Liposomes containing a prodrug effectively exploited hypoxic areas of lung cancer tumors.
A new drug delivery method was observed to exploit the oxygen-depleted areas of tumors, which allows the cancer to become resistant to chemotherapy and radiation.
Carcinomas of the breast, lung, prostate, and colon, lymphomas, and sarcomas typically contain hypoxic areas, where oxygen in the tissue is low. These cancer cells are known to grow slowly, making them less susceptible to drug therapy.
In a new study published by the Journal of Controlled Release, the authors developed a new way to use a “prodrug” loaded into nanostructured delivery devices. A prodrug is an inactive compound that becomes active when it is metabolized. The authors used the cancer drug vinblastine to bypass hypoxic areas.
The scientists created 2 liposomes to encapsulate vinblastine-N-oxide and carry it to the hypoxic regions of the cancer. One of the liposomes has polyethylene glycol on its surface (pegylated) and the other does not (non-pegylated). Once at the targeted regions, the lack of oxygen triggers the conversion to the active drug, according to the study.
The authors discovered that both formulations were found to be safe and more effective in lung cancer than when the drug was delivered without a liposome.
“One of the hallmarks of these solid tumors is their hypoxic regions,” said lead study author Adam Alani, PhD. “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 one of the very well established tumors and there’s a very strong hypoxia associated with that — as well as, lung cancer is one of these cancers that in its advanced stages, it’s a terminal disease, and there’s a need for new treatments.”
Previous studies have shown that vinblastine-N-oxide is less effective alone due to its half-life of less than a half-hour.
“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,” Dr Alani said.
The pegylated and non-pegylated liposomes were observed to increase the half-life to 9.5 hours and 5.5 hours, respectively, which can drastically improve care.
“The nano carriers performed much better than the prodrug itself,” Dr Alani said. “We were able to literally cure the tumor.”
The novel method has been tested in laboratory cultures and has progressed to testing its efficacy and safety in animal models, according to the study.
“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,” Dr Alani said. “Then we determined how long the nano carriers could keep the drug in the blood compared to the drug without the nanostructures.”
Once optimal results were observed, the authors then explored the nanocarriers’ efficacy in mice with tumors grafted on them.
Without the liposomes, the drug treatment resulted in some tumor suppression, but the mice experienced disease progression and had to be euthanized after 70 days, according to the study. However, the mice who received the drug with the liposome were healthy and disease-free for nearly 100 days.
The authors plan to continue their studies in animal models with the hopes of an FDA approval down the line.
“The formulations clearly performed better than the unformulated drug as well as much better than Cisplatin, the standard-of-care drug for this research,” Dr Alani concluded.