The administration of chemotherapy together with anti-angiogenic drugs seems to be a particularly effective way of slowing tumour growth. However, this combination also poses some practical problems — cutting off the tumour blood supply makes it difficult to achieve a high drug concentration, and hypoxia can trigger the expression of chemotherapy-resistance genes. Now, a group led by Ram Sasisekharan has designed a sophisticated delivery system that gets around these complications — a ‘nanocell’ that localizes to tumours and then shuts down the tumour vasculature before delivering a cytotoxic agent to tumour cells.

Their nanocell consists of a phosopholipid envelope and, inside it, a nanoparticle made of a biodegradable polymer. The researchers incorporated an anti-angiogenic agent — in this case combretastatin — into the liposome, and attached the chemotherapeutic agent doxorubicin to the nanoparticle.

They found that combretastatin escapes rapidly from the lipid envelope, while the conjugated doxorubicin is freed more slowly, degrading into smaller, inactive fragments before breaking down further into free, active doxorubicin. These release kinetics correlate well with the effect of the nanocell combination on the tumour endothelium in vitro — the system caused the vasculature to collapse as early as 12 hours post-administration, and tumours to be completely ablated by 30 hours.

The authors tested the therapeutic efficacy of this system in vivo using mice with B16:F10 melanomas and mice with Lewis lung carcinoma. They compared the effects of sequential drug delivery using nanocells with several other treatments —one or both drugs delivered simultaneously in simple liposomes, nanocells containing doxorubicin alone or co-administration of doxorubicin-containing nanocells and combrestatin-containing liposomes. Animals treated with nanocells containing both drugs had a better tumour response than any of the other treatment groups. In fact, the increase in survival of mice given the drugs sequentially was about twice that of those given the drugs simultaneously.

Furthermore, the nanocells containing both drugs resulted in the lowest systemic toxicity of all of the treatments. This is probably because the cytotoxic agent is localized to the tumour so effectively — the researchers confirmed this by attaching the dye fluorescein to the nanocell and measuring concentration of the dye in tumours and highly vascular organs. They speculate that the nanocell might be retained preferentially in tumours because tumour vasculature is ‘leakier’ than normal vasculature, and allows tumour tissue to absorb large particles.

How does the temporal delivery system elicit such a good response? The authors found that the nanocells containing both drugs caused higher levels of apoptosis than the other treatments, as well as the lowest expression of hypoxia-inducible factor 1 (HIF1), which they attribute to the high concentration of doxorubicin inside the tumour.

So what next for this new system? The nanocells used in this study could be developed further by adding probes that target the tumour vasculature more specifically. The authors point out that temporal drug delivery could substantially improve the efficacy of existing drugs, thereby reducing the risk and time for developing new therapies.

References (Original Research Paper)
Sengupta, S. et al. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature 436, 568–572 (2005)