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Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size

Nature Nanotechnology volume 6, pages 815–823 (2011)Cite this article

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Abstract

A major goal in cancer research is to develop carriers that can deliver drugs effectively and without side effects. Liposomal and particulate carriers with diameters of ∼100 nm have been widely used to improve the distribution and tumour accumulation of cancer drugs, but so far they have only been effective for treating highly permeable tumours. Here, we compare the accumulation and effectiveness of different sizes of long-circulating, drug-loaded polymeric micelles (with diameters of 30, 50, 70 and 100 nm) in both highly and poorly permeable tumours. All the polymer micelles penetrated highly permeable tumours in mice, but only the 30 nm micelles could penetrate poorly permeable pancreatic tumours to achieve an antitumour effect. We also showed that the penetration and efficacy of the larger micelles could be enhanced by using a transforming growth factor-β inhibitor to increase the permeability of the tumours.

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Figure 1: Construction and physicochemical properties of DACHPt-loaded micellar nanomedicines (DACHPt/m) with different diameters.
Figure 2: Anticancer activity and tumour accumulation of DACHPt/m with different diameters.
Figure 3: Microdistribution of fluorescently labelled DACHPt/m of varying sizes in tumours.
Figure 4: In vivo real-time microdistribution of DACHPt/m with different diameters in tumours.
Figure 5: Effect of TGF-β inhibitor (TGF-β-I) on antitumour activity and tumour accumulation of DACHPt/m in BxPC3 tumours.

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Acknowledgements

The authors are grateful to S. Fukuda from the University of Tokyo Hospital for his valuable support in conducting transmission electron microscopy and to S. Ogura for assistance with animal care. This study was supported by the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) from the Japan Society for the Promotion of Science (JSPS) and Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labour, and Welfare. μ-SR-XRF studies were supported by the Nanotechnology Support Program of the Japan Synchrotron Radiation Research Institute (JASRI).

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Authors and Affiliations

  1. Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan

    H. Cabral & K. Kataoka

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

    Y. Matsumoto, M. Murakami, M. Kimura, N. Nishiyama & K. Kataoka

  3. Department of Nuclear Engineering and Management, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan

    K. Mizuno & M. Uesaka

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

    Q. Chen & K. Kataoka

  5. SPring 8, JASRI, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo, 679-5198, Japan

    Y. Terada

  6. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    M. R. Kano & K. Miyazono

  7. Center for NanoBio Integration (CNBI), The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan

    K. Miyazono, M. Uesaka, N. Nishiyama & K. Kataoka

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  1. H. Cabral
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Contributions

H.C. designed and performed all the experiments. Y.M. assisted with in vivo confocal microscopies. K.M. and Y.T. helped in the μ-X-ray fluorescence measurements. Q.C. performed transmission electron microscopy of the micelles. M.M and M.K. aided in the biodistribution experiments. H.C. wrote the manuscript. M.R.K., K.M. and M.U. commented on the manuscript. N.N. and K.K. edited the manuscript. K.K., with help from N.N., supervised the whole project.

Corresponding authors

Correspondence to N. Nishiyama or K. Kataoka.

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The authors declare no competing financial interests.

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Cabral, H., Matsumoto, Y., Mizuno, K. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nature Nanotech 6, 815–823 (2011). https://doi.org/10.1038/nnano.2011.166

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