Using nanoparticles as “Trojan horses”, scientists have designed and lab-tested a way to deliver an arsenic-based chemo drug that ferociously attacks cancer, but is gentler on the ovaries. They hope the new method will help to protect the fertility of women undergoing cancer treatment.
The team also developed a rapid way to test existing and new chemo drugs for their effect on ovarian function, so doctors and their female patients can make treatment decisions that minimize damage to ovaries and thus increase the chance of having a future family.
The new nanoparticle chemo drug they designed is the first cancer drug to be tested while in development for its effect on fertility using the new rapid toxicity test.
Advances in cancer therapy means more patients are surviving, but many female patients often face a temporary or permanent loss of fertility after undergoing traditional chemotherapy.
Co-principal study investigator Teresa Woodruff, chief of fertility preservation at Northwestern University Feinberg School of Medicine in Chicago, says in a statement:
“Our overall goal is to create smart drugs that kill the cancer but don’t cause sterility in young women.”
Woodruff and colleagues report their work on the new drug and the rapid test in the 20 March issue of PLOS ONE.
Currently, the testing of cancer drugs for their effect on fertility is time-consuming and expensive.
Woodruff and the team’s other co-principal investigator Thomas O’Halloran, director of the Chemistry of Life Processes Institute at Northwestern, are husband and wife. His expertise lies in cancer drug development, hers in fertility preservation, and their natural interest in each other’s work sparked the idea of a collaborative study.
To deliver the cancer drug arsenic trioxide, the researchers packed it in a “nanobin”. The nanobin contains nano-sized crystals of arsenic densely packed in a capsule made of fat.
So the “Trojan horse” appears to be a normal bubble of fat, a liposome, but in reality contains half a million molecules of deadly anti-cancer drug.
O’Halloran describes the challenge they faced in designing the nanobin:
“You have to wallop the tumor with a significant dose of arsenic but at the same time prevent exposure to normal tissue from the drug.”
Liposomes are hundreds of times smaller than the average human cell and slip easily through holes in the leaky blood vessels that tumors grow to feed them.
Another feature the researchers quickly turned to their advantage, is that tumor tissue is slightly more acidic than healthy tissue, which helps the nanobin release its deadly cargo in the right place.
Using the new toxicity test, the team was able to show that the nanobin approach had the desired effect on tumor cells but prevented damage to ovarian tissue, follicles or eggs.
They note that the reduced toxicity is based on the fact that “encapsulated arsenic is not bioactive until it is released, which occurs over a 48 h period”.
When tested against lymphoma, the nanobin form of the cancer drug was more potent than the drug in its traditional free form.
O’Halloran says the “drug was designed to maximize its effectiveness but reduce fertotoxicity.”
“Many cancer drugs cause sterilization, that’s why the reproductive tract is really important to focus on in the new stages of drug design. Other body systems get better when people stop taking the drug, but fertility you can’t recover,” he explains.
One of the reasons the researchers chose to test the new drug on lymphoma, is because, as they note, “Hodgkin’s lymphoma and Burkitt’s lymphoma are highly prevalent in patients of reproductive age”.
Arsenic trioxide is already approved for treating leukemia and other blood cancers in humans.
O’Halloran thinks in nanobin form it could also be used to treat solid tumors, including breast cancer. He has already published research showing nanobins can reduce tumor growth in triple-negative breast cancer, which often responds poorly to traditional chemo and has a poor survival rate.
Meanwhile, in the other half of the study, the team developed an in vitro follicle culture that can quickly test for the early effects of chemo drugs on fertility.
With the new test they compared the effects of the nanobin and of the free form of the arsenic drug used in the cell cultures and mice experiments, and showed the nanobin form was much less toxic to female fertility.
Woodruff explains that the test can easily be adapted for any cancer drug under development to “get an early peek under the tent”.
Results of such a test will help cancer doctors evaluate treatment options for female patients who wish to preserve their chances of having a future family.
“They may prescribe less toxic drug regimens or refer them to specialists in fertility preservation,” explains Woodruff.
Speaking of the nanobin form of the arsenic drug, she adds:
“As this new drug goes forward in development, we can say this is a good drug for young female cancer patients who are concerned about fertility.”
Funds from the National Institute of Child Health and Development of the National Institutes of Health, the National Cancer Institute of the National Institutes of Health, and the Department of Defense helped finance the study.
In a recent issue of Fertility & Sterility, researchers from the National Cancer Institute report a study on Israeli women receiving fertility treatments that finds IVF (in vitro fertilization) does not appear to raise the risk of breast and other female cancers.
Written by Catharine Paddock PhD