January 22, 2013
No Chemo Needed: Nanoparticle Double Agent Kills Lymphoma Cells
April Flowers for redOrbit.com - Your Universe Online
Is it possible to annihilate lymphoma without the use of chemotherapy drugs?
Researchers at Northwestern University Feinberg School of Medicine say yes, by starving it of its favorite food: HDL cholesterol.
They have discovered a new nanoparticle that acts as a secret double agent, appearing to the cancerous lymphoma cell like natural HDL. When the cell engages with the particle, the particle blocks cholesterol from entering, killing the cell off eventually.
The new study, published in a recent issue of Proceedings of the National Academy of Sciences, shows that synthetic HDL nanoparticles killed B-cell lymphoma — the most common form of the disease — in cultured human cells. It also inhibited human B-cell lymphoma tumor growth in mice.
"This has the potential to eventually become a nontoxic treatment for B-cell lymphoma which does not involve chemotherapy," said Leo I. Gordon, professor of medicine in hematology/oncology. "It's an exciting preliminary finding."
B-cell lymphoma is dependent on the uptake of natural HDL -- short for high-density lipoprotein -- from which it derives fat content, such as cholesterol, according to recent studies.
C. Shad Thaxton, assistant professor of urology, originally developed the nanoparticle as a possible therapy for heart disease. The particle mimics the size, shape and surface chemistry of natural HDL particles with one key difference: a five nanometer gold particle at its core. The gold delivers a double whammy to lymphoma. When the nanoparticle is incubated with human B-cell lymphoma cells or used to treat a mouse with the human tumor, the gold particle's spongy surface sucks out the lymphoma cell's cholesterol while the gold core prevents the cell from absorbing more cholesterol typically carried in the core of natural HDL particles.
The study results showed that the HDL nanoparticle had more than one trick up its sleeve.
"At first I was heavily focused on developing nanoparticles that could remove cholesterol from cells, especially those involved in heart disease," Thaxton said. "The lymphoma work has broadened this focus to how the HDL nanoparticles impact both the removal and uptake of cholesterol by cells. We discovered the particles are multi-taskers." The study also revealed that natural HDL did not kill the cells or inhibit tumor growth, the nanoparticle was essential in this process.
The collaboration between Gordon and Thaxton started shortly after Thaxton gave a lecture in 2010 to the Feinberg faculty about his new HDL nanoparticle. Gordon knew that patients with advanced forms of B-cell lymphoma sometimes have dropping levels of cholesterol and he was looking for new methods to deliver drugs to patients.
The team tested the HDL particle alone and transporting drugs. They found that the nanoparticle was just as effective at killing the B-cell lymphoma without the drugs.
"We thought, 'That's odd. Why don't we need the drug?'" Gordon recalled.
This led them to delving into the mechanism by which the HDL particles were sticking to the lymphoma cells' HDL receptors to manipulate cholesterol transport. Collaborators at Duke University analyzed patient samples to reveal that lymphoma cells in patients had an overproduction of HDL receptors compared to normal lymphocytes.
In 2012, the National Cancer Institutes reports that there were about 70,000 new cases of non-Hodgkin lymphoma in the U.S. with nearly 19,000 deaths. Approximately 90 percent of those new cases were B-cell lymphoma.
"Gold has a good track record of being compatible with biologic systems," Thaxton said.
The scientists are encouraged by the early data that shows HDL particles do not appear toxic to other human cells normally targeted by HDLs, normal human lymphocytes or to mice. Gold nanoparticles are excellent scaffolds for creating synthetic HDLs that closely mimic those found in nature because they can be made in a discreet size and shape.
"Like every new drug candidate, the HDL nanoparticle will need to undergo further testing," Thaxton noted.