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Researchers at Massachusetts Institute of Technology and the Whitehead Institute for Biomedical Research, both in the US, have engineered a nanocell that uses two different strategies to attack cancer. The cell contains an anti-angiogenesis agent, which destroys tumour blood vessels, and a chemotherapy drug that acts against the cancer cell itself.
To make the nanocells, the team created an envelope of pegylated-phospholipid block-copolymer. The envelope contained the anti-angiogenesis agent combretastatin-A4 and a nanoparticle of poly-(lactic-co-glycolic) acid that was conjugated to the chemotherapeutic drug doxorubicin. The resulting cell-like structures were 180-200 nm in diameter.
"We brought together three elements: cancer biology, pharmacology and engineering," said Ram Sasisekharan of MIT. "The fundamental challenges in cancer chemotherapy are its toxicity to healthy cells and drug resistance by cancer cells. So, cancer researchers were excited about anti-angiogenesis."
But, although anti-angiogenesis cuts off blood supply to the tumours, it may also increase the likelihood that the cancer spreads to other parts of the body and cause other problems. "You can't deliver chemotherapy to tumours if you have destroyed the vessels that take it there," said Sasisekharan. The researchers designed their nanocells to cut off the blood supply to the tumour whilst trapping the chemotherapy agent inside.
The nanocells permeate preferentially into tumour vessels, which have larger pores (400 - 600 nm in diameter) than other blood vessels. Breakage of the envelope surrounding the nanocell then releases the anti-angiogenesis agent. This causes collapse of the tumour blood vessels, trapping the contents of the nanocell inside the tumour. The doxorubicin component is then released more slowly as it separates out from the nanoparticle.
Tests of the drug release rates indicated that the combretastatin reached significant levels within 12 hours. The doxorubicin was released over about 15 days, in contrast.
Mice with B16/F10 melanomas or Lewis lung carcinoma that were treated with the nanocells survived for longer, although melanomas were more susceptible to the treatment than the Lewis lung carcinoma. Of the mice treated, 80% with nanocells survived for more than 65 days, whereas those animals treated with the best current therapy survived for 30 days.
"This model enables us to rationally and systematically evaluate drug combinations and loading mechanisms," said Sasisekharan. "It's not going to stop here. We want to build on this concept." The team believes it will be possible to target the nanocells to tumour vasculature by using probes that recognize specific molecular signatures.