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Nano Research 2015, 8(8): 2533-2547 https://doi.org/10.1007/s12274-015-0760-8
Research Article | Issue | Published: 29 August 2015

Anti-migratory and increased cytotoxic effects of novel dual drug-loaded complex hybrid micelles in triple negative breast cancer cells

Show Author's Information Rajaletchumy Veloo Kutty1,§,  Chor Yong Tay1,§,  Chen Siew Lim1,  Si-Shen Feng1,2( ),  David Tai Leong1,3( )
Department of Chemical and Biomolecular EngineeringNational University of Singapore4 Engineering DriveSingapore117585Singapore
International Joint Cancer InstituteThe Second Military Medical University800 Xiang Yin RoadShanghai200433China
NUS Graduate School for Integrative Science and EngineeringNational University of Singapore28 Medical DriveSingapore117456Singapore

§ These authors contributed equally to this work.

Keywords:
biomaterials, nanomedicine, nanobiology, drug targeting, biodegradable polymers
Cite this article:
Kutty RV, Tay CY, Lim CS, et al. Anti-migratory and increased cytotoxic effects of novel dual drug-loaded complex hybrid micelles in triple negative breast cancer cells. Nano Research, 2015, 8(8): 2533-2547. https://doi.org/10.1007/s12274-015-0760-8
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Abstract Full text Electronic supplementary material About this article

A polymer-based nanocarrier was developed for the co-delivery of epigenetic and chemotherapeutic drugs. The sterically stabilized hybrid micelle system uses micelles composed of D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS) and 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000). In this study, suberoylanilide hydroxamic acid (SAHA) and paclitaxel were used as model drugs for combination chemotherapy to enhance therapeutic efficiency in targeting mesenchyme-like triple negative breast cancer (TNBC) cells. Combination therapy of paclitaxel and SAHA in a dual drug micelle system, (P + S)mic, exhibited an IC50 value of 0.52 μg/mL, which is about 5.91-fold more cytotoxic than the mere combination of free drugs (P + S). Furthermore, the (P + S)mic formulation was far more effective at inhibiting cell migration by more than 3.4-fold than the control. Thus, our findings show that the co-delivery of these drugs using the micelle system greatly enhances their therapeutic effect at a lower dosage, thereby minimizing toxicity. In addition, this formulation is proved to be remarkably effective in preventing cell migration at low dosage.


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Abstract
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Electronic supplementary material
About this article

Anti-migratory and increased cytotoxic effects of novel dual drug-loaded complex hybrid micelles in triple negative breast cancer cells

Show Author's information Rajaletchumy Veloo Kutty1,§, Chor Yong Tay1,§, Chen Siew Lim1, Si-Shen Feng1,2( ), David Tai Leong1,3( )
Department of Chemical and Biomolecular EngineeringNational University of Singapore4 Engineering DriveSingapore117585Singapore
International Joint Cancer InstituteThe Second Military Medical University800 Xiang Yin RoadShanghai200433China
NUS Graduate School for Integrative Science and EngineeringNational University of Singapore28 Medical DriveSingapore117456Singapore

§ These authors contributed equally to this work.

Abstract

A polymer-based nanocarrier was developed for the co-delivery of epigenetic and chemotherapeutic drugs. The sterically stabilized hybrid micelle system uses micelles composed of D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS) and 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000). In this study, suberoylanilide hydroxamic acid (SAHA) and paclitaxel were used as model drugs for combination chemotherapy to enhance therapeutic efficiency in targeting mesenchyme-like triple negative breast cancer (TNBC) cells. Combination therapy of paclitaxel and SAHA in a dual drug micelle system, (P + S)mic, exhibited an IC50 value of 0.52 μg/mL, which is about 5.91-fold more cytotoxic than the mere combination of free drugs (P + S). Furthermore, the (P + S)mic formulation was far more effective at inhibiting cell migration by more than 3.4-fold than the control. Thus, our findings show that the co-delivery of these drugs using the micelle system greatly enhances their therapeutic effect at a lower dosage, thereby minimizing toxicity. In addition, this formulation is proved to be remarkably effective in preventing cell migration at low dosage.

Keywords: biomaterials, nanomedicine, nanobiology, drug targeting, biodegradable polymers

References(65)

1

Baylin, S. B. Resistance, epigenetics and the cancer ecosystem. Nat. Med. 2011, 17, 288-289.
DOI Google Scholar
2

Setyawati, M. I.; Tay, C. Y.; Leong, D. T. Exploiting cancer's antioxidative weakness through p53 with nanotoxicology. Nanomedicine 2014, 9, 369-371.
DOI Google Scholar
3

Jones, P. A.; Laird, P. W. Cancer epigenetics comes of age. Nat. Genet. 1999, 21, 163-167.
DOI Google Scholar
4

Portela, A.; Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol. 2010, 28, 1057-1068.
DOI Google Scholar
5

Wolffe, A. P.; Matzke, M. A. Epigenetics: Regulation through repression. Science 1999, 286, 481-486.
DOI Google Scholar
6

Momparler, R. L. Cancer epigenetics. Oncogene 2003, 22, 6479-6483.
DOI Google Scholar
7

Yoo, C. B.; Jones, P. A. Epigenetic therapy of cancer: Past, present and future. Nat. Rev. Drug Discov. 2006, 5, 37-50.
DOI Google Scholar
8

Devinoy, E.; Rijnkels, M. Epigenetics in mammary gland biology and cancer. J. Mammary Gland Biol. Neoplasia 2010, 15, 1-4.
DOI Google Scholar
9

Baylin, S. B.; Herman, J. G.; Graff, J. R.; Vertino, P. M.; Issa, J. P. Alterations in DNA methylation: A fundamental aspect of neoplasia. Adv. Cancer Res. 1998, 72, 141-196.
DOI Google Scholar
10

Herman, J. G.; Baylin, S. B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 2003, 349, 2042-2054.
DOI Google Scholar
11

Grant, S.; Easley, C.; Kirkpatrick, P. V. Nat. Rev. Drug Discov. 2007, 6, 21-22.
DOI
12

Marks, P. A.; Breslow, R. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat. Biotechnol. 2007, 25, 84-90.
DOI Google Scholar
13

Cortez, C. C.; Jones, P. A. Chromatin, cancer and drug therapies. Mutat. Res. -Fundam. Mol. Mech. Mutagen. 2008, 647, 44-51.
DOI Google Scholar
14

Dokmanovic, M.; Clarke, C.; Marks, P. A. Histone deacetylase inhibitors: Overview and perspectives. Mol. Cancer Res. 2007, 5, 981-989.
DOI Google Scholar
15

Carew, J. S.; Giles, F. J.; Nawrocki, S. T. Histone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 2008, 269, 7-17.
DOI Google Scholar
16

McGrogan, B. T.; Gilmartin, B.; Carney, D. N.; McCann, A. Taxanes, microtubules and chemoresistant breast cancer. Biochim. Biophys. Acta 2008, 1785, 96-132.
DOI Google Scholar
17

Gascoigne, K. E.; Taylor, S. S. How do anti-mitotic drugs kill cancer cells? J. Cell Sci. 2009, 122, 2579-2585.
DOI Google Scholar
18

Kavallaris, M. Microtubules and resistance to tubulin-binding agents. Nat. Rev. Cancer 2010, 10, 194-204.
DOI Google Scholar
19

Angelucci, A.; Mari, M.; Millimaggi, D.; Giusti, I.; Carta, G.; Bologna, M.; Dolo, V. Suberoylanilide hydroxamic acid partly reverses resistance to paclitaxel in human ovarian cancer cell lines. Gynecol. Oncol. 2010, 119, 557-563.
DOI Google Scholar
20

Cooper, A. L.; Greenberg, V. L.; Lancaster, P. S.; van Nagell, J. R.; Zimmer, S. G.; Modesitt, S. C. In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer. Gynecol. Oncol. 2007, 104, 596-601.
DOI Google Scholar
21

Dietrich, C. S.; Greenberg, V. L.; DeSimone, C. P.; Modesitt, S. C.; van Nagell, J. R.; Craven, R.; Zimmer, S. G. Suberoylanilide hydroxamic acid (SAHA) potentiates paclitaxel induced apoptosis in ovarian cancer cell lines. Gynecol. Oncol. 2010, 116, 126-130.
DOI Google Scholar
22

Cai, Y. Y.; Yap, C. W.; Wang, Z.; Ho, P. C.; Chan, S. Y.; Ng, K. Y.; Ge, Z. G.; Lin, H. S. Solubilization of vorinostat by cyclodextrins. J. Clin. Pharm. Ther. 2010, 35, 521-526.
DOI Google Scholar
23

Hu, C. M. J.; Aryal, S.; Zhang, L. Nanoparticle-assisted combination therapies for effective cancer treatment. Ther. Deliv. 2010, 1, 323-334.
DOI Google Scholar
24

Cho, K.; Wang, X.; Nie, S.; Chen, Z.; Shin, D. M. Therapeutic nanoparticles for drug delivery in cancer. Clin. Cancer Res. 2008, 14, 1310-1316.
DOI Google Scholar
25
Alexis, F.; Pridgen, E. M.; Langer, R.; Farokhzad, O. C. Nanoparticle technologies for cancer therapy. In Handbook of Experimental Pharmacology (Volume 197). Rosenthal, W., Ed. Springer Science+Business Media: Heidelberg, 2010, pp 55-86.https://doi.org/10.1007/978-3-642-00477-3_2
DOI
26

Xing, R.; Bhirde, A. A.; Wang, S.; Sun, X.; Liu, G.; Hou, Y.; Chen, X. Hollow iron oxide nanoparticles as multidrug resistant drug delivery and imaging vehicles. Nano Res. 2012, 6, 1-9.
DOI Google Scholar
27

Chen, H.; Yeh, J.; Wang, L.; Khurshid, H.; Peng, N.; Wang, A. Y.; Mao, H. Preparation and control of the formation of single core and clustered nanoparticles for biomedical applications using a versatile amphiphilic diblock copolymer. Nano Res. 2010, 3, 852-862.
DOI Google Scholar
28

Muthu, M. S.; Kutty, R. V.; Luo, Z.; Xie, J.; Feng, S. S. Theranostic vitamin E TPGS micelles of transferrin conjugation for targeted co-delivery of docetaxel and ultra bright gold nanoclusters. Biomaterials 2014, 39, 234-248.
DOI Google Scholar
29

Li, Y.; Zheng, S.; Liang, X.; Jin, Y.; Wu, Y.; Bai, H.; Liu, R.; Dai, Z.; Liang Z.; Shi, T. Doping hydroxylated cationic lipid into PEGylated cerasome boosts in vivo siRNA transfection efficacy. Bioconjug. Chem. 2014, 25, 2055-2066.
DOI Google Scholar
30

Tay, C. Y.; Yu, Y.; Setyawati, M. I.; Xie, J.; Leong, D. T. Presentation matters: Identity of gold nanocluster capping agent governs intracellular uptake and cell metabolism. Nano Res. 2014, 7, 805-815.
DOI Google Scholar
31

Tay, C. Y.; Fang, W.; Setyawati, M. I.; Chia, S. L.; Tan, K. S.; Hsu, C.; Hong, C. H.; Leong, D. T. Nano-hydroxyapatite and nano-titanium dioxide exhibit different subcellular distribution and apoptotic profile in human oral epithelium. ACS Appl. Mater. Interfaces 2014, 6, 6248-6256.
DOI Google Scholar
32

Setyawati, M. I.; Kutty, R. V.; Tay, C. Y.; Yuan, X.; Xie, J.; Leong, D. T. Novel theranostic DNA nanoscaffolds for the simultaneous detection and killing of Escherichia coli and Staphylococcus aureus. ACS Appl. Mater. Interfaces 2014, 6, 21822-21831.
DOI Google Scholar
33

Setyawati, M. I.; Tay, C. Y.; Chia, S. L.; Goh, S. L.; Fang, W.; Neo, M. J.; Chong, H. C.; Tan, S. M.; Loo, S. C. J.; Ng, K. W. et al. Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE-cadherin. Nat. Commun. 2013, 4, 1673.
DOI Google Scholar
34

Tay, C. Y.; Setyawati, M. I.; Xie, J.; Parak, W. J.; Leong, D. T. Back to basics: Exploiting the innate physico-chemical characteristics of nanomaterials for biomedical applications. Adv. Funct. Mater. 2014, 24, 5936-5955.
DOI Google Scholar
35

Leong, D. T.; Ng, K. W. Probing the relevance of 3D cancer models in nanomedicine research. Adv. Drug Deliv. Rev. 2014, 79-80, 95-106.
DOI Google Scholar
36

Kutty, R. V.; Feng, S. S. Cetuximab conjugated vitamin E TPGS micelles for targeted delivery of docetaxel for treatment of triple negative breast cancers. Biomaterials 2013, 34, 10160-10171.
DOI Google Scholar
37

Kutty, R. V.; Wei Leong, D. T.; Feng, S. S. Nanomedicine for the treatment of triple-negative breast cancer. Nanomedicine 2014, 9, 561-564.
DOI Google Scholar
38

Sun, Z.; Wang, W.; Meng, J.; Chen, S.; Xu, H.; Yang, X. D. Multi-walled carbon nanotubes conjugated to tumor protein enhance the uptake of tumor antigens by human dendritic cells in vitro. Cell Res. 2010, 20, 1170-1173.
DOI Google Scholar
39

Ma, K.; Wang, D. D.; Lin, Y.; Wang, J.; Petrenko, V.; Mao, C. Synergetic targeted delivery of sleeping-beauty transposon system to mesenchymal stem cells using LPD nanoparticles modified with a phage-displayed targeting peptide. Adv. Funct. Mater. 2013, 23, 1172-1181.
DOI Google Scholar
40

Zhang, Z.; Tan, S.; Feng, S. S. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials 2012, 33, 4889-4906.
DOI Google Scholar
41

Mu, L.; Feng, S. S. Vitamin E TPGS used as emulsifier in the solvent evaporation/extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol). J. Control. Release 2002, 80, 129-144.
DOI Google Scholar
42

Muthu, M. S.; Leong, D. T.; Mei, L.; Feng, S. S. Nanotheranostics—Application and further development of nanomedicine strategies for advanced theranostics. Theranostics 2014, 4, 660-677.
DOI Google Scholar
43

Sarfstein, R.; Bruchim, I.; Fishman, A.; Werner, H. The mechanism of action of the histone deacetylase inhibitor vorinostat involves interaction with the insulin-like growth factor signaling pathway. PLoS One 2011, 6, e24468.
DOI Google Scholar
44

Rodriguez, L. G.; Wu, X.; Guan, J. Wound-healing assay. Methods Mol. Biol. 2005, 294, 23-29.
Google Scholar
45

Sawant, R. R.; Torchilin, V. P. Polymeric micelles: Polyethylene glycol-Phosphatidylethanolamine (PEG-PE)- based micelles as an example. Methods Mol. Biol. 2010, 624, 131-149.
DOI Google Scholar
46

Taurin, S.; Nehoff, H.; Greish, K. Anticancer nanomedicine and tumor vascular permeability: Where is the missing link? J. Control. Release 2012, 164, 265-275.
DOI Google Scholar
47

Verma, M. S.; Liu, S. Y.; Chen, Y. Y.; Meerasa, A.; Gu, F. X. Size-tunable nanoparticles composed of dextran-b poly(D, Llactide) for drug delivery applications. Nano Res. 2011, 5, 49-61.
DOI Google Scholar
48

Shan, X.; Yuan, Y.; Liu, C.; Tao, X.; Sheng, Y.; Xu, F. Influence of PEG chain on the complement activation suppression and longevity in vivo prolongation of the PCL biomedical nanoparticles. Biomed. Microdevices 2009, 11, 1187-1194.
DOI Google Scholar
49

Gill, K. K.; Kaddoumi, A.; Nazzal, S. Mixed micelles of PEG2000-DSPE and vitamin-E TPGS for concurrent delivery of paclitaxel and parthenolide: Enhanced chemosenstization and antitumor efficacy against non-small cell lung cancer (NSCLC) cell lines. Eur. J. Pharm. Sci. 2012, 46, 64-71.
DOI Google Scholar
50

Mu, L.; Elbayoumi, T. A.; Torchilin, V. P. Mixed micelles made of poly(ethylene glycol)-phosphatidylethanolamine conjugate and D-α-tocopheryl polyethylene glycol 1000 succinate as pharmaceutical nanocarriers for camptothecin. Int. J. Pharm. 2005, 306, 142-149.
DOI Google Scholar
51

Owen, S. C.; Chan, D. P. Y.; Shoichet, M. S. Polymeric micelle stability. Nano Today 2012, 7, 53-65.
DOI Google Scholar
52

Feng, S.S.; Zhao, L.; Zhang, Z.; Bhakta, G.; Win, K. Y.; Dong, Y.; Chien, S. Chemotherapeutic engineering: Vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168 h in vivo. Chem. Eng. Sci. 2007, 62, 6641-6648.
DOI Google Scholar
53

Hasan, A. S.; Socha, M.; Lamprecht, A.; Ghazouani, F. E.; Sapin, A.; Hoffman, M.; Maincent, P.; Ubrich, N. Effect of the microencapsulation of nanoparticles on the reduction of burst release. Int. J. Pharm. 2007, 344, 53-61.
DOI Google Scholar
54
Chiao, J.; Paradise, C.; Frankel, S. R.; Ramalingam, S. S.; Belani, C. Methods of treating cancers with SAHA, carboplatin, and paclitaxel and other combination therapies. U.S. Patent 20090105329, April 23, 2009.
55

Zhao, B.; Wang, X. Q.; Wang, X. Y.; Zhang, H.; Dai, W. B.; Wang, J.; Zhong, Z. L.; Wu, H. N.; Zhang, Q. Nanotoxicity comparison of four amphiphilic polymeric micelles with similar hydrophilic or hydrophobic structure. Part. Fibre Toxicol. 2013, 10, 47.
DOI Google Scholar
56

Tan, G. R.; Feng, S. S.; Leong, D. T. The reduction of anticancer drug antagonism by the spatial protection of drugs with PLA-TPGS nanoparticles. Biomaterials 2014, 35, 3044-3051.
DOI Google Scholar
57

Modesitt, S. C.; Parsons, S. J. In vitro and in vivo histone deacetylase inhibitor therapy with vorinostat and paclitaxel in ovarian cancer models: Does timing matter? Gynecol. Oncol. 2010, 119, 351-357.
DOI Google Scholar
58

Mi, Y.; Liu, X. L.; Zhao, J.; Ding, J.; Feng, S. S. Multimodality treatment of cancer with herceptin conjugated, thermomagnetic iron oxides and docetaxel loaded nanoparticles of biodegradable polymers. Biomaterials 2012, 33, 7519-7529.
DOI Google Scholar
59

Yvon, A. M. C.; Wadsworth, P.; Jordan, M. A. Taxol suppresses dynamics of individual microtubules in living human tumor cells. Mol. Biol. Cell 1999, 10, 947-959.
DOI Google Scholar
60

Terzis, A. J.; Thorsen, F.; Heese, O.; Visted, T.; Bjerkvig, R.; Dahl, O.; Arnold, H.; Gundersen, G. Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (taxol) in vitro. Br. J. Cancer 1997, 75, 1744-1752.
DOI Google Scholar
61

An, Z.; Gluck, C. B.; Choy, M. L.; Kaufman, L. J. Suberoylanilide hydroxamic acid limits migration and invasion of glioma cells in two and three dimensional culture. Cancer Lett. 2010, 292, 215-227.
DOI Google Scholar
62

Chong, W.; Li, Y.; Liu, B.; Zhao, T.; Fukudome, E. Y.; Liu, Z.; Smith, W. M.; Velmahos, G. C.; deMoya, M. A.; Alam, H. B. Histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates Toll-like receptor 4 signaling in lipopolysaccharide-stimulated mouse macrophages. J. Surg. Res. 2012, 178, 851-859.
DOI Google Scholar
63

Westerlund, A.; Hujanen, E.; Höyhtyä, M.; Puistola, U.; Turpeenniemi-Hujanen, T. Ovarian cancer cell invasion is inhibited by paclitaxel. Clin. Exp. Metastasis 1997, 15, 318-328.
DOI Google Scholar
64

Koo, C. X.; Fang, W.; Salto-Tellez, M.; Leong, D. T. Coexpressing shRNA with fluorescence tags for quantification of cell migration studies. Mol. Biol. Rep. 2012, 39, 7695- 7703.
DOI Google Scholar
65

Leong, D. T.; Lim, J.; Goh, X.; Pratap, J.; Pereira, B. P.; Kwok, H. S.; Nathan, S. S.; Dobson, J. R.; Lian, J. B.; Ito, Y. et al. Cancer-related ectopic expression of the bone-related transcription factor RUNX2 in non-osseous metastatic tumor cells is linked to cell proliferation and motility. Breast Cancer Res. 2010, 12, R89.
DOI Google Scholar
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Publication history
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Acknowledgements

Publication history

Received: 14 January 2015
Revised: 26 February 2015
Accepted: 02 March 2015
Published: 29 August 2015
Issue date: August 2015

Copyright

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2015

Acknowledgements

Acknowledgements

This work was supported by the Singapore China Cooperative Research Project between the Agency of Science, Technology and Research (A*STAR), Singapore and Chinese Ministry of Science and Technology (MOST) (R-398-000-077-305 to DTL and SSF), National University of Singapore, FSF research grant (R-397- 000-136-731, R-397-000-136-112 to DTL and SSF), and Ministry of Education Research grant (R-279-000-376- 112 to CYT). C. S. L. and R. V. K. received research scholarships from National University of Singapore and the Ministry of Higher Education (MOHE) of Malaysia respectively. C. Y. T. was supported by the Lee Kuan Yew Postdoctoral Fellowship.

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