As the field of nanomedicine matures, an emerging point of contention has been what shape nanoparticles deliver their drug or DNA payloads most effectively. A pair of publications from a team led by Paulo Decuzzi of the Texas Center for Cancer Nanomedicine suggests these microscopic workhorses ought to be disc-shaped, not spherical or rod-shaped, when targeting cancers at or near blood vessels.
"The vast majority, maybe 99 percent, of the work being done right now is using nanoparticles that are spherical," said Dr. Decuzzi. "But evidence is showing there may be better ways to get chemotherapy drugs to the site of a vascularizing cancer."
Despite their popularity, there are problems with sphere-shaped nanoparticles. First, they are relatively small, which limits the amount of drug they can deliver when they reach their target. In addition, they are more likely to get pushed downstream by blood's powerful flow instead of sticking to their target tissue.
"The small surface exposed by spherical nanoparticles to the blood vessel walls – theoretically a single point – in the tumor tissue cannot support stable, firm adhesion and they are easily washed away. This hampers their effective accumulation within the diseased tissue," explained Dr. Decuzzi. "So a number of laboratories have been asking, how can we maximize the accumulation of nanoparticles in the diseased tissues? Is there a better shape?"
In the journal Biomaterials, Decuzzi and his colleagues, including Texas Center for Cancer Nanotechnology principal investigator Mauro Ferrari, show that at biologically relevant flow speeds, disc-shaped nanoparticles were less likely to get pushed off their targets than rod-shaped nanoparticles -- another shape previously proposed as an alternative to spheres. The ideal size was 1,000 in diameter by 400 nanometers thick. The experiments were conducted in vitro and confirmed by computational modeling.
To create these nanodiscs, the Methodist nanomedicine group used photolithographic technology, the same tools used to make the tiniest components in computers. Photolithography allowed the investigators to specify the size, shape, and surface properties of the nanoparticles with a great deal of accuracy. The nanoparticles were constructed with sponge-like holes through them, creating niches into which drugs are loaded. Using photolithography enables the researchers to can change the size, shape, and surface properties of the particles independently.
The nanoparticles are made of silica, and biologically relevant molecules are later attached to the outside to improve binding to target cells and to delay destruction by the immune system. Silicon has an extremely low toxicity profile at the doses typically used in humans and animal models. Dr. Decuzzi said silica nanoparticles are readily broken down and removed from the body within 24 to 48 hours.
In a second paper, published in the Journal of Controlled Release, the Texas team used mouse models to show that 1,000 by 400 nm disc-shaped nanoparticles bind more readily to and near melanoma cells than spherical particles. The researchers also showed that the 1000 by 400 nm discs were less likely than smaller or larger discs, or rods, to end up in the liver.
"These two papers are the culmination of eight years of work, looking at the properties of disc-, rod-, and spherical nanoparticles in computer simulations, in vitro, and then in vivo," Dr. Decuzzi said. "What has been most rewarding is that all the important things we predicted via mathematical models turned out to be true in real-life experiments. We are getting close to answering crucial questions about what these nanoparticles need to look like."
Dr. Decuzzi says his group will continue working on the optimization of nanoparticles and, in particular, will be looking at what he calls the "4S" problem. After establishing the right size, shape, and surface chemistry, Decuzzi says he wants to see if the right amount of stiffness, or flexibility, can further enhance the in vivo performance of nanoparticles.
This work is detailed in two papers paper titled, "Size and shape effects in the biodistribution of intravascularly injected particles," and, "The preferential targeting of the diseased microvasculature by disk-like particles." This research was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer.
Investigators from Harvard Medical School, Rice University, and the University of Houston also participated in these studies. An abstract of these papers are available at the journals websites.
Fonte: National Cancer Institute
