Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
cytotoxicity experiments showed that WP5
vesicles could not only kill cancer cellDsOeI:f1fi0c.1ie0n39tl/yC,9CbCu0t58a5ls9oA
could reduce the side effects on normal cells. Meanwhile,
CLSM experiments and flow cytometric ananlysis further
proved that these prodrug vesicles could lead to significant
drug accumulation in HepG2 cancer cells and release SN-38 to
induce the cell apoptosis. More importantly, in vivo
experiments by using murine xenograft model further
demonstrated the excellent tumor-selective accumulation of
these prodrug nanocarriers, which could be used to track the
tumor tissue distribution. This work provides a novel approach
for the construction of bifunctional supramolecular prodrug
nanocarriers with GSH responsiveness, which has great
potential application in the fields of cancer diagnosis and
therapy.
Fig. 5 In vivo fluorescent imaging of HepG2 tumor-bearing
mice at different time intervals after tail vein injection of DNS-
CPT and WP5
respectively. Red circles indicate the tumor location.
DNS-CPT vesicles (a dose of 5.0 mg kg-1),
This work was supported by the National Natural Science
Foundation of China (No. 21572101, 21871136), and the
Natural Science Foundation of Jiangsu Province (No.
BK20180055). L. Wang is grateful to UM Macao Distinguished
induced by WP5DNS-CPT vesicles, flow cytometry analysis
was performed to identify the apoptotic cells at different
stages by Annexin V-FITC/PI dual-staining technology. As
Visiting Scholar Scheme
.
shown in Fig. 4b, after being incubated with SN
WP5 DNS-CPT vesicles at the same concentration (8 µM) for
24 h, the apoptosis rate of HepG2 cancer cells was 35.53% and
40.35%, respectively. The cell apoptosis rate of WP5 DNS-CPT
-38 and
Conflicts of interest
There are no conflicts to declare.
vesicles is slightly higher than the SN-38 group, which was in
accordance with the MTT results. Moreover, cell apoptosis of
SN-38 group was mainly induced by early apoptosis, whereas,
both early and late apoptosis led to the cell apoptosis of
Notes and references
1
2
3
4
5
6
7
8
9
T. A. Ahles and J. C. Root, Annu. Rev. Clin. Psychol., 2018, 14,
425-451.
D. I. Quinn, H. M. Sandler, L. G. Horvath, A. Goldkorn and J. A.
Eastham, Ann. Oncol., 2017, 28, 2658-2669.
J. Ferlay, H.-R. Shin, F. Bray, D. Forman, C. Mathers and D.
Parkin, Int. J. Cancer, 2010, 127, 2893-2917.
H. Zhu, L. Shangguan, B. Shi, G. Yu and F. Huang, Mater. Chem.
Front., 2018, 2, 2152-2174.
WP5DNS-CPT vesicle group, indicating WP5DNS-CPT
vesicles have more potential therapeutic effects.
To study the in vivo drug release and distribution in tumor
tissues, animal experiments were investigated by using
hepatocellular carcinoma xenografts in nude mice. After
intravenous injection into tumor-bearing mice, the intrinsic
fluorescence of SN-38 was used to monitor the drug release
and distribution at different time periods. As shown in Fig. 5,
for the prodrug DNS-CPT group, due to the low GSH
concentration in blood circulation system, DNS-CPT couldn’t
be effectively triggered to release free drug SN-38, thus no
obvious fluorescent signal could be observed. In contrary,
X. Chi, H. Zhang, G. I. Vargas-Zuniga, G. M. Peters and J. L.
Sessler, J. Am. Chem. Soc., 2016, 138, 5829-5832.
S. Cerritelli, D. Velluto and J. A. Hubbell, Biomacromolecules,
2007, 8, 1966-1972.
K. Kataoka, A. Harada and Y. Nagasaki, Adv. Drug Deliver. Rev.,
2012, 64, 37-48.
N. Song and Y.-W. Yang, Chem. Soc. Rev., 2015, 44, 3474-
3504.
X. Wu, Y. Zhang, Y. Lu, S. Pang, K. Yang, Z. Tian, Y. Pei, Y. Qu, F.
Wang and Z. Pei, J. Mater. Chem. B, 2017, 5, 3483-3487.
10 W. Feng, M. Jin, K. Yang, Y. Pei and Z. Pei, Chem. Commun.,
2018, 54, 13626-13640.
WP5DNS-CPT vesicles could be efficiently accumulated in
HepG2 tumor on account of EPR effect and prodrug SN-38 was
released rapidly under the higher GSH concentration of cancer
cells, so obvious fluorescence signal could be observed from
11 Y. Wang, D. Li, H. Wang, Y. Chen, H. Han, Q. Jin and J. Ji, Chem.
Commun., 2014, 50, 9390-9392.
12 Y.-M. Zhang, N.-Y. Zhang, K. Xiao, Q. Yu and Y. Liu, Angew.
Chem. Int. Ed., 2018, 57, 8649-8653.
the tumor tissues. The above results suggest that WP5DNS-
13 X. Guan, Y. Chen, X. Wu, P. Li and Y. Liu, Chem. Commun.,
2019, 55, 953-956.
CPT vesicles could be efficiently accumulated at the tumor
sites during the long-circulation time in body and the time-
dependent drug release process could also be tracked.
In summary, we have successfully developed a bifunctional
supramolecular prodrug delivery system based on the host-
guest interaction between water-soluble pillar[5]arene (WP5)
and a GSH-sensitive prodrug molecule DNS-CPT. The obtained
supramolecular amphiphile WP5DNS-CPT could self-
assemble into prodrug vesicles with higher drug loading
efficiency. It was found that these prodrug vesicles were very
14 D. Wu, Y. Li, J. Shen, Z. Tong, Q. Hu, L. Li and G. Yu, Chem.
Commun., 2018, 54, 8198-8201.
15 C.-H. Whang, E. Yoo, S. K. Hur, K. S. Kim, D. Kim and S. Jo,
Chem. Commun., 2018, 54, 9031-9034.
16 Q.-Y. Li, X.-Q. Deng, Y.-G. Zu, H. Lv, L. Su, L. Yao, Y. Zhang and
L. Li, Eur. J. Med. Chem., 2010, 45, 3200-3206.
17 G. Sun, Z. He, M. Hao, M. Zuo, Z. Xu, X.-Y. Hu, J.-J. Zhu and L.
Wang, J. Mater. Chem B, 2019, 7, 3944-3949.
18 T. Ogoshi, M. Hashizume, T.-A. Yamagishi and Y. Nakamoto,
Chem. Commun., 2010, 46, 3708-3710.
19 L. B. Meng, W. Zhang, D. Li, Y. Li, X.-Y. Hu, L. Wang and G. Li,
Chem. Commun., 2015, 51, 14381-14384.
stable under physiological condition, but the free drug SN-38
could be released efficiently with the presence of high GSH
concentration for tumor diagnosis and therapy. Moreover,
20 W. Shao, X. Liu, G. Sun, X.-Y. Hu, J.-J. Zhu and L. Wang, Chem.
Commun., 2018, 54, 9462-9465.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins