May 9, 2006
Tumour enzymes trigger nanoparticle self-assembly
Researchers at MIT, the University of California, San Diego, and the Burnham Institute, all in the US, have for the first time demonstrated nanoparticle self-assembly triggered by a protease. The technique could have applications in magnetic resonance imaging (MRI) and drug delivery to cancerous tumours, which release specific proteases.
Many other nanotech approaches to cancer have focused on active targeting of receptors found only on cancer cells. But once all the receptors are saturated, nanoparticles can no longer attach to the cells.
"We wanted to devise a targeting approach that wouldn't be limited by the number of receptors on the surface of cancer cells, but would allow continuous activation of nanoparticle homing," Todd Harris of MIT told nanotechweb.org. "We've designed nanoparticles that act similarly to platelets and fibrin – they are separate and non-interactive in solution until a specific protease is added, whereupon they rapidly self-assemble. In the body, this enzyme-actuated platelet/fibrin assembly enables very rapid deposition at sites of vascular injury. We're hoping to use proteases associated with tumour processes to do the same thing with our nanoparticles."
Harris and colleagues coated nanoparticles of Fe3O4 with either biotin or neutravidin. Under normal circumstances, the biotin would bind to the neutravidin but the researchers inhibited this process by adding a layer of polyethylene glycol (PEG) polymers to the nanoparticles. The presence of the protease matrix metalloproteinase-2 (MMP-2), however, removed the PEG and initiated self-assembly of the nanoparticles. MMP-2 is associated with cancer invasion, angiogenesis and metastasis.
"We have engineered nanoparticles to have a dual nature," said Harris. "Before activation, the properties of these nanoparticles are dictated by an outer coating of PEG, which inhibits interparticle binding. Once activated by proteases that are overexpressed by invasive cancer cells, the PEG coating is shed and these nanoparticles take on new properties dictated by their surface coating of neutravidin and biotin. These two moieties bind one another with very high affinity causing the nanoparticles to rapidly self-assemble into clusters that have enhanced magnetic properties that can be detected with MRI."
According to Sangeeta Bhatia of MIT, the nanoparticles should self-assemble when they are exposed to proteases inside invasive tumours. "When they assemble they should get stuck inside the tumour and be more visible on an MRI," she said. "This might allow for non-invasive imaging of fast-growing cancer 'hot spots' in tumours."
The researchers say that the technique could enable them to image protease expression with MRI. "Protease levels can be correlated with malignancy and invasiveness and could be used for diagnosis and prognosis as well as for prescribing treatment and monitoring efficacy," said Harris. "Other applications may be a bit further off, but as self-assembly is used to build materials that have other imaging or therapeutic properties, one can imagine applying this strategy to build these at the site of tumours."
Now the researchers are trying to demonstrate the technique's efficiency in in vivo tumour models. They are also interested in which other functions on the surface of a nanoparticle could be temporarily shielded by cleavable polymers.
The researchers reported their work in Angewandte Chemie.
About the author
Liz Kalaugher is editor of nanotechweb.org.