1. Biological Engineering Division and
2. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
4. *These authors contributed equally to this work

Correspondence to: Ram Sasisekharan¹ Correspondence and requests for materials should be addressed to R.S. (Email: rams@MIT.edu).

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-1 (HIF1-); overexpression of HIF1- is correlated with increased tumour invasiveness and resistance to chemotherapy^{2, 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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