Researchers at Oregon State University (OSU) have found a way to turn the tables on cancer cells in the oxygen-poor areas of solid tumors using a “prodrug” loaded into nanostructured platforms.
Carcinomas that affect the breast, lung, prostate and colon are among the solid-tumor cancers, as are malignancies in the lymphatic system, known as lymphomas, and the much less common sarcomas that arise in connective tissue.
The solid masses often contain hypoxic regions, where the concentration of oxygen in the tissue is low.
Hypoxic cancer cells grow slowly, making them less susceptible to the drugs prescribed to kill or damage them, and to standard chemotherapy and radiation treatment.
“One of the hallmarks of these solid tumors is their hypoxic regions,” said Adam Alani of the OSU College of Pharmacy and lead author of a study published in the Journal of Controlled Release. “One reason these cancers become very aggressive is the development of this hypoxia.”
The tumor model chosen by the researchers was lung cancer, which is known to have a very strong hypoxia association.
A prodrug is a pharmacologically inactive compound that the body metabolizes into an active drug, in the OSU case the cancer drug vinblastine-N-oxide provided by research partners at Cascade Prodrug Inc. of Eugene, Oregon.
The OSU researchers developed two different lipid-based platform formulations known as liposomes to carry the prodrug to the tumor's hypoxic regions.
There, the lack of oxygen triggers its metabolic conversion to vinblastine.
In both formulations, one with polyethylene glycol on its surface and the other without, the prodrug proved both safe and much more effective against non-small cell lung cancer than when it was delivered without a liposome.
And by itself, vinblastine-N-oxide had shown less than optimal efficacy in testing by Cascade Prodrug because of how fast the body clears it from the system, as it has a half-life of less than half an hour.
But the liposomes, both the “pegylated” one containing polyethylene glycol and the non-pegylated one, increased the half-life dramatically: to 9.5 and 5.5 hours, respectively.
The research began with laboratory cultures and progressed to safety and efficacy testing in animals.
“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.”
Without any liposome, the drug showed some tumor suppression, but the mice that had received the drug alone had to be euthanized after 70 days because of tumors that were no longer being controlled.
Mice that had received the drug with one of the liposomes were healthy and tumor-free for the nearly 100-day run of the experiment.
“The nano carriers performed much better than the prodrug itself,” Alani was quoted as saying in a news release. “We were able to literally cure the tumor.”