Journal Home > Volume 11 , Issue 9
Nano Research 2018, 11(9): 4846-4858 https://doi.org/10.1007/s12274-018-2074-0
Research Article | Issue | Published: 11 May 2018

NVP-BEZ235/Chlorin-e6 co-loaded nanoparticles ablate breast cancer by biochemical and photodynamic synergistic effects

Show Author's Information Ahmed Shaker Eltahan1,2,§,  Lu Liu1,2,4,§,  Chukwunweike Ikechukwu Okeke1,2,  Min Huang5,  Lu Han5,  Jing Chen1,  Xue Xue3( ),  Massimo Bottini1,4,  Weisheng Guo1( ),  Xing-Jie Liang1,2( )
CAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNationalCenter for Nanoscience and Technology of ChinaBeijing100190China
University of Chinese Academy of SciencesBeijing100049China
State Key Laboratory of Medicinal Chemical BiologyCollege of PharmacyNankai UniversityTianjin300350China
Department of Experimental Medicine and SurgeryUniversity of Rome Tor VergataRome00133Italy
Beijing Engineering Research Center of Printed ElectronicsBeijing Institute of Graphic CommunicationBeijing102600China

§ Ahmed Shaker Eltahan and Lu Liu contributed equally to this work.

Keywords:
nanomedicine, photodynamic therapy, triple-negative breast cancer, NVP-BEZ235, synergistic therapy
Cite this article:
Eltahan AS, Liu L, Okeke CI, et al. NVP-BEZ235/Chlorin-e6 co-loaded nanoparticles ablate breast cancer by biochemical and photodynamic synergistic effects. Nano Research, 2018, 11(9): 4846-4858. https://doi.org/10.1007/s12274-018-2074-0
Download citation
EndNote(RIS)
BibTeX

542

Views

9

Downloads

Citations

6

Crossref

N/A

WoS

6

Scopus

0

CSCD

Abstract Full text Electronic supplementary material About this article

Seeking profitable therapies for triple-negative breast cancer (TNBC) has attracted intense research interest. However, an efficient cure for TNBC remains an unresolved challenge in oncology. Herein, for the first time, we describe the use of polymeric nanoparticles loaded with NVP-BEZ235 and Chlorin-e6, denoted as NVP/Ce6@NPs, to overcome the adaptive treatment tolerance of TNBC by taking advantage of the synergistic effect between biochemical and photodynamic therapies. Upon laser irradiation, the NVP/Ce6@NPs generated reactive oxygen species (ROS) and efficiently induced the apoptosis of tumor cells through DNA damage. Furthermore, the released NVP-BEZ235 could prevent Chk1 phosphorylation-induced DNA damage repair, thus enhancing the sensitivity of tumor cells to ROS. Animal studies on mice bearing an MDA- MB-231 tumor validated that the NVP/Ce6@NPs had a greater therapeutic efficacy compared to that of monotherapies, with an inhibition ratio of 89.3%. Western blotting and cell viability analyses confirmed the inhibition of both MDA-MB-231 cell proliferation and Chk1 phosphorylation by NVP/Ce6@NPs. These findings provide a rational understanding of the synergistic effect of the biochemical/photodynamic therapy and pave the way for the development of efficient therapeutic approaches to fight against TNBC.


menu
Abstract
Full text
Outline
Electronic supplementary material
About this article

NVP-BEZ235/Chlorin-e6 co-loaded nanoparticles ablate breast cancer by biochemical and photodynamic synergistic effects

Show Author's information Ahmed Shaker Eltahan1,2,§, Lu Liu1,2,4,§, Chukwunweike Ikechukwu Okeke1,2, Min Huang5, Lu Han5, Jing Chen1, Xue Xue3( ), Massimo Bottini1,4, Weisheng Guo1( ), Xing-Jie Liang1,2( )
CAS Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNationalCenter for Nanoscience and Technology of ChinaBeijing100190China
University of Chinese Academy of SciencesBeijing100049China
State Key Laboratory of Medicinal Chemical BiologyCollege of PharmacyNankai UniversityTianjin300350China
Department of Experimental Medicine and SurgeryUniversity of Rome Tor VergataRome00133Italy
Beijing Engineering Research Center of Printed ElectronicsBeijing Institute of Graphic CommunicationBeijing102600China

§ Ahmed Shaker Eltahan and Lu Liu contributed equally to this work.

Abstract

Seeking profitable therapies for triple-negative breast cancer (TNBC) has attracted intense research interest. However, an efficient cure for TNBC remains an unresolved challenge in oncology. Herein, for the first time, we describe the use of polymeric nanoparticles loaded with NVP-BEZ235 and Chlorin-e6, denoted as NVP/Ce6@NPs, to overcome the adaptive treatment tolerance of TNBC by taking advantage of the synergistic effect between biochemical and photodynamic therapies. Upon laser irradiation, the NVP/Ce6@NPs generated reactive oxygen species (ROS) and efficiently induced the apoptosis of tumor cells through DNA damage. Furthermore, the released NVP-BEZ235 could prevent Chk1 phosphorylation-induced DNA damage repair, thus enhancing the sensitivity of tumor cells to ROS. Animal studies on mice bearing an MDA- MB-231 tumor validated that the NVP/Ce6@NPs had a greater therapeutic efficacy compared to that of monotherapies, with an inhibition ratio of 89.3%. Western blotting and cell viability analyses confirmed the inhibition of both MDA-MB-231 cell proliferation and Chk1 phosphorylation by NVP/Ce6@NPs. These findings provide a rational understanding of the synergistic effect of the biochemical/photodynamic therapy and pave the way for the development of efficient therapeutic approaches to fight against TNBC.

Keywords: nanomedicine, photodynamic therapy, triple-negative breast cancer, NVP-BEZ235, synergistic therapy

References(37)

1

Jenkins, S. V.; Nima, Z. A.; Vang, K. B.; Kannarpady, G.; Nedosekin, D. A.; Zharov, V. P.; Griffin, R. J.; Biris, A. S.; Dings, R. P. M. Triple-negative breast cancer targeting and killing by EpCAM-directed, plasmonically active nanodrug systems. npj Precis. Oncol. 2017, 1, 27.
DOI Google Scholar
2

Bianchini, G.; Balko, J. M.; Mayer, I. A.; Sanders, M. E.; Gianni, L. Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease. Nat. Rev. Clin. Oncol. 2016, 13, 674-690.
DOI Google Scholar
3

Lund, M. J.; Butler, E. N.; Hair, B. Y.; Ward, K. C.; Andrews, J. H.; Oprea-Ilies, G.; Bayakly, A. R.; O'Regan, R. M.; Vertino, P. M.; Eley, J. W. Age/race differences in HER2 testing and in incidence rates for breast cancer triple subtypes. Cancer 2010, 116, 2549-2559.
DOI Google Scholar
4

Malorni, L.; Shetty, P. B.; De Angelis, C.; Hilsenbeck, S.; Rimawi, M. F.; Elledge, R.; Osborne, C. K.; De Placido, S.; Arpino, G. Clinical and biologic features of triple-negative breast cancers in a large cohort of patients with long-term follow-up. Breast Cancer Res. Treat. 2012, 136, 795-804.
DOI Google Scholar
5

Gonda, K.; Miyashita, M.; Higuchi, H.; Tada, H.; Watanabe, T. M.; Watanabe, M.; Ishida, T.; Ohuchi, N. Predictive diagnosis of the risk of breast cancer recurrence after surgery by single-particle quantum dot imaging. Sci. Rep. 2015, 5, 14322.
DOI Google Scholar
6

Kast, K.; Link, T.; Friedrich, K.; Petzold, A.; Niedostatek, A.; Schoffer, O.; Werner, C.; Klug, S. J.; Werner, A.; Gatzweiler, A. et al. Impact of breast cancer subtypes and patterns of metastasis on outcome. Breast Cancer Res. Treat. 2015, 150, 621-629.
DOI Google Scholar
7

Kennecke, H.; Yerushalmi, R.; Woods, R.; Cheang, M. C. U.; Voduc, D.; Speers, C. H.; Nielsen, T. O.; Gelmon, K. Metastatic behavior of breast cancer subtypes. J. Clin. Oncol. 2010, 28, 3271-3277.
DOI Google Scholar
8

Lobbezoo, D. J. A.; van Kampen, R. J. W.; Voogd, A. C.; Dercksen, M. W.; van den Berkmortel, F.; Smilde, T. J.; van de Wouw, A. J.; Peters, F. P. J.; van Riel, J. M. G. H.; Peters, N. A. J. B. et al. Prognosis of metastatic breast cancer subtypes: The hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res. Treat. 2013, 141, 507-514.
DOI Google Scholar
9

Shi, J. J.; Kantoff, P. W.; Wooster, R.; Farokhzad, O. C. Cancer nanomedicine: Progress, challenges and opportunities. Nat. Rev. Cancer 2017, 17, 20-37.
DOI Google Scholar
10

Blanco, E.; Shen, H. F.; Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 2015, 33, 941-951.
DOI Google Scholar
11

Ma, X. W.; Zhao, Y. L.; Liang, X. J. Theranostic nanoparticles engineered for clinic and pharmaceutics. Acc. Chem. Res. 2011, 44, 1114-1122.
DOI Google Scholar
12

Bottini, M.; Sacchetti, C.; Pietroiusti, A.; Bellucci, S.; Magrini, A.; Rosato, N.; Bottini, N. Targeted nanodrugs for cancer therapy: Prospects and challenges. J. Nanosci. Nanotechnol. 2014, 14, 98-114.
DOI Google Scholar
13

Sacchetti, C.; Rapini, N.; Magrini, A.; Cirelli, E.; Bellucci, S.; Mattei, M.; Rosato, N.; Bottini, N.; Bottini, M. In vivo targeting of intratumor regulatory T cells using PEG-modified single-walled carbon nanotubes. Bioconjugate Chem. 2013, 24, 852-858.
DOI Google Scholar
14

Yoo, J. O.; Lim, Y. C.; Kim, Y. M.; Ha, K. S. Transglutaminase 2 promotes both caspase-dependent and caspase-independent apoptotic cell death via the calpain/bax protein signaling pathway. J. Biol. Chem. 2012, 287, 14377-14388.
DOI Google Scholar
15

Zhuang, X. X.; Ma, X. W.; Xue, X. D.; Jiang, Q.; Song, L. L.; Dai, L. R.; Zhang, C. Q.; Jin, S. B.; Yang, K. N.; Ding, B. Q. et al. A photosensitizer-loaded DNA origami nanosystem for photodynamic therapy. ACS Nano 2016, 10, 3486-3495.
DOI Google Scholar
16

Agostinis, P.; Berg, K.; Cengel, K. A.; Foster, T. H.; Girotti, A. W.; Gollnick, S. O.; Hahn, S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D. et al. Photodynamic therapy of cancer: An update. CA: Cancer J. Clin. 2011, 61, 250-281.
DOI Google Scholar
17

Polo, S. E.; Jackson, S. P. Dynamics of DNA damage response proteins at DNA breaks: A focus on protein modifications. Genes Dev. 2011, 25, 409-433.
DOI Google Scholar
18

Essers, J.; Vermeulen, W.; Houtsmuller, A. B. DNA damage repair: Anytime, anywhere? Curr. Opin. Cell Biol. 2006, 18, 240-246.
DOI Google Scholar
19

Azzam, E. I.; Jay-Gerin, J. -P.; Pain, D. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett. 2012, 327, 48-60.
DOI Google Scholar
20

Negritto, M. C. Repairing double-strand DNA breaks. Nat. Educ. 2010, 3, 26.
Google Scholar
21

Gordon, V.; Banerji, S. Molecular pathways: PI3K pathway targets in triple-negative breast cancers. Clin. Cancer Res. 2013, 19, 3738-3744.
DOI Google Scholar
22

Lehmann, B. D.; Bauer, J. A.; Chen, X.; Sanders, M. E.; Chakravarthy, A. B.; Shyr, Y.; Pietenpol, J. A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 2011, 121, 2750-2767.
DOI Google Scholar
23

Woo, S. U.; Sangai, T.; Akcakanat, A.; Chen, H.; Wei, C.; Meric-Bernstam, F. Vertical inhibition of the PI3K/Akt/mTOR pathway is synergistic in breast cancer. Oncogenesis 2017, 6, e385.
DOI Google Scholar
24

Saal, L. H.; Johansson, P.; Holm, K.; Gruvberger-Saal, S. K.; She, Q. B.; Maurer, M.; Koujak, S.; Ferrando, A. A.; Malmström, P.; Memeo, L. et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc. Natl. Acad. Sci. USA 2007, 104, 7564-7569.
DOI Google Scholar
25

Khalaileh, A.; Dreazen, A.; Khatib, A.; Apel, R.; Swisa, A.; Kidess-Bassir, N.; Maitra, A.; Meyuhas, O.; Dor, Y.; Zamir, G. Phosphorylation of ribosomal protein S6 attenuates DNA damage and tumor suppression during development of pancreatic cancer. Cancer Res. 2013, 73, 1811-1820.
DOI Google Scholar
26

Barkić, M.; Crnomarković, S.; Grabušić, K.; Bogetić, I.; Panić, L.; Tamarut, S.; Cokarić, M.; Jerić, I.; Vidak, S.; Volarević, S. The p53 tumor suppressor causes congenital malformations in Rpl24-deficient mice and promotes their survival. Mol. Cell. Biol. 2009, 29, 2489-2504.
DOI Google Scholar
27

Gil del Alcazar, C. R.; Hardebeck, M. C.; Mukherjee, B.; Tomimatsu, N.; Gao, X. H.; Yan, J. S.; Xie, X. J.; Bachoo, R.; Li, L.; Habib, A. A. et al. Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. Clin. Cancer Res. 2014, 20, 1235-1248.
DOI Google Scholar
28

Zeng, X. W.; Tao, W.; Wang, Z. Y.; Zhang, X. D.; Zhu, H. J.; Wu, Y. P.; Gao, Y. F.; Liu, K. W.; Jiang, Y. Y.; Huang, L. Q. et al. Docetaxel-loaded nanoparticles of dendritic amphiphilic block copolymer H40-PLA-b-TPGS for cancer treatment. Part. Part. Syst. Char. 2015, 32, 112-122.
DOI Google Scholar
29

Bancroft, J. D.; Gamble, M. Theory and Practice of Histological Techniques, 6th ed; Elsevier Health Sciences: London, 2007.
30

Huang, P.; Lin, J.; Wang, X. S.; Wang, Z.; Zhang, C. L.; He, M.; Wang, K.; Chen, F.; Li, Z. M.; Shen, G. X. et al. Light-triggered theranostics based on photosensitizer-conjugated carbon dots for simultaneous enhanced-fluorescence imaging and photodynamic therapy. Adv. Mater. 2012, 24, 5104-5110.
DOI Google Scholar
31

Robertson, C. A.; Evans, D. H.; Abrahamse, H. Photodynamic therapy (PDT): A short review on cellular mechanisms and cancer research applications for PDT. J. Photochem. Photobiol. B 2009, 96, 1-8.
DOI Google Scholar
32

Toledo, L. I.; Murga, M.; Zur, R.; Soria, R.; Rodriguez, A.; Martinez, S.; Oyarzabal, J.; Pastor, J.; Bischoff, J. R.; Fernandez-Capetillo, O. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat. Struct. Mol. Biol. 2011, 18, 721-727.
DOI Google Scholar
33

Mukherjee, B.; Tomimatsu, N.; Amancherla, K.; Camacho, C. V.; Pichamoorthy, N.; Burma, S. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 2012, 14, 34-43.
DOI Google Scholar
34

Desmarais, J. A.; Hoffmann, M. J.; Bingham, G.; Gagou, M. E.; Meuth, M.; Andrews, P. W. Human embryonic stem cells fail to activate CHK1 and commit to apoptosis in response to DNA replication stress. Stem Cells 2012, 30, 1385-1393.
DOI Google Scholar
35

Bertrand, N.; Wu, J.; Xu, X. Y.; Kamaly, N.; Farokhzad, O. C. Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Deliv. Rev. 2014, 66, 2-25.
DOI Google Scholar
36

Montano, R.; Chung, I.; Garner, K. M.; Parry, D.; Eastman, A. Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites. Mol. Cancer Ther. 2012, 11, 427-438.
DOI Google Scholar
37

Wicki, A.; Witzigmann, D.; Balasubramanian, V.; Huwyler, J. Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications. J. Control Release 2015, 200, 138-157.
DOI Google Scholar
File
12274_2018_2074_MOESM1_ESM.pdf (1.4 MB)
Publication history
Copyright
Acknowledgements

Publication history

Received: 31 January 2018
Revised: 12 April 2018
Accepted: 13 April 2018
Published: 11 May 2018
Issue date: September 2018

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Acknowledgements

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Nos. 31630027, 31430031 and 81601603), the National Distinguished Young Scholars grant (No. 31225009). The authors also appreciate the support by the external cooperation program of the Chinese Academy of Science (No. 121D11KYSB20160066), the "Strategic Priority Research Program" of the Chinese Academy of Sciences (No. XDA09030301), and the Cross-training Program for High Level Talents of Beijing Universities (No. 03150117009/002/003).

Return