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Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy

Nature Nanotechnology volume 9, pages 907–912 (2014)Cite this article

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Abstract

When designing drug carriers, the drug-to-carrier ratio is an important consideration, because the use of high quantities of carriers can result in toxicity as a consequence of poor metabolism and elimination of the carriers1. However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (−)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects2,3,4,5,6,7, anti-HIV effects8, neuroprotective effects9 and DNA-protective effects10. Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein. The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)–EGCG to form the shell. When injected into mice, the Herceptin-loaded micellar nanocomplex demonstrates better tumour selectivity and growth reduction, as well as longer blood half-life, than free Herceptin.

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Figure 1: Schematic diagram and morphology of self-assembled MNCs loaded with proteins.
Figure 2: Formation and dissociation of protein/OEGCG complexes.
Figure 3: Core–shell MNC formation.
Figure 4: Anticancer effect and biodistribution of the MNCs.

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References

  1. Allen, T. M. & Cullis, P. R. Drug delivery systems: entering the mainstream. Science 303, 1818–1822 (2004).

    Article  CAS  Google Scholar 

  2. Cao, Y. & Cao, R. Angiogenesis inhibited by drinking tea. Nature 398, 381 (1999).

    Article  CAS  Google Scholar 

  3. Jankun, J., Selman, S. H., Swiercz, R. & Skrzypczak-Jankun, E. Why drinking green tea could prevent cancer. Nature 387, 561 (1997).

    Article  CAS  Google Scholar 

  4. Tachibana, H., Koga, K., Fujimura, Y. & Yamada, K. A receptor for green tea polyphenol EGCG. Nature Struct. Mol. Biol. 11, 380–381 (2004).

    Article  CAS  Google Scholar 

  5. Liang, G. et al. Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. Int. J. Oncol. 37, 111–123 (2010).

    CAS  Google Scholar 

  6. Garbisa, S. et al. Tumor invasion: molecular shears blunted by green tea. Nature Med. 5, 1216 (1999).

    Article  CAS  Google Scholar 

  7. Du, G. J. et al. Epigallocatechin gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients 4, 1679–1691 (2012).

    Article  CAS  Google Scholar 

  8. Li, S., Hattori, T. & Kodama, E. N. Epigallocatechin gallate inhibits the HIV reverse transcription step. Antivir. Chem. Chemother. 21, 239–243 (2011).

    Article  CAS  Google Scholar 

  9. Yu, J. et al. Epigallocatechin-3-gallate protects motor neurons and regulates glutamate level. FEBS Lett. 584, 2921–2925 (2010).

    Article  CAS  Google Scholar 

  10. Morley, N. et al. The green tea polyphenol (–)-epigallocatechin gallate and green tea can protect human cellular DNA from ultraviolet and visible radiation-induced damage. Photodermatol. Photoimmunol. Photomed. 21, 15–22 (2005).

    Article  CAS  Google Scholar 

  11. Miyata, K., Christie, R. J. & Kataoka, K. Polymeric micelles for nano-scale drug delivery. React. Funct. Polym. 71, 227–234 (2011).

    Article  CAS  Google Scholar 

  12. Musacchio, T. & Torchilin, V. P. Recent developments in lipid-based pharmaceutical nanocarriers. Front. Biosci. 16, 1388–1412 (2011).

    Article  CAS  Google Scholar 

  13. Duncan, R. The dawning era of polymer therapeutics. Nature Rev. Drug Discov. 2, 347–360 (2003).

    Article  CAS  Google Scholar 

  14. Hubbell, J. A. Materials science. Enhancing drug function. Science 300, 595–596 (2003).

    Article  CAS  Google Scholar 

  15. Kopecek, J. & Kopeckova, P. HPMA copolymers: origins, early developments, present, and future. Adv. Drug Deliv. Rev. 62, 122–149 (2010).

    Article  CAS  Google Scholar 

  16. Duncan, R. Polymer conjugates as anticancer nanomedicines. Nature Rev. Cancer 6, 688–701 (2006).

    Article  CAS  Google Scholar 

  17. Farokhzad, O. C. et al. Nanoparticle–aptamer bioconjugates: a new approach for targeting prostate cancer cells. Cancer Res. 64, 7668–7672 (2004).

    Article  CAS  Google Scholar 

  18. Miura, Y. et al. Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood–brain tumor barrier. ACS Nano 7, 8583–8592 (2013).

    Article  CAS  Google Scholar 

  19. Cabral, H. et al. Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis. Proc. Natl Acad. Sci. USA 110, 11397–11402 (2013).

    Article  CAS  Google Scholar 

  20. Wang, F. et al. Selective tissue distribution and long circulation endowed by paclitaxel loaded PEGylated poly(epsilon-caprolactone-co-L-lactide) micelles leading to improved anti-tumor effects and low systematic toxicity. Int. J. Pharm. 456, 101–112 (2013).

    Article  CAS  Google Scholar 

  21. Harris, J. M. & Chess, R. B. Effect of pegylation on pharmaceuticals. Nature Rev. Drug Discov. 2, 214–221 (2003).

    Article  CAS  Google Scholar 

  22. Kim, D., Gao, Z. G., Lee, E. S. & Bae, Y. H. In vivo evaluation of doxorubicin-loaded polymeric micelles targeting folate receptors and early endosomal pH in drug-resistant ovarian cancer. Mol. Pharmacol. 6, 1353–1362 (2009).

    Article  CAS  Google Scholar 

  23. Ishii, T. et al. Treatment of cerebral ischemia-reperfusion injury with PEGylated liposomes encapsulating FK506. FASEB J. 27, 1362–1370 (2013).

    Article  CAS  Google Scholar 

  24. Yang, C. S. & Wang, Z. Y. Tea and cancer. J. Natl Cancer Inst. 85, 1038–1049 (1993).

    Article  CAS  Google Scholar 

  25. Kuzuhara, T., Sei, Y., Yamaguchi, K., Suganuma, M. & Fujiki, H. DNA and RNA as new binding targets of green tea catechins. J. Biol. Chem. 281, 17446–17456 (2006).

    Article  CAS  Google Scholar 

  26. Chung, J. E., Kurisawa, M., Kim, Y. J., Uyama, H. & Kobayashi, S. Amplification of antioxidant activity of catechin by polycondensation with acetaldehyde. Biomacromolecules 5, 113–118 (2004).

    Article  CAS  Google Scholar 

  27. Saucier, C., Guerra, C., Pianet, I., Laguerre, M. & Glories, Y. (+)-Catechin-acetaldehyde condensation products in relation to wine-ageing. Phytochemistry 46, 229–234 (1997).

    Article  CAS  Google Scholar 

  28. Jobstl, E., O'Connell, J., Fairclough, J. P. & Williamson, M. P. Molecular model for astringency produced by polyphenol/protein interactions. Biomacromolecules 5, 942–949 (2004).

    Article  Google Scholar 

  29. Villalba, J. J. & Provenza, F. D. Preference for polyethylene glycol by sheep fed a quebracho tannin diet. J. Anim. Sci. 79, 2066–2074 (2001).

    Article  CAS  Google Scholar 

  30. Hisaka, T. et al. Interferon-αCon1 suppresses proliferation of liver cancer cell lines in vitro and in vivo. J. Hepatol. 41, 782–789 (2004).

    Article  CAS  Google Scholar 

  31. Choi, H. S. et al. Synthesis and in vivo fate of zwitterionic near-infrared fluorophores. Angew. Chem. Int. Ed. 50, 6258–6263 (2011).

    Article  CAS  Google Scholar 

  32. Chou, T. C., Motzer, R. J., Tong, Y. & Bosl, G. J. Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J. Natl Cancer Inst. 86, 1517–1524 (1994).

    Article  CAS  Google Scholar 

  33. Sun, J. et al. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, taxol, and gemcitabine. Cancer Res. 59, 4919–4926 (1999).

    CAS  Google Scholar 

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Acknowledgements

This research was funded by the Institute of Bioengineering and Nanotechnology (Biomedical Research Council, Agency for Science, Technology and Research, Singapore) and the National Institutes of Health (NIBIB grant no. R01-EB-011523, to H.S.C.). The authors thank A. Yamashita and J.P.K. Tan for their assistance with cell culture and TEM experiments, respectively.

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  1. Joo Eun Chung and Susi Tan: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, 138669, Singapore

    Joo Eun Chung, Susi Tan, Shu Jun Gao, Nunnarpas Yongvongsoontorn, Hirohisa Yano, Lang Zhuo, Motoichi Kurisawa & Jackie Y. Ying

  2. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Soon Hee Kim, Jeong Heon Lee & Hak Soo Choi

  3. Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan

    Hirohisa Yano

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Contributions

J.E.C. and M.K. conceived and designed the experiments. J.E.C., S.T., N.Y. and S.J.G. performed the experiments. S.H.K., J.H.L. and H.S.C. performed experiments and analysed data regarding biodistribution and pharmacokinetics. H.Y. provided HAK-1B cells. J.E.C. and M.K. reviewed, analysed and interpreted the data. J.E.C., S.T., H.S.C., M.K and J.Y.Y wrote the paper. All authors discussed the results. J.E.C. and M.K. supervised the project.

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Correspondence to Joo Eun Chung or Motoichi Kurisawa.

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Chung, J., Tan, S., Gao, S. et al. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy. Nature Nanotech 9, 907–912 (2014). https://doi.org/10.1038/nnano.2014.208

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