Nanoparticles Mimic Cholesterol Transporter and Attack Lymphoma
High-density lipoprotein (HDL) is well-known for its role in protecting the body from developing coronary artery disease, but HDL also helps lymphomas and other cancers acquire the large amounts of cholesterol they need to maintain the structure of their cell membranes as they grow rapidly. Researchers at Northwestern University have taken advantage of this dependency on HDL to create an HDL-mimicking nanoparticle that starves lymphoma cells of cholesterol, triggering them to commit programmed cell death without the use of any other anticancer agent.
C. Shad Thaxton, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern and member of the Northwestern University Center of Cancer Nanotechnology Excellence, and Leo Gordon, of Northwestern’s Feinberg School of Medicine, led the team that developed this biomimetic HDL nanostructure. The investigators published their findings in the Proceedings of the National Academy of Sciences.
To create their biomimetic HDL nanostructures, the researchers start with spherical gold nanoparticles that are five nanometers in diameter and add the human protein ApoA1 and two phospholipids found in native HDLs. The gold nanoparticle serves two functions. First, it acts as a template that controls the shape and size of the biomimetic particles so that they recognize and bind tightly to a specific receptor, known as scavenger receptor type B-1 (SR-B1), which is expressed by lymphoma cells. Second, the gold core occupies the space that is normally filled by cholesterol esters, which thereby limits the ability of these particles to deliver cholesterol to the receptor-targeted lymphoma cells.
Initial experiments with lymphoma cells growing in culture showed that these nanoparticles are taken up by cells that have the target (SR-B1) receptor and have the desired effect of triggering programmed cell death, also known as apoptosis. They also demonstrated that apoptosis resulted from cholesterol flowing out of the cells. In contrast, the biomimetic HDL nanoparticles did not trigger cholesterol outflow from or apoptosis in normal human liver cells, macrophages, or lymphocytes.
Drs. Thaxton and Gordon and their collaborators then treated mice with human lymphomas with the biomimetic HDL nanoparticles. This treatment stopped tumor growth when the tumors were derived from lymphoma cells that expressed SR-B1, but had no effect on tumors derived from SR-B1 negative cells. The researchers note that because SR-B1 is not expressed in the majority of human tissue that the toxicity of these nanoparticles may be minimal compared to conventional chemotherapeutics.
This work is detailed in a paper titled, "Biomimetic, synthetic HDL nanostructures for lymphoma." An abstract of this paper is available at the journal’s website.