“Nanoburrs” are nanoparticles coated with a sticky protein that makes them cling onto artery walls while they slowly release drugs: the US researchers who are developing them hope they will one day provide an alternative to drug-releasing stents in fighting heart disease.
The researchers, based at the Massachusetts Institute of Technology, (MIT) and Harvard Medical School, wrote about how they developed and tested the nanoburrs as potential drug-releasing agents for targeting and repairing damaged blood vessels in a paper that was published online on 19 January in the Proceedings of the National Academy of Sciences.
The nanoburrs can release their drug payload over several days, and could be used to deliver drugs to treat treat atherosclerosis and other inflammatory cardiovascular diseases, the researchers told the press.
They hope one day the nanoburrs can be used with vascular stents, the standard of care for most cases of clogged and damaged arteries, and in some cases may even replace stents in locations they are not well suited for, such as near a fork in the artery.
Co-author Omid Farokhzad, associate professor at Harvard Medical School, said that the nanoparticles are one of the first designed to home in precisely on damaged vascular tissue. He and co-author Robert Langer, a professor at MIT, have already developed nanoparticles that target and destroy tumors.
“This is a very exciting example of nanotechnology and cell targeting in action that I hope will have broad ramifications.”
The researchers designed the nanoburrs to target a specific structure in the artery wall, the basement membrane, which only becomes exposed when the walls are damaged.
In the study they used a drug called paclitaxel that inhibits cell division and helps prevent the growth of scar tissue that can clog arteries.
The nanoburrs are 60 nanometer-diameter spheres (the head of a pin is about 1 million nanometers), and comprise three layers: an inner core, a middle layer and an outer coating.
The inner core contains the drug payload and a polymer chain called PLA. The middle layer is made of a fatty material, soybean lecithin, and the outer coating is a polymer, PEG which protects the nanoburr as it travels through the bloodstream.
The drug release is controlled by varying the length of the PLA chain in the core: the longer the chain, the longer the duration of the release, which occurs through a reaction called ester hydrolysis whereby the drug becomes detached from the polymer.
To make the “burrs”, the researchers screened a library of short peptide sequences to find one that bound most effectively to molecules on the surface of the arterial basement membrane. They selected the most effective one, the seven-amino-acid sequenced C11, to coat the outer layer of the nanospheres.
Uday Kompella, professor of pharmaceutical sciences at the University of Colorado, who was not involved with the study, said the fact the targeted peptides are attached to an outer shell and not directly to the drug-carrying core, which would require a more complicated chemical reaction, could make it easier to manufacture the nanoburrs. He said this design also reduced the risk of bursting and releasing the drug too soon.
The researchers said they have managed to achieve drug release periods lasting 12 days in cultured cells.
They also injected the nanoburrs intravenously into the tails of rats and showed they reached their intended target: the damaged walls of the left carotid artery (the vessel that supplies the head and neck with oxygenated blood). They found that the nanoburrs bound to the damaged walls at twice the rate of non-targeting particles.
The authors wrote that:
“The nanoparticles inhibited human aortic smooth muscle cell proliferation in vitro and showed greater in vivo vascular retention during percutaneous angioplasty over nontargeted controls.”
Lead author Juliana Chan, a graduate student in Langer’s lab at MIT, said that if introavenously injectable particles that deliver drugs over a longer period were available, patients wouldn’t have to undergo repeated and invasive injections directly into the affected area.
Mark Davis, professor of chemical engineering at Caltech, and who was not involved in the study, told the press that this work is a promising step toward developing new treatments for cardiovascular and other diseases:
“If they could do this in patients — target particles to injured areas — that could open up all kinds of new opportunities,” said Davis.
The team is now testing the nanoburrs in rats to find the most effective dose for repairing damaged vascular tissue.
Farokhzad said the nanoburrs could also be useful in targeting tumors:
“This technology could have broad applications across other important diseases, including cancer and inflammatory diseases where vascular permeability or vascular damage is commonly observed,” he said.
Funding for the study came from the National Institutes of Health, Agency for Science, Technology and Research (Singapore).
“Spatiotemporal controlled delivery of nanoparticles to injured vasculature.”
Juliana M Chan, Liangfang Zhang, Rong Tong, Debuyati Ghosh, Weiwei Gao, Grace Liao, Kai P. Yuet, David Gray, June-Wha Rhee, Jianjun Cheng, Gershon Golomb, Peter Libby, Robert Langer, and Omid C. Farokhzad.
PNAS, published online before print January 19, 2010.
Written by: Catharine Paddock, PhD