New drug delivery system shows promise in life-threatening treatment

PORTLAND, Ore. — Researchers at Oregon State University College of Pharmacy have developed a drug delivery system that holds promise for greatly increasing the efficacy of drugs given to women with the life-threatening condition ectopic pregnancy, which occurs when a fertilized egg implants somewhere other than the lining of the uterus.

Olena Taratula of OSU College of Pharmacy, and Maureen Baldwin and Leslie Myatt of Oregon Health & Science University led a team that used a mouse model to show that the drug, methotrexate, terminates pregnancy at relatively low doses when administered via nanoparticles known as polymersomes.

Findings published in a journal Small.

Ectopic pregnancies do not survive and are the leading cause of maternal death in the first trimester. Methotrexate, usually abbreviated as MTX, fails at rates greater than 10% because it does not always accumulate properly at the implantation site – a problem addressed by polymersomes.

MTX ends ectopic pregnancies by causing embryonic cells to stop dividing, and even when it does, it comes with a host of potential negatives for the patient: nausea, vomiting, diarrhea, elevated liver enzymes, kidney damage, and lung disease. Lower doses, scientists say, would be a step in the right direction for reducing side effects as well as increasing efficacy.

Two percent of all pregnancies in the United States, and between 1% and 2% worldwide, are ectopic, the authors wrote. In the US alone that translates to about 100,000 ectopic pregnancies annually.

About 98% of ectopic implantations occur in the fallopian tube, putting the woman at risk for bleeding and death.

“Developing drugs capable of targeting specific locations in the body remains one of biomedical’s greatest challenges,” said Taratula. “Most of the drugs prescribed today, including MTX, do not only work on certain tissues or cells. When drugs affect healthy cells, it can drastically reduce a patient’s quality of life – think of the severe effects of chemotherapy like hair loss, loss of intestinal lining, ulcer formation, nausea, etc.”

Taratula, Baldwin and other researchers at OHSU and the Oregon State College of Pharmacy are looking to mitigate the drawbacks of MTX by exploring whether encapsulating it in a special type of nanoparticle, a polymersome, will allow the drug to target only embryonic cells.

Polymersomes are hollow spheres that are synthetic versions of liposomes, lipid-based sacs found in all living cells. Scientists developed polymersomes that would respond to high concentrations of a substance known as glutathione in placental cells; loading MTX into the polymersome prevents it from working until glutathione triggers its release.

“A single dose of MTX delivered by the polymersome induced termination of pregnancy in mice, whereas the same dose of MTX alone did not,” said Taratula. “To achieve the same therapeutic efficacy with MTX alone, we had to increase the dose sixfold. What is also very promising is that, once pregnancies are terminated with MTX-containing polymersomes, mice successfully conceive and give birth to healthy offspring.”

Collaborators in this study included Babak Mamnoon, Abraham Moses, Constanze Raitmayr and Dari Taratula from OSU’s School of Pharmacy and Terry Morgan from OHSU. The College of Pharmacy, OHSU School of Medicine, and the National Institutes of Health provided funding.

Taratula is also continuing its research to use other types of nanoparticles to diagnose and terminate ectopic pregnancies. A year ago he led a collaboration developing light-sensitive nanoparticles for that purpose, and he just received a $3 million grant from the National Institutes of Health to develop a magnetic nanoparticle platform.

Magnetic nanoparticles are potentially more effective than light-sensitive ones, he says, because magnetic fields have deeper tissue penetration than light.