Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system

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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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Figure 1: Synthesis and characterization of a combretastatin–doxorubicin nanocell.
Figure 2: Bioassay of the nanocell with a GFP-positive melanoma–endothelial cell three-dimensional co-culture system.
Figure 3: Nanocell therapy inhibits B16/F10 melanoma and Lewis lung carcinoma growth.
Figure 4: Effect of nanocell treatment on tumour vasculature and apoptosis.

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Acknowledgements

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

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Correspondence to Ram 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) doi:10.1038/nature03794

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