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Bioflavonoid Fisetin Loaded α-Tocopherol-Poly(lactic acid)-Based Polymeric Micelles for Enhanced Anticancer Efficacy in Breast Cancers

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Abstract

Purpose

In this study, tocopherol based polymeric micelles were successfully prepared to enhance the anticancer effect of fisetin (FIS) in breast cancer cells.

Methods

The drug-loaded carrier was characterized in terms of physicochemical and in vivo parameters.

Results

Compared to FIS, FIS-TPN showed higher cellular uptake in MCF-7 breast cancer cells as revealed by CLSM and flow cytometry. The cytotoxicity assay results clearly showed that the free FIS and FIS-TPN exhibited a typical dose-dependent toxic effect in MCF-7 breast cancer cells. Especially, enhanced cytotoxic effect of FIS was observed when loaded in a nanocarrier. Free FIS induced a ~11% apoptosis whereas FIS-TPN induced a significantly greater apoptosis of ~20% by the end of 24 h. At 48 h, similar trend continued and free FIS showed ~30% of apoptosis whereas ~42% cell apoptosis was observed in FIS-TPN treated group. Notably, migration of cancer cell was significantly inhibited when treated with FIS-TPN formulations. The FIS-TPN significantly reduced to tumor burden and H&E staining showed the lowest tumor volume and higher cell apoptosis.

Conclusions

All the findings suggest that the fisetin-loaded TPGS-PLA polymeric micelles serve as a potential candidate and promising alternative for the effective treatment of breast cancers.

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Abbreviations

DLS:

Dynamic might scattering

EPR:

Enhanced permeation and retention effect

FIS:

Fisetin

FIS-TPN:

Fisetin-loaded TPGS/PLA nanoparticles

NP:

Nanoparticles

PLA:

Poly(lactide)

TPGS:

D-α-tocopheryl polyethylene glycol 1000

References

  1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212–36.

    Article  PubMed  Google Scholar 

  2. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137–50.

    Article  PubMed  Google Scholar 

  3. Coley HM. Mechanisms and strategies to overcome chemotherapy resistancein metastatic breast cancer. Cancer Treat Rev. 2008;34:378–90.

    Article  CAS  PubMed  Google Scholar 

  4. Carey L, Winer E, Viale G, Cameron D, Gianni L. Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol. 2010;7:683–92.

    Article  PubMed  Google Scholar 

  5. Carey LA. Triple-negative (basal-like) breast cancer: a new entity. Breast Cancer Res. 2007;9 Suppl 1:S1.

    Article  Google Scholar 

  6. Arai Y, Watanabe S, Kimira M, Shimoi S, Mochizuki R, Kinae N. Dietaryintakes of flavonols, flavones and isoflavones by Japanese women and theinverse correlation between quercetin intake and plasma LDL cholesterolconcentration. J Nutr. 2000;130:2243–50.

    CAS  PubMed  Google Scholar 

  7. Kimira M, Arai Y, Shimoi K, Watanabe S. Japanese intake of flavonoids andisoflavonoids from foods. J Epidemiol. 1998;8:168–75.

    Article  CAS  PubMed  Google Scholar 

  8. Woodman OL, Chan EC. Vascular and anti-oxidant actions of flavonols andflavones. Clin Exp Pharmacol Physiol. 2004;31:786–90.

    Article  CAS  PubMed  Google Scholar 

  9. Park HH, Lee S, Oh JM, Lee MS, Yoon KH, Park BH, et al. Anti-inflammatory activity of fisetin in human mast cells (HMC-1). Pharmacol Res. 2007;55:31–7.

    Article  CAS  PubMed  Google Scholar 

  10. Jang KY, Jeong SJ, Kim SH, Jung JH, Kim JH, Koh W, et al. Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. Cancer Lett. 2012;319:197–202.

    Article  CAS  PubMed  Google Scholar 

  11. Suh Y, Afaq F, Johnson JJ, Mukhtar A. A plant flavonoid fisetin inducesapoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis. 2009;30:300–7.

    Article  CAS  PubMed  Google Scholar 

  12. Syed DN, Afaq F, Maddodi N, Johnson JJ, Sarfaraz S, Ahmad A, et al. Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/beta-catenin signaling and decreased Mitf levels. J Invest Dermatol. 2011;131:1291–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang PM, Tseng HH, Peng CW, Chen WS, Chiu SJ. Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7 associated apoptosis and inhibition of autophagy. Int J Oncol. 2012;40:469–78.

    PubMed  Google Scholar 

  14. Ying TH, Yang SF, Tsai SJ, Hsieh SC, Huang YC, Bau DT, et al. Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2- mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol. 2012;86:263–73.

    Article  CAS  PubMed  Google Scholar 

  15. Guzzo MR, Uemi M, Donate PM, Nikolaou S, Machado AE, Okano LT. Study of the complexation of fisetin with cyclodextrins. J Phys Chem A. 2006;110:10545–51.

  16. Rong X, Xie Y, Hao X, Chen T, Wang Y, Liu Y. Applications of polymeric nanocapsules in field of drug delivery systems. Curr Drug Discov Technol. 2011;8:173–87.

    Article  CAS  PubMed  Google Scholar 

  17. Craparo EF, Bondi ML. Application of polymeric nanoparticles in immunotherapy. Curr Opin Allergy Clin Immunol. 2012;12:658–64.

    Article  CAS  PubMed  Google Scholar 

  18. Kamaly N, Xiao Z, Valencia PM, Radovic-Moreno AF, Farokhzad OC. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem Soc Rev. 2012;41:2971–3010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ramasamy T, Haidar ZS, et al. Layer-by-layer assembly of liposomal nanoparticles with PEGylated polyelectrolytes enhances systemic delivery of multiple anticancer drugs. Acta Biomater. 2014;10:5116–27.

    Article  CAS  PubMed  Google Scholar 

  20. de Melo-Diogo D, Gaspar VM, Costa EC, Moreira AF, Oppolzer D, Gallardo E, et al. Combinatorial delivery of Crizotinib-Palbociclib-Sildenafil using TPGS-PLA micelles for improved cancer treatment. Eur J Pharm Biopharm. 2014;88:718–29.

    Article  PubMed  Google Scholar 

  21. Zhang Z, Feng SS. Biomaterials. 2006;27:4025–33.

    Article  CAS  PubMed  Google Scholar 

  22. Kanai K, Kikuchi E, Mikami S, Suzuki E, Uchida Y, Kodaira K, et al. Vitamin E succinate induced apoptosis andenhanced chemosensitivity to paclitaxel in human bladder cancer cellsin vitro and in vivo. Cancer Sci. 2010;101:216–23.

    Article  CAS  PubMed  Google Scholar 

  23. Tran TH, Ramasamy T, Choi JY, et al. Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells. Int J Nanomed. 2015;10:5249.

    CAS  Google Scholar 

  24. Ramasamy T et al. Engineering of a lipid-polymer nanoarchitectural platform for highly effective combination therapy of doxorubicin and irinotecan. Chem Comm. 2015;51:5758–61.

    Article  CAS  PubMed  Google Scholar 

  25. Tang N, Du G, Wang N, Liu C, Hang H, Liang W. Improving penetration in tumors with nanoassemblies of phospholipids and doxorubicin. JNCI J Natl Cancer Inst. 2007;99:1004–15.

    Article  CAS  PubMed  Google Scholar 

  26. Prajakta D, Ratnesh J, Chandan K, Suresh S, Grace S, Meera V, et al. Curcumin loaded pH-sensitive nanoparticles for the treatment of colon cancer. J Biomed Nanotechnol. 2009;5:445–55.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

The study was supported from the Research Grant of Xinxiang Medical University, PR. China.

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Authors and Affiliations

  1. Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, 453100, Xinxiang, People’s Republic of China

    Lei Wang & De-Zhong Zhang

  2. Department of Pathophysiology, Xinxiang Medical University, No. 602, Jinsui Avenue, Xinxiang, 453003, People’s Republic of China

    Yu-Xia Wang

Authors
  1. Lei Wang
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  2. De-Zhong Zhang
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Correspondence to Yu-Xia Wang.

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Wang, L., Zhang, DZ. & Wang, YX. Bioflavonoid Fisetin Loaded α-Tocopherol-Poly(lactic acid)-Based Polymeric Micelles for Enhanced Anticancer Efficacy in Breast Cancers. Pharm Res 34, 453–461 (2017). https://doi.org/10.1007/s11095-016-2077-z

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  • DOI: https://doi.org/10.1007/s11095-016-2077-z

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