Molecular tinkering doubles cancer drug's efficacy

Researchers have packaged a widely used cancer drug into nanoparticles, more than doubling its effectiveness at destroying tumors. They found significantly longer lives in mice with tumors, and published their results in Nature Communications (2015; doi:10.1038/ncomms8939).

The drug paclitaxel (Abraxane) 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. These properties allow the body to clear the drug too quickly, which reduces its accumulation in tumors.

Many molecular packaging systems have been developed to deliver Abraxane while counteracting these effects, with a protein-bound version of paclitaxel currently the leading therapy.

But Ashutosh Chilkoti, PhD, professor and chair of the Department of Biomedical Engineering at Duke University, thought his team could do better.

By surrounding molecules of paclitaxel with self-assembling spheres composed of amino acids, the Duke team doubled tumor exposure to the drug while simultaneously reducing its effects on healthy tissue. This kept mice with tumors alive significantly longer and, in some cases, completely eradicated the tumors.

The big difference between paclitaxel and the Duke approach is the types of molecular bonds that are formed. In the Abraxane form of paclitaxel, the drug is physically surrounded by albumin, a common blood protein. 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 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, PhD, senior researcher in Chilkoti's laboratory and first author on the paper. "This delivers the drug directly to the tumor and helps prevent it from randomly absorbing into healthy tissue, reducing side effects."

To test their system, the researchers used two groups of mice. The first group had human breast cancer growing in their own mammary glands. While none of the mice treated with 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 their skin. Similarly, while they did not survive past 60 days when treated with paclitaxel, every single mouse 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 the Abraxane form, 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, an oncologist at Duke Medicine 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, which is just icing on the cake. And since this platform could potentially be used for such a broad array of drugs, it could be a game-changer for cancer therapy."

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