The oxygen-poor regions of solid tumors usually help make them resistant to chemotherapy and other forms of treatment. But researchers at Oregon State University have devised away to take advantage of those hypoxic areas and improve solid tumor treatment with a targeted, liposomal drug delivery system.
The team used the cancer drug, vinblastine, which is a “prodrug” – a pharmacologically inactive compound that the body meatbolizes into an active compound.
The researchers developed 2 liposomes to carry the prodrug to the tumor’s hypoxic regions, where the lack of oxygen triggered the drug’s metabolic conversion.
In both liposomes, the prodrug was safe and more effective against non-small cell lung cancer compared to standard of care.
“One of the hallmarks of these solid tumors is their hypoxic regions,” lead author Adam Alani said. “One reason these cancers become very aggressive is the development of this hypoxia. Since the late 1990s, researchers have been trying to take advantage of the hypoxia. The tumor model we chose, lung cancer, is 1 of the very well established tumors and there’s a very strong hypoxia associated with that – as well as, lung cancer is 1 of these cancers that in its advanced stages, it’s a terminal disease, and there’s a need for new treatments.”
Alone, vinblastine has a half-life of less than half an hour. In other words, the body clears the drug out of a patient’s system very quickly.
“When it was tested in mice and dogs, it did not have a chance to assimilate in the cancer tissue to produce the desired pharmacological effect,” Alani said.
The team’s liposomal system increased the drug’s half-life to 9.5 hours for the liposome containing polyethylene glycol and 5.5 hours for the liposome without the polyethylene glycol.
“We made sure the nanostructure platform worked properly against lung cancer in vitro, then looked at the safety of the formulation in healthy mice and looked at the maximum tolerated dose – the biggest dose you can use without producing side effects,” Alani said. “Then we determined how long the nano carriers could keep the drug in the blood compared to the drug without the nanostructures.”
The team also evaluated the delivery system’s efficacy in mice that had tumors grafted into them and found that mice that received the drug through the liposome-based system were healthy and tumor-free for the duration of the study.
Mice that received the drug alone had to be euthanized after 70 days because of tumors that could not be controlled, according to the team.
“The formulations clearly performed better than the unformulated drug as well as much better than cisplatin, the standard-of-care drug for this research,” Alani said. “Now we’re collaborating with Cascade Prodrug and the College of Veterinary Medicine to assess safety and efficacy in dog models, and trying to look at other tumors, like bladder cancer, associated with dogs.”
Alani added that the team hopes to use dogs as a model for drug development to get preliminary data for a New Drug Application with the FDA.
