Lymphoma can be starved to death by depriving it of what appears to be a favorite food: high-density lipoprotein (HDL) cholesterol. A new nanoparticle appears to the cancerous lymphoma cell like a preferred meal of natural HDL. When the particle engages the cell, it plugs it up and blocks cholesterol from entering. Deprived of an essential nutrient, the cell eventually dies.
B-cell lymphoma is dependent on the uptake of natural HDL, from which it derives fat content, such as cholesterol. The nanoparticle, which was originally developed as a possible therapy for heart disease, closely mimics the size, shape, and surface chemistry of natural HDL particles. Its key difference is a 5-nm gold particle at its core. When the nanoparticle is incubated with human B-cell lymphoma cells or used to treat a mouse with a human tumor, the spongy surface of the gold particle sucks the cholesterol out of the cell, and the gold core prevents the cell from absorbing more cholesterol that is typically carried in the core of natural HDL particles.
Natural HDL does not kill the cells or inhibit tumor growth. The nanoparticle is essential to starve the lymphoma cell.
C. Shad Thaxton, MD, of Northwestern Medicine, the original developer of the HDL nanoparticle, gave a lecture that was attended by Leo I. Gordon, MD, also of Northwestern. Gordon knew that patients with advanced forms of B-cell lymphoma sometimes have diminishing levels of cholesterol, and he was looking for new ways to deliver drugs to patients. He contacted Thaxton, and they began the collaboration that led to this publication in Proceedings of the National Academy of Sciences (2013;doi:10.1073/pnas.1213657110).
They tested the HDL nanoparticle alone and the HDL nanoparticle transporting cancer drugs. Surprisingly, the nanoparticle without drugs was just as effective at killing the B-cell lymphoma cells.
“We thought, “’That’s odd. Why don’t we need the drug?’” Gordon recalled.
That’s when the scientists began delving into the mechanism by which the HDL nanoparticles were sticking to the HDL receptors on the lymphoma cell and manipulating cholesterol transport. In addition, patient samples analyzed by collaborators at Duke University for the study showed that lymphoma cells in patients had an overproduction of these HDL receptors compared to normal lymphocytes.
Thaxton and Gordon are encouraged by their early data showing that the HDL nanoparticles do not appear toxic to other human cells normally targeted by HDLs, normal human lymphocytes, or to mice. Also, because gold nanoparticles can be made in discreet sizes and shapes, they are excellent scaffolds for creating synthetic HDLs that closely mimic those found in nature.
“Gold has a good track record of being compatible with biologic systems,” Thaxton said, and added, “Like every new drug candidate, the HDL nanoparticle will need to undergo further testing.”