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Biomolecular robotics for chemomechanically driven guest delivery fuelled by intracellular ATP

Nature Chemistry volume 5, pages 613–620 (2013)Cite this article

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Abstract

The development of nanocarriers that selectively release guest molecules on sensing a particular biological signal is being actively pursued in nanomedicine for diagnostic and therapeutic purposes. Here we report a protein-based nanocarrier that opens in the presence of intracellular adenosine-5′-triphosphate (ATP). The nanocarrier consists of multiple barrel-shaped chaperonin units assembled through coordination with Mg2+ into a tubular structure that protects guest molecules against biological degradation. When its surface is functionalized with a boronic acid derivative, the nanocarrier is able to enter cells. The hydrolysis of intracellular ATP into adenosine-5′-diphosphate (ADP) induces conformational changes of the chaperonin units, which in turns generate a mechanical force that leads to the disassembly of the tube and release of the guests. This scission occurs with a sigmoidal dependence on ATP concentration, which means that the nanocarrier can differentiate biological environments in terms of the concentration of ATP for selective guest release. Furthermore, biodistribution tests reveal preferential accumulation of the nanocarriers in a tumour tissue.

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Figure 1: Schematics of the basic strategy for ATP-responsive intracellular drug delivery.
Figure 2: Dissociation of nanotube induced by the action of nucleoside triphosphates.
Figure 3: ATP-responsiveness of GFPdenat-containing nanotube (NT ⊃ GFPdenat) and cellular uptake of BANT.
Figure 4: ATP-responsive intracellular delivery with cell-penetrable BANT.

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Acknowledgements

This work was partially supported by the MEXT, Grant-in-Aid for Scientific Research on Innovative Areas ‘Emergence in Chemistry’ (no. 20111010). S.B. acknowledges financial support from a JSPS Young Scientist Fellowship.

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Authors and Affiliations

  1. Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo, 113-8656, Tokyo, Japan

    Shuvendu Biswas & Takuzo Aida

  2. Institute of Multidisciplinary Research for Advance Materials, Tohoku University, Katahira 2-1-1, Aoba-ku, 980-8577, Sendai, Japan

    Kazushi Kinbara

  3. Department of Biomolecular Engineering, Graduate School of Biosciences and Biotechnology, Tokyo Institute of Technology, B56, 4259 Nagatsuta, Midori-ku, 226-8501, Yokohama, Japan

    Tatsuya Niwa & Hideki Taguchi

  4. Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central-6, 1-1-1 Higashi, Tsukuba, 305-8566, Japan

    Noriyuki Ishii

  5. Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan

    Sumiyo Watanabe, Kanjiro Miyata & Kazunori Kataoka

  6. Department of Materials Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo, 113-8656, Tokyo, Japan

    Kazunori Kataoka

  7. Riken Center for Emergent Matter Science, 2-1 Hirosawa, Wako, 351-0198, Saitama, Japan

    Takuzo Aida

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  1. Shuvendu Biswas
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  9. Takuzo Aida
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Contributions

S.B. designed and performed all experiments. K. Ki., K.M. and K. Ka. discussed the results. T.N. and H.T. helped with GroELCys production and discussed the mechanism. N.I. obtained TEM micrographs. S.B. and S.W. performed biodistribution studies. S.B. and T.A. analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Takuzo Aida.

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Biswas, S., Kinbara, K., Niwa, T. et al. Biomolecular robotics for chemomechanically driven guest delivery fuelled by intracellular ATP. Nature Chem 5, 613–620 (2013). https://doi.org/10.1038/nchem.1681

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