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inhibitor. In the presence of the MMP inhibitor, the peptide Notes and references
linkage cannot be cleaved and the conjugated drug cannot
1
2
A. I. Minchinton and I. F. Tannock, Nat. Rev. Cancer, 2006, 6, 583.
(a) M. Ferrari, Nat. Rev. Cancer, 2005, 5, 161; (b) D. Peer, J. M. Karp,
S. Hong, O. C. Farokhzad, R. Margalit and R. Langer, Nat. Nanotechnol.,
be released from the micelles. In contrast, without the MMP
inhibitor, MMP protease could hydrolyze the peptide linkage to
induce drug release as well as the apoptosis of cancer cells.
However, as shown in Fig. 4B, the viability of COS7 normal cells
incubated with Biotin-PEG-b-PLL(Mal)-peptide-DOX micelles was
more than 85% with or without the MMP inhibitor. This high
cell viability of COS7 cells was attributed to the low uptake of
polymeric micelles and the lack of a specific MMP protease. In
addition, the polymer backbone Biotin-PEG-b-PLL did not exhibit
an obvious cytotoxicity in all cell lines (Fig. S10, ESI†). These
results confirm that the selective therapy to cancer cells of the
multifunctional micelles can be achieved due to the drug release
upon applying the stimulus of cancer cells excessive secreted
protease.
2007, 2, 751; (c) A. Mukerjee, A. P. Ranjan and J. K. Vishwanatha, Curr.
Med. Chem., 2012, 19, 3714.
(a) P. Sharma and S. Garg, Adv. Drug Delivery Rev., 2010, 62, 491;
(b) H. Wei, R. X. Zhuo and X. Z. Zhang, Prog. Polym. Sci., 2013,
3
(
3
8, 503; (c) Z. Ge and S. Liu, Chem. Soc. Rev., 2013, 42, 7289;
d) J. Ding, L. Chen, C. Xiao, L. Chen, X. Zhuang and X. Chen,
Chem. Commun., 2014, 50, 11274.
4 (a) J. Z. Du, X. J. Du, C. Q. Mao and J. Wang, J. Am. Chem. Soc., 2011,
33, 17560; (b) W. Xu, J. F. Burke, S. Pilla, H. Chen, R. Jaskula-Sztul
1
and S. Gong, Nanoscale, 2013, 5, 9924.
5
(a) J. Nicolas, S. Mura, D. Brambilla, N. Mackiewicz and P. Couvreur,
Chem. Soc. Rev., 2013, 42, 1147; (b) A. Mahmud, X. B. Xiong,
H. M. Aliabadi and A. Lavasanifar, J. Drug Targeting, 2007, 15, 553;
(
c) Y. Zou, Y. Song, W. Yang, F. Meng, H. Liu and Z. Zhong,
J. Controlled Release, 2014, DOI: 10.1016/j.jconrel.2014.05.016;
d) W. H. Chen, X. D. Xu, G. F. Luo, H. Z. Jia, Q. Lei, S. X. Cheng,
(
In summary, the preparation of multifunctional Biotin-PEG-
b-PLL(Mal)-peptide-DOX polymeric micelles was demonstrated,
which can specially respond to physiopathological signals of
cancer cells. The biotin ligand could promote cancer cell
uptake via the receptor-mediated endocytosis. Upon applica-
tion of the stimulus of the overexpressed MMP protease in
cancer cells, the anticancer drug DOX could be released effec-
tively, leading to significant apoptosis of cancer cells. The
targeted therapy to cancer cells could be achieved with much
R. X. Zhuo and X. Z. Zhang, Sci. Rep., 2013, 3, 3468.
(a)J. Dai, S. Lin, D. Cheng, S. ZouandX. Shuai,Angew. Chem., Int. Ed., 2011,
6
50, 9404; (b)Z.Chu,C.A.DreissandY.Feng,Chem. Soc. Rev., 2013, 42, 7174;
(c) M. Nakayama, J. Akimoto and T. Okano, J. Drug Targeting, 2014, 22, 584;
(d) S. Mura, J. Nicolas and P. Couvreur, Nat. Mater., 2013, 12, 991.
X. Tian, K. H. Baek and I. Shin, Chem. Sci., 2013, 4, 947.
S. Bhuniya, S. Maiti, E. J. Kim, H. Lee, J. L. Sessler, K. S. Hong and
J. S. Kim, Angew. Chem., Int. Ed., 2014, 53, 4469.
7
8
9 (a) P. Vihinen, R. Ala-aho and V. M. K ¨a h ¨a ri, Curr. Cancer Drug
Targets, 2005, 5, 203; (b) L. Aureli, M. Gioia, I. Cerbara, S. Monaco,
G. F. Fasciglione, S. Marini, P. Ascenzi, A. Topai and M. Coletta,
Curr. Med. Chem., 2008, 15, 2192.
reduced side effects to normal cells, which will find great 10 (a) K. Wang, G. F. Luo, Y. Liu, C. Li, S. X. Cheng, R. X. Zhuo and
potential in cancer therapy.
X. Z. Zhang, Polym. Chem., 2012, 3, 1084; (b) B. Yang, Y. Lv, J. Y. Zhu,
Y. T. Han, H. Z. Jia, W. H. Chen, J. Feng, X. Z. Zhang and R. X. Zhuo,
Acta Biomater., 2014, 10, 3686.
1 P. Huang, D. Wang, Y. Su, W. Huang, Y. Zhou, D. Cui, X. Zhu and
D. Yan, J. Am. Chem. Soc., 2014, 136, 11748.
This work was supported by the National Natural Science
Foundation of China (51125014 and 51233003), the Ministry of
Science and Technology of China (2011CB606202), the Ministry
of Education of China (20120141130003) and supported by the
Fundamental Research Funds for the Central Universities
1
1
1
2 L. Rajendran, H. J. Kn o¨ lker and K. Simons, Nat. Rev. Drug Discovery,
2010, 9, 29.
3 L. Pan, Q. He, J. Liu, Y. Chen, M. Ma, L. Zhang and J. Shi, J. Am.
Chem. Soc., 2012, 134, 5722.
(2014203020201 and 2014203020204).
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