10.1002/ange.202009888
Angewandte Chemie
RESEARCH ARTICLE
change in MMP was assessed by JC-1 staining. A549 cells
treated with Ir4 demonstrated significant MMP reduction in
comparison with the controls, while Ir1-3 showed no obvious
change (Figure S30-S33). These results, together with those from
the ESR experiments indicate that Ir4 is a mitochondrion-
targeting photosensitizer which initiates cell death by the
generation of carbon radicals under hypoxic conditions leading to
ROS over production, MMP loss, and cell death.
Keywords: Bioinorganic Chemistry • Medicinal Inorganic
Chemistry • Metals in Medicine • Photodynamic Therapy •
Carbon Radicals
[1]
[2]
[3]
(a) H. Huang, S. Banerjee, K. Qiu, P. Zhang, O. Blacque, T. Malcomson,
M. J. Paterson, G. J. Clarkson, M. Staniforth, V. G. Stavros, G. Gasserꢀ,
H. Chao, P. J. Sadlerꢀ, Nat. Chem. 2019, 11, 1041–1048; (b) C. Mari, V.
Pierroz, S. Ferrari, G. Gasser, Chem. Sci. 2015, 6, 2660-2686; (c) X. H.
Wang, X. Y. Wang, S. X. Jin, N. Muhammad, Z. J. Guo, Chem. Rev. 2019,
119, 1138-1192.
The excellent in vitro properties of Ir4 encouraged the further
in vivo evaluation of PDT cancer therapy under hypoxic conditions.
Male nude (nu/nu) mice bearing A549 xenografted tumors were
utilized as the in vivo model. When the xenografted tumor
volumes reached ca. 80 mm3, the mice were randomly separated
into four groups (5 mice per group). Groups 1 and 2 were injected
with physiological saline intratumorally. Groups 3 and 4 were
injected with 0.2 mg/kg Ir4 respectively. After injection for 2 h,
group 2 and 4 were irradiated by two-photon excitation (730 nm,
50 mW, 1 kHz, pulse width 35 fs, 5 sec/mm). The xenograft
volumes and body weights were recorded every two days. As
show in Figure 4A, after treatment, the mice body weights did not
significantly decrease in all groups, showing the low side effects
of Ir4. After 14 days treatment the growth of the tumors in group
4 had been significantly inhibited when compared with the other
three groups (Figure 4B and 4C). Histochemical analysis of the
tumors and major organs stained with haematoxylin and eosin
(H&E) was performed. The clear pathological changes were
observed for the tumors of group 4, while no serious cellular
structure changes, pathological alterations or organ damage was
observed in any of the other groups (Figure 4D and S34).
(a) H. Huang, B. Yu, P. Zhang, J. Huang, Y. Chen, G. Gasser, L. Ji and
H. Chao, Angew. Chem., Int. Ed. 2015, 54, 14049-14052; (b) V. N.
Nguyen, S. Qi, S. Kim, N. Kwon, G. Kim, Y. Yim, S. Park, J. Yoon, J. Am.
Chem. Soc. 2019, 141, 16243-16248; (c) Y. Yu, Q. Xu, S. He, H. Xiong,
Q. Zhang, W. Xu, V. Ricotta, L. Bai, Q. Zhang, Z. Yu, J. Ding, H. Xiao, D.
Zhou, Coord. Chem. Rev. 2019, 387, 154-179.
(a) Z. Yang, W. Fan, J. Zou, W. Tang, L. Li, L. He, Z. Shen, Z. Wang, O.
Jacobson, M. A. Aronova, P. Rong, J. Song, W. Wang, X. Chen, J. Am.
Chem. Soc. 2019, 141, 14687-14698; (b) I. Roy, S. Bobbala, R. M. Young,
Y. Beldjoudi, M. T. Nguyen, M. M. Cetin, J. A. Cooper, S. Allen, O.
Anamimoghadam, E. A. Scott, M. R. Wasielewski, J. F. Stoddart, J. Am.
Chem. Soc. 2019, 141, 12296-12304; (c) F. Xu, H. Li, Q. Yao, H. Ge, J.
Fan, W. Sun, J. Wang, X. Peng, Chem. Sci. 2019, 10, 10586-10594.
(a) S. Monro, K. L. Colon, H. Yin, J. Roque, P. Konda, S. Gujar, R. P.
Thummel, L. Lilge, C. G. Cameron, S. A. McFarland, Chem. Rev. 2019,
119, 797-828; (b) R. Ho-Wu, S, H, Yau, T. Goodson, J. Phys. Chem. B
2017, 121, 10073-10080.
[4]
[5]
[6]
[7]
(a) R. Bevernaegie, B. Doix, E. Bastien, A. Diman, A. Decottignies, O.
Feron, B. Elias, J. Am. Chem. Soc. 2019, 141, 18486-18491; (b) F. Bolze,
S. Jenni, A. Sour, V. Heitz, Chem. Commun. 2017, 53, 12857-12877.
(a) G. Solaini, A. Baracca, G. Lenaz and G. Sgarbi, Biochim. Biophys.
Acta 2010, 1797, 1171-1177; (b) P. Vaupel, M. Hockel, A. Mayer,
Antioxid. Redox Sign. 2007, 9, 1221-1235.
(a) D. Wang, H. Wu, S. Z. F. Phua, G. Yang, W. Qi Lim, L. Gu, C. Qian,
H. Wang, Z. Guo, H. Chen, Y. Zhao, Nat. Commun. 2020, 11, 357; (b) Q.
Yu, T. Huang, C. Liu, M. Zhao, M. Xie, G. Li, S. Liu, W. Huang, Q. Zhao,
Chem. Sci. 2019, 10, 9091-9098; (c) E. Ju, K. Dong, Z. Chen, Z. Liu, C.
Liu, Y. Huang, Z. Wang, F. Pu, J. Ren, Xi. Qu, Angew. Chem. Int. Ed.
2016, 55, 11467-11471; (d) H. Chen, J. Tian, W. He, Z. Guo, J. Am.
Chem. Soc. 2015, 137, 1539-1547; (e) H. Cao, L. Wang, Y. Yang, J. Li,
Y. Qi, Y. Li, Y. Li, H. Wang, J. Li, Angew. Chem. Int. Ed. 2018, 57, 7759-
7763; (f) Q. Jia, J. Ge, W. Liu, X. Zheng, S. Chen, Y. Wen, H. Zhang, P.
Wang, Adv. Mater. 2018, 30, 1706090.
Conclusion
An iridium(III) anthraquinone complex Ir4 was developed for two-
photon PDT under hypoxic conditions. Ir4 exhibits hypoxia
specific reduction and turn-on emission. The carbon radical
generation properties of Ir4 were demonstrated by ESR, DNA
photocleavage, and TD-DFT calculations. Ir4 enters A549 cells
via an energy dependent mechanism and localizes in the
mitochondria. Upon irradiation, Ir4 initiates cell death by
generating carbon radicals, ROS over production, and
mitochondrial membrane potential loss. With the additional
advantage of two-photon excitation, the efficacy of Ir4 for PDT
under hypoxic conditions was demonstrated in MCTSs and in vivo.
To the best of our knowledge, Ir4 is the first metal complex-based
oxygen-independent phototheranostic agent for the treatment of
hypoxic tumours.
[8]
[9]
J. Shi, P. W. Kantoff, R. Wooster, O. C. Farokhzad, Nat. Rev. Cancer
2017, 17, 20-37.
(a) Z. Lv, H. Wei, Q. Li, X. Su, S. Liu, K. Y. Zhang, W. Lv, Q. Zhao, X. Li,
W. Huang, Chem. Sci. 2018, 9, 502-512; (b) L. He, M. F. Zhang, Z. Y.
Pan, K. N. Wang, Z. J. Zhao, Y. Li, Z. W. Mao, Chem. Commun. 2019,
55, 10472-10475; (c) L. N. Lameijer, D. Ernst, S. L. Hopkins, M. S. Meijer,
S. H. C. Askes, S. E. Le Dévédec, S. A. Bonnet, Angew. Chem. Int. Ed.
2017, 56, 11549-11553; (d) V. Novohradsky, A. Rovira, C. Hally, A.
Galindo, G. Vigueras, A. Gandioso, M. Svitelova, R. Bresolí-Obach, H.
Kostrhunova, L. Markova, J. Kasparkova, S. Nonell, J. Ruiz, V. Brabec,
V. Marchán, Angew. Chem. Int. Ed. 2019, 58, 6311-6315; (e) M. Li, Y.
Shao, J. H. Kim, Z. Pu, X. Zhao, H. Huang, T Xiong, Y. Kang, G. Li, K.
Shao, J. Fan, J. W. Foley, J. S. Kim, X. Peng, J. Am. Chem. Soc. 2020,
142, 5380-5388.
Acknowledgements
[10] (a) S. Shen, C. Zhu, D. Huo, M. Yang, J. Xue, Y. Xia, Angew. Chem. Int.
Ed. 2017, 56, 8801-8804; (b) X. Q. Wang, F. Gao, X. Z. Zhang, Angew.
Chem. Int. Ed. 2017, 56, 9029-9033.
This work was supported by the National Science Foundation of
China (Nos. 21525105, 21778079, 21977126), the Ministry of
Education of China (No. IRT-17R111), the Fundamental
Research Funds for the Central Universities of China (No.
20lgjc01) and the Pearl River S&T Nova Program of Guangzhou
(No. 201806010136). We thank for Junhua Wei’s help in the
measurement of fs-TA.
[11] Y. Wan, G. Lu, J. Zhang, Z. Wang, X. Li, R. Chen, X. Cui, Z. Huang, Y.
Xiao, J. Chelora, W. Zhang, Y. Liu, M. Li, H. Y. Xie, C. S. Lee, Adv. Funct.
Mater. 2019, 29, 1903436.
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