Surprise Finding When Humble Protein and Nanoparticles Tag-Team to Kill Cancer Cells
A normally benign protein found in the human body appears to be able when paired with nanoparticles to zero in on and kill certain cancer cells, without having to also load those particles with chemotherapy drugs. The finding could lead to a new strategy for targeted cancer therapies, according to Joseph DeSimone and his colleagues at the University of North Carolina at Chapel Hill. However, Dr. DeSimone, who is also co-principal investigator of the Carolina Center of Cancer Nanotechnology Excellence, also cautioned that the result raises concerns about unanticipated "off-target" effects when designing nano-delivery agents.
Transferrin, the fourth most abundant protein in human blood, has been used as a tumor-targeting agent for delivering cancer drugs for almost two decades. The protein's receptor is over-expressed on the surface of many rapidly growing cancers cells, so treatments combined with transferrin ligands are able to seek out and bind to them. Based on substantial preclinical safety testing, nanoparticles infused with transferrin are regarded as safe and nontoxic.
Now, UNC researchers have shown that, surprisingly, attaching transferrin to a nanoparticle surface can effectively and selectively target and kill B-cell lymphoma cells, found in an aggressive form of non-Hodgkin's lymphoma. It had been thought that nanoparticles would also need to carry toxic chemotherapy agents to have such an effect. The investigators published their surprising findings in the Journal of the American Chemical Society.
Using PRINT (Particle Replication in Non-wetting Templates) technology — a technique invented in Dr. DeSimone's lab that allows scientists to produce nanoparticles with well-defined size and shape — the UNC researchers produced biocompatible nanoparticles bonded with human transferrin, and demonstrated that the particles can safely and accurately recognize a broad spectrum of cancers. As well as B-cell lymphoma cells, the particles also effectively targeted non-small cell lung, ovarian, liver and prostate cancer cells.
Generally, the nanoparticles were non-toxic to such cells and should therefore be able to be loaded with standard chemotherapy agents and used to hone in on those cancers. However, for Ramos cells, an aggressive form of B-cell lymphoma, the transferrin-bonded PRINT nanoparticles not only recognized them but also induced cell death. Meanwhile, free transferrin which was incubated with Ramos cells but not bound to any nanoparticles did not kill any Ramos cells, even at high concentrations. The investigators are now carrying out further studies to determine how and why the transferrin-carrying nanoparticles proved toxic to the Ramos cells but not the other tumor types.
"Although this is potentially exciting for the development of entirely new strategies for treating certain types of lymphomas with potentially lower side effects, this study also raises concerns for unanticipated off-target effects when one is designing targeted chemotherapy agents for other types of cancers," said Dr. DeSimone.
This work, which is detailed in a paper titled, "The Complex Role of Multivalency in Nanoparticles Targeting the Transferrin Receptor for Cancer Therapies," was supported in part by the NCI Alliance for Nanotechnology in Cancer, a comprehensive initiative designed to accelerate the application of nanotechnology to the prevention, diagnosis, and treatment of cancer. An abstract of this paper is available at the journal's Web site.