Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system (original) (raw)

Nature volume 436, pages 568–572 (2005)Cite this article

Abstract

In the continuing search for effective treatments for cancer, the emerging model is the combination of traditional chemotherapy with anti-angiogenesis agents1 that inhibit blood vessel growth. However, the implementation of this strategy has faced two major obstacles. First, the long-term shutdown of tumour blood vessels by the anti-angiogenesis agent can prevent the tumour from receiving a therapeutic concentration of the chemotherapy agent. Second, inhibiting blood supply drives the intra-tumoural accumulation of hypoxia-inducible factor-1α (HIF1-α); overexpression of HIF1-α is correlated with increased tumour invasiveness and resistance to chemotherapy2,3,4,5. Here we report the disease-driven engineering of a drug delivery system, a ‘nanocell’, which overcomes these barriers unique to solid tumours. The nanocell comprises a nuclear nanoparticle within an extranuclear pegylated-lipid envelope, and is preferentially taken up by the tumour. The nanocell enables a temporal release of two drugs: the outer envelope first releases an anti-angiogenesis agent, causing a vascular shutdown; the inner nanoparticle, which is trapped inside the tumour, then releases a chemotherapy agent. This focal release within a tumour results in improved therapeutic index with reduced toxicity. The technology can be extended to additional agents, so as to target multiple signalling pathways or distinct tumour compartments, enabling the model of an ‘integrative’ approach in cancer therapy.

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Acknowledgements

We thank S. R. Kabir, K. Holley and G. T. Franzesi for assistance.

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Author notes

  1. Shiladitya Sengupta and David Eavarone: *These authors contributed equally to this work

Authors and Affiliations

  1. Biological Engineering Division,
    Shiladitya Sengupta, David Eavarone, Ishan Capila, Ganlin Zhao & Ram Sasisekharan
  2. Department of Chemistry, Massachusetts Institute of Technology, Massachusetts, 02139, Cambridge, USA
    Tanyel Kiziltepe
  3. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, 02142, USA
    Nicki Watson

Authors

  1. Shiladitya Sengupta
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  2. David Eavarone
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  3. Ishan Capila
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  4. Ganlin Zhao
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  5. Nicki Watson
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  6. Tanyel Kiziltepe
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  7. Ram Sasisekharan
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Corresponding author

Correspondence toRam Sasisekharan.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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Sengupta, S., Eavarone, D., Capila, I. et al. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system.Nature 436, 568–572 (2005). https://doi.org/10.1038/nature03794

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