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Laser-controlled switch turns blood clotting on, off

CAMBRIDGE, Mass. – Laser-controlled gold nanoparticles that release DNA molecules to switch blood clotting on and off could help physicians better control the process in patients undergoing surgery, or to promote wound healing.

Natural clotting is produced by a long cascade of protein interactions, culminating in the formation of fibrin, a fibrous protein that seals wounds. Surgery, wound healing and other conditions require manipulation of this process, typically through the use of anticoagulants such as heparin and warfarin. Administering blood thinners reduces clotting, but reversing their effects is difficult.

“It’s like you have a light bulb, and you can turn it on with the switch just fine, but you can’t turn it off. You have to wait for it to burn out,” said Kimberly Hamad-Schifferli, who is a technical staff member at MIT Lincoln Laboratory.

A better solution, she says, would be an agent that targets only the last step – the conversion of fibrinogen to fibrin, a reaction mediated by an enzyme called thrombin.

Several years ago, scientists discovered that DNA with a specific sequence inhibits thrombin by blocking the site where it would typically bind to fibrinogen. The complementary DNA sequence can shut off the inhibition by binding to the original strand and preventing it from attaching to thrombin.

Hamad-Schifferli and colleagues previously demonstrated that gold nanorods can be designed to release drugs or other compounds when activated with IR light. The size of the nanorod determines the wavelength of light that will activate it, so two rods of different lengths can carry different payloads and be controlled separately.

To manipulate the clotting cascade, Hamad-Schifferli loaded a smaller, 35-nm-long gold nanorod with the DNA thrombin inhibitor and a larger, 60-nm-long particle with the complementary DNA strand. At first, the investigators tried chemically bonding DNA to the gold nanoparticles, but discovered they could not load enough DNA onto each particle to make this process effective.

“We realized we could use a bad side effect of nanoparticle biology to our advantage,” Hamad-Schifferli said. That is, the particles tend to attract a halo of proteins that bind to gold, making the particles sticky. In previous studies, she has shown that this large cloud of proteins can be used to hold a drug payload.

“If you do that, you can get way more drug on the nanorod than you normally would if you had to chemically link them together,” she said. By soaking the nanorods in a solution of human serum protein and the DNA molecules, the researchers attached six times more DNA than through chemical bonding.

When the nanorods are exposed to IR light, the electrons within the gold become excited and generate so much heat that they melt slightly, taking on a more spherical shape and releasing their DNA payload.

The nanoparticles were tested using blood donated to hospitals, and the researchers found that the particles successfully turned clotting on and off in all of the samples tested.

For practical use, the particles would need to be targeted to the site of injury, which the investigators are now working to achieve. Once they reach the site, they would need to be within a few millimeters of the skin surface for the IR light shone on the skin to reach them. System modifications are also in the works to allow particle activation using a smaller, less powerful CW laser.

The research appeared in PLOS ONE (doi: 10.1371/journal.pone.0068511).

For more information on the research of Hamad-Schifferli and her colleagues, see “Controlled Time Release of Multiple Drugs for Combination Therapy” at www.photonics.com/a36337.



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