Nanotech News

July 11, 2005

Understanding How Targeted Nanoparticles Enhance Drug Activity

The ability to target nanoparticles to tumors in order to enhance the antitumor activity of potent anticancer drugs while reducing potential side effects is one of the most promising applications of cancer nanotechnology (see Nanoparticles Transport Cancer-Killing Drug Into Tumor Cells in Mice to Increase Efficacy, Lower Drug Toxicity). Now, new evidence suggests that the increased activity of drugs delivered using at least one specific targeting molecule results from the fact that drug is released from targeted nanoparticles over a longer time inside tumor cells.

In work published in the journal Molecular Pharmaceutics, Vinod Labhasetwar, Ph.D., and Sanjeeb Sahoo, Ph.D., of the University of Nebraska Medical Center in Omaha, found that biodegradable nanoparticles loaded with the anticancer drug paclitaxel (the active ingredient in Taxol®) and targeted to breast cancer cells using the protein transferrin were more effective at killing those cells than were untargeted, drug-containing nanoparticles or paclitaxel alone. The reason for this enhanced cell-killing activity was that cells were better able to import the targeted nanoparticles and less able to export them. As a result, the targeted nanoparticles were able to release more drug over a longer time inside cells - so much so that drug delivered in this manner was able to kill breast cancer cells that have developed resistance to paclitaxel therapy.

Transferrin, a naturally occurring protein that transports iron through the bloodstream, is being investigated as a targeting agent for cancer therapeutic agents because many types of malignant cells contain excessive amounts of transferrin receptors on their surfaces. In addition, transferrin can help drugs cross the blood-brain barrier and thus may prove particularly valuable in targeting drugs to malignancies in the brain.

Dr. Labhasetwar's laboratory has focused on developing biodegradable nanoparticles made of the polymer poly(lactic-co-glycoside), or PLGA. Earlier work had shown that untargeted nanoparticles were taken up by cancer cells, but that the imported nanoparticles remained trapped within intracellular vesicles known as endosomes and do not escape efficiently into the cell's cytoplasm. Adding transferrin to the surface of these nanoparticles allows the nanoparticles to enter breast cancer cells using a different import mechanism, which dumps the nanoparticles almost immediately into the cytoplasm.

Using a fluorescent marker to track drug accumulation, the researchers were able to show that very little of the targeted, drug-loaded PLGA nanoparticles had been exported eight days after treatment. In contrast, both untargeted, drug-loaded nanoparticles and free paclitaxel were largely gone from cells within five days.

This work is detailed in a paper titled, "Enhanced antiproliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention." This paper was posted online in advance of print publication. An abstract is available at the journal's website.
View abstract.