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

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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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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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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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The authors declare no competing financial interests.

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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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