicts of interest
The authors report no conflicts of interest in this work.
The mechanism of untrasound-induced drug release could be
explained that untrasound (US) applied with a very low acoustic
pressures could promote liposomal microbubble to move along the
axis of the US beam without disrupting the agent (Dayton, Allen, &
Ferrara, 2002; Shortencarier et al., 2004). This radiation force can
promote the movement and accumulation of liposomal microbub-
ble at a designated area which could be used to increase both
specificity of drug delivery to the targeting site and transfection
efficiency (Dayton et al., 2002; Shortencarier et al., 2004).
Acknowledgments
This work was supported by the National Basic Research Pro-
gram of China (973 Plan, 2010CB735600 and 2012CB724003),
Taishan Scholar Project, Open Project Program of State Key
Laboratory of Long-acting and Targeting Drug Delivery System
(YX12H071,Yantai,China) and Yantai University Doctoral Research
Program (YX10B29).
In this study, we aimed to apply NCHOSC to ultrasould-sensitive
drug release system for improving its stability and hemocompa-
tibility. Shelma and Sharma prepared a hemocompatible lauroyl
sulfated chitosan (LSCS) which could improve the hemocompati-
bility of chitosan and reduce the protein adsorption on chitosan
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(
NOSC) in micellar or liposomal delivery (Mo, Xiao, Sun, Zhang, &
Ping, 2011; Mo, Jin, et al., 2011; Qu, Yao, Zhang, Wu, & Ping, 2009;
Qu, Wu, Yin, & Zhang, 2012). However, there was not reported
research about novel chitosan for the hemocompatible activity.
There was also no further application research to increase stability
of nano-drug delivery system.
In this study, the key feature of gel system is the temperature
and ultrasound dual-sensitive system which is the combina-
tion of injectability and mechanical integrity (Epstein-Barash
et al., 2010). Each component served a specific aim: the NCHOSC