Antibody-based imaging of a particularly aggressive form of breast cancer is undergoing clinical trials worldwide, but the path from trial to application is being hampered by a major obstacle: safety.
Concerns stem from inefficient tumor targeting, which can result in accumulation in the bone marrow, liver and kidneys of the radioactive material necessary for the imaging. Recent efforts have focused on nanoscale delivery vehicles with immune components, but these vehicles are often still too large (20 nanometers or larger) for renal clearance after imaging.
Researchers now have proposed a novel approach using ultrasmall silica nanoparticles - better known as "Cornell dots" (or C dots). Their team equipped the C dots with antibody fragments. Because the resulting conjugates are smaller than 8 nanometers, these C dots allow for renal clearance while achieving the specificity needed for efficient tumor targeting.They report their discovery in Nature Communications.
Cornell dots and their newer generation - termed "Cornell prime dots," or simply C' dots - have evolved since the group introduced them in 2005 and since, a first clinical trial deemed them safe for humans in 2014. Two years ago, the dots were shown to have the ability not only to detect cancer cells but to be self-therapeutic thereby actually killing them.
This latest research puts C dots back into the role of cancer-finder, but adds a "tumor finder" in the form of an antibody fragment. They used a particular fragment of the Y-shaped antibody, as opposed to the whole molecule, to keep the C' dot within the size threshold for renal clearance.
The target: HER2-positive breast cancer, more aggressive and deadly than HER2-negative cancer, making it an attractive target for new diagnostics and therapies. In the collaboration, MedImmune engineered an antibody fragment specifically to target the HER2 protein and a conjugation site not interfering with its binding activity. The dot itself was synthesized in a way that gave it five distinct functions, all within its ultrasmall size of 6 to 7 nanometers.
Both in vitro and in vivo (mouse) targeting of HER2-positive breast cancer cells were successful, with in vivo tumor uptake of the injected dots as high as 17.2 percent. "The injection circulates through the blood and has to escape the vasculature, has to diffuse through the connective tissue, has to associate with the tumor and then kind of penetrate the tumor body," the author said. "We want 100 percent - everybody wants 100 percent. But when you consider all of the other things that are competing for the vehicle elsewhere in the body, 17 percent is not that small."
Antibodies targeted with ultra-small nanoparticles to detect breast cancer
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