Packaging Paclitaxel in Nanoparticles May Increase Drug Efficacy in Preclinical Models
Duke University researchers found that packaging the widely used cancer drug paclitaxel into nanoparticles more than doubled the drug’s effectiveness in destroying tumors in preclinical models. Their findings were published by Bhattacharyya et al in Nature Communications.
Paclitaxel has been used for decades to fight breast, ovarian, lung, and other cancers. However, its effectiveness has been limited by its small molecular size and insolubility in water—properties that allow the body to clear the drug too quickly, reducing its accumulation in tumors. Many molecular packaging systems have been developed to deliver the drug while counteracting these effects, with the protein-bound version of the drug (nab-paclitaxel [Abraxane]) currently the leading therapy.
Ashutosh Chilkoti, PhD, Professor and Chair of the Department of Biomedical Engineering at Duke University, and his team surrounded molecules of paclitaxel with self-assembling spheres composed of amino acids. This formulation doubled tumor exposure to the drug compared with nab-paclitaxel while simultaneously reducing its effects on healthy tissue. This process kept mice with tumors alive significantly longer and, in some cases, completely eradicated the tumors.
Drug Differences
The difference between nab-paclitaxel and the Duke approach is the type of molecular bonds formed. In nab-paclitaxel, the paclitaxel is physically surrounded by the common blood protein albumin. In the new packaging system, multiple copies of the drug are chemically bonded to an amino acid polypeptide, forming a water-soluble nanoparticle with the drug hidden in its core.
These nanoparticles are highly soluble in blood and are the perfect size to penetrate and accumulate in tumors, where they can take advantage of a tumor's acidic environment.
“The chemical bonds holding the polypeptide cage together are stable in blood but dissolve in a tumor's lower pH levels,” said Jayanta Bhattacharyya, Senior Research Scientist in Dr. Chilkoti's laboratory. “This delivers the drug directly to the tumor and helps prevent it from randomly absorbing into healthy tissue, reducing side effects.”
Study Results
To test the system, the Duke team used two groups of mice. The first group had human breast cancer growing in the mammary glands. Although none of the mice treated with nab-paclitaxel survived past 85 days, most of the mice treated with the new packaging system survived past 100 days.
A second group of mice had human prostate tumors growing under the skin. Similarly, although they did not survive past 60 days when treated with nab-paclitaxel, all mice treated with the new packaging system survived past 70 days, with some experiencing a complete cure.
As the mortality rates suggest, the Duke technology showed a higher concentration of paclitaxel in the tumors with more staying power than nab-paclitaxel while simultaneously showing much lower levels throughout the rest of the mice's bodies.
“Clearly in the animal model there is a night and day difference, and if that translates to people, it will be transformative for patients,” said Neil Spector, MD, a member of the Duke Cancer Institute familiar with the work. “But it's not just the increase in clinical efficacy and outcomes that are exciting, it's also the improvement in targeting and reduction in toxicity. And since this platform could potentially be used for such a broad array of drugs, it could be a game-changer for cancer therapy.”
In future work, Dr. Chilkoti and colleagues will begin applying the packaging system to other cancer drugs, with the goal of developing a “one-size-fits-all” technology to improve the effectiveness of many other cancer drugs.
Dr. Chilkoti is the corresponding author of the Nature Communications article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
