May 15, 2006
Lipid-Coated Nanoparticles Yield Breathable Anticancer Agent
As anticancer agents go, 5-fluorouracil (5-FU) belongs to the category of drugs that have reasonable tumor-killing activity but whose use is limited by adverse side effects that occur at even moderate doses of the drug. Now, a series of papers published in the Journal of Pharmaceutical Sciences has demonstrated that lipid-coated polymer nanoparticles may significantly alter the balance between efficacy and toxicity. As an added benefit, these nanoparticles can be breathed into the lungs and may therefore be useful for delivering sustained doses of 5-FU for treating lung cancer.
Timothy Wiedmann, Ph.D., and Lee Wattenberg, M.D., both of the University of Minnesota, led a team of investigators that created and tested a variety of nanoparticle and microparticle formulations to identify which might serve as a useful delivery vehicle for 5-FU. The idea behind this research was the understanding that 5-FU’s cancer killing activity is limited by the fact that the drug is not toxic until the body first adds what is known as a triphosphate group to the drug molecule. Unfortunately, the body can convert only about 20 percent of an injected dose into the active form before the rest of the dose is excreted.
The investigators reasoned that entrapping 5-FU in a nanoparticle that would release it slowly into the bloodstream might enable the body to convert more of the drug into the active form. They also hypothesized that using a nanoparticle that could be administered directly into the lungs might have the effect of increasing the local dose of this drug in areas with lung tumors while reducing the amount of drug in the general circulation, where it can cause unwanted toxicities.
In the three recent papers, the Minnesota team presents data showing that this approach does have merit. In the first two papers, the investigators reported on their work creating and testing numerous nanoparticles and microparticles to find a formulation that had the proper drug release characteristics for use in the lungs. These studies showed that a polymer-lipid core-shell nanoparticle had the optimal properties for delivery to the lungs while releasing drug over time periods exceeding 24 hours. Preliminary studies in hamsters showed that the drug-loaded nanoparticles could reach the deepest recesses of the lung and produce sustained drug levels in lung.
In the third paper, the investigators characterize the pharmacokinetic behavior of the particles in more detail, again using hamsters. This work showed that when inhaled, the drug-containing nanoparticles concentrated in tumor-bearing regions of the lung. More importantly, drug release from the nanoparticles into lung tissue was as expected from their studies, suggesting to the investigators that they are on the right track. Further tests in animals are already underway.
This work is detailed in three papers. Abstracts of all three papers are available through PubMed. The three papers are titled:
“Development of a respirable, sustained release microcarrier for 5-fluorouracil I: In vitro assessment of liposomes, microspheres, and lipid coated nanoparticles.”
“Development of a respirable, sustained release microcarrier for 5-fluorouracil II: In vitro and in vivo optimization of lipid coated nanoparticles.”
“Pharmacokinetics of 5-fluorouracil in the hamster following inhalation delivery of lipid-coated nanoparticles.”