Targeted nanoparticles to improve Boron-Neutron capture therapy

Sep 5 2006

Boron-neutron capture therapy (BNCT) is an experimental treatment for virulent brain cancer that aims to kill malignant cells by generating high-energy alpha particles inside tumors.

Clinical trials of BNCT have been disappointing, however, because of the difficulty in getting enough boron, which produces alpha particles when irradiated with a neutron beam, into tumors and in clearing from the body any boron not taken up by cancer cells. Now, two recent papers in the journal Bioconjugate Chemistry suggest that targeted nanoparticles may be able to solve this problem.

Werner Tjarks, Ph.D., and his colleagues at Ohio State University used lipid-based nanoparticles to encapsulate novel boron-containing compounds for delivery to tumors. The investigators designed these boron-containing compounds to mimic the chemical structure of cholesterol with the aim of having tumor cells incorporate these compounds into their cell membranes, just as they do with cholesterol. But because all cells put cholesterol in their cell membranes, the investigators knew that it would be critical to develop a targeted delivery agent for their boron-containing cholesterol mimics.

Cholesterol associates closely with lipids, so the investigators created a lipid-based nanoparticle as their delivery agent and chose folic acid and vascular endothelial growth factor (VEGF) as tumor-targeted agents. Tests with cancer cells growing in culture showed that both targeting agents successfully delivered their boron-containing payload only to tumor cells expressing the receptor for the particular targeting agent – the nanoparticle targeted with VEGF, for example, delivered its payload only to cancer cells containing the VEGF receptor on their surfaces. The next step in this research will be to see if these targeted nanoparticles hone in on tumors in animals.

Taking a similar approach, a team of investigators led by Hiroyuki Nakamura, Ph.D., at Gakushuin University in Japan created a set of boron-containing lipids that should also incorporate into cell membranes. Again, the investigators chose lipid-based nanoparticles as their delivery vehicle, but as a targeting agent they chose transferrin, which binds to a receptor that many types of tumors overexpress on their surfaces. The researchers note that in addition to ferrying boron into tumors, these nanoparticles could also deliver other anticancer agents simultaneously.

The investigators tested their targeted boron-loaded lipid nanoparticles in tumor-bearing mice. After injecting the mice with the nanoparticles, the researchers first showed that boron accumulated in far greater amounts in tumors than in healthy tissues, though they did note that they did find some boron in circulation 72 hours after administration, a finding they attribute to the slow release of the boron compound from the nanoparticles.

Next, the researchers subjected the animals to neutron irradiation in a manner that approximated how human cancer patients would receive therapy. Animals that did not receive the nanoparticles survived an average of 21 days, while those receiving the nanoparticles survived an average of 31 days after a single treatment, with one animal living 52 days after therapy. The researchers note that in addition to ferrying boron into tumors, these nanoparticles could also deliver other anticancer agents simultaneously, providing a one-two punch to tumor cells.

The work with cholesterol-mimicking boron compounds, which was supported in part by the National Cancer Institute, is detailed in a paper titled, "Receptor-targeted liposomal delivery of boron-containing cholesterol mimics for boron neutron capture therapy (BNCT)." Investigators from SibTech, in Newington, CT, also participated in this study. This paper was published online in advance of print publication. An abstract of this paper is available at the journal's website. View abstract.

The work with transferrin-targeted delivery is detailed in a paper titled, "Transferrin-loaded nido-carborane liposomes: tumor-targeting boron delivery system for neutron capture therapy." Investigators from Teikyo University and Kyoto University, both in Japan, also participated in this study. This paper was published online in advance of print publication. An abstract of this paper is available at the journal's website. View abstract