Researchers at Yale have discovered that the use of “sticky” bioadhesive nanoparticles to deliver a potent chemotherapy drug may be a safer and more effective way of fighting ovarian and uterine cancers than traditional treatments.
The results of the research — led by Mark Saltzman, a professor at the Yale School of Engineering and Applied Science, and Alessandro Santin, a professor at the Yale School of Medicine — were published in the Proceedings of the National Academy of Sciences on Sept. 19.
A drug called epothilone B (EB) has traditionally been used in clinical trials to target tumor cells resistant to traditional chemotherapy agents. According to the study authors, although EB was effective during these trials, its high toxicity gave rise to severe side effects in patients, such as diarrhea, precluding further use.
In an attempt to harness the cancer-killing capacity of EB while at the same time limit its injurious side effects, the researchers encased the potent drug in a nanoparticle prior to injecting it into the fluid of the abdominal cavity. This unique delivery method was tested on mice with human tumors growing in their abdominal regions. Saltzman and Santin found that the nanoparticles delivered EB precisely to its target sites and then released it gradually in high concentrations.
According to the study, 60 percent of the mice receiving the treatment with the nanoparticles survived for four months — a significant improvement over mice in the control groups, where 10 percent or fewer lived as long.
“We showed that animals that have cancer disseminated throughout their abdominal cavities can be treated more effectively with these sticky nanoparticles than with free drugs alone,” Saltzman said.
The nanoparticles are referred to as “sticky” because they are covered with aldehyde groups, which chemically adhere to cells in the abdominal cavity. According to the study, the creation of this “unique formulation of bioadhesive nanoparticles” was a response to the fast clearance of conventional nanoparticles from their target sites by abdominal fluids. By adding aldehyde groups, the researchers hoped to “significantly extend the retention of the nanoparticles” in the abdominal cavity such that EB could be released as steadily and precisely as possible. The study authors found that the bioadhesive nanoparticles stayed in place for at least 24 hours, whereas nonadhesive nanoparticles injected into control mice began to leave the abdominal cavity after five minutes.
According to Santin, this treatment could be particularly crucial for patients suffering from more severe forms of ovarian and uterine cancer, which are particularly difficult to cure given how easily these cancers spread throughout the abdomen.
While the study focused largely on cancers present in the abdominal cavity, the researchers said they are confident that sticky nanoparticles can be used to fight cancers in other parts of the body as well. Saltzman said that the researchers are currently working on a paper that will articulate how bioadhesive nanoparticles can be used to fight brain tumors, adding that there is great potential to use sticky nanoparticles in a “variety of [treatment] settings.”
While the researchers believe that additional studies need to be conducted in order to guarantee the safety of the delivery mechanism, they hope that they can convince the relevant authorities to develop the drug for clinical use within a few years.
“The next step is to design a phase I clinical trial to administer these nanoparticles in patients who have a chemotherapy-resistant disease in order to really determine if what we saw in animals is reproducible in humans,” Santin said.
The research was funded by grants from the National Institutes of Health and Women’s Health Research at Yale.