Researcher Highlights
Targeting better outcomes for mothers and babies

A leader in the field of reproductive medicine, Dr Jonathan Paul is internationally recognised for his work on targeting therapeutic nanoparticles to the muscle cells of the uterus.

The Delivery Suite

Dr Jonathan Paul is a Senior Research Fellow within a multidisciplinary team of researchers at the University of Newcastle’s Mothers and Babies Research Program (MBRP). Based within the Hunter Medical Research Institute (HMRI), MBRP researchers work to determine the cause, and most effective therapeutic approach, to maternal, fetal, and neonatal health problems in humans.

As Leader of the Myometrial Research Group and the Reproductive Nanomedicine Program, Jonathan is applying his expertise to a new mode of medication delivery to the uterus, which has the potential to radically decrease risks related to childbirth.

Jonathan’s revolutionary drug delivery vector has the capacity to target therapeutics specifically to the muscle cells of the pregnant uterus, which improves drug effectiveness while simultaneously improving patient safety. The revolutionary approach opens up new avenues for therapeutic intervention during pregnancy, potentially resulting in: halting preterm labour, inducing or accelerating non-productive labour, or stemming postpartum bleeding.

The unique system has garnered Jonathan much attention due to the potential to save countless lives before, during and after childbirth. In early 2015, Jonathan was awarded the President’s New Investigator Award by The Society for Reproductive Investigation at their 62^nd Annual Meeting in San Francisco.

The Cell Express

Jonathan completed his PhD as a member of the Reproductive Science Group at the University of Newcastle, focusing on proteins expressed on the surface of ova and their relevance to sperm-ova interaction.

Jonathan then joined the Mothers and Babies team to undertake analyses of the gene expression and protein changes that occur during the transition of uterine muscle cells from a non-contractile to a contractile state. His skills in the lab have secured his involvement in many projects within the program.

The uterus is one of the organs in the body that is made of smooth muscle. Currently, medications administered to stimulate or relax the uterus have been designed for use in other areas of the body. As such, they can have off-target effects, limiting both the range of drugs that can be administered safely and the effectiveness of those chosen drugs.

Jonathan’s new system targets a particular protein, ensuring the medication is directed specifically to the uterus.

Nanoparticles on Target

Targeted lipid-based nanoparticles (tiny bubbles made from the same material as a cell membrane) deliver the medication by seeking out specific proteins. Jonathan explains:

“Our cells are surrounded by a membrane made of lipids. We use similar lipids to make tiny (nano-scale) spheres that encapsulate drugs and other therapies inside that sphere, then we target that sphere to the uterus.”

“What we have done is identified a particular protein that is expressed in high abundance on uterine muscle cells during pregnancy.  We’ve then targeted the nanoparticles to that protein.”

This targeted delivery system has the following benefits: it increases the effectiveness of existing medication; and offers the possibility of utilising drugs previously considered unsafe due to effects on other organs and tissues.

Working in collaboration with the MBRP Director, Distinguished Laureate Professor Roger Smith, Jonathan has adapted uterine-targeted nanomedicines for the delivery of nucleic acids, which are a new class of therapeutics with almost limitless potential.

Addressing Unmet Needs

Complications related to childbirth create considerable short- and long-term strains on mother and baby, as well as the health care system. There are several stages of pregnancy and labour that present a danger, especially in less developed countries.

Preterm birth is the worldwide leading cause of neonatal morbidity and mortality, accounting for ~75% of perinatal deaths and >50% of long-term infant disease. Prematurity affects ~15 million pregnancies annually, leading to an estimated 1 million deaths per year. Babies who survive being born preterm are at increased risk of short- and long-term morbidities. Short-term morbidities include breathing disorders, brain bleeding, bowel tissue death and heart defects, while long-term morbidities include cerebral palsy (responsible for >50% of cases), mental retardation, diabetes, cardiovascular, renal and eye disease, asthma, cancer, depression, autism, anxiety, and more.

If a pregnancy approaches 42 weeks a caesarean section will be performed to counter the increased risk of intrauterine death. This resource-intensive procedure may discourage the mother from giving birth naturally in future deliveries. In less developed countries, a c-section may not be an option.

If the uterus fails to contract following delivery, post-partum haemorrhage may result. In less developed countries, where there is limited or no access to medicines such as oxytocin (which promotes contractions and the restriction of blood vessels), excessive blood loss can result in death.

Using the targeted drug delivery system, nanoparticles could be filled with medication aimed at maximising uterine contraction, thus restricting the body’s ability to lose blood. When a pregnancy has continued past 42 weeks, the nanoparticles could be loaded with medication aimed at stimulating or increasing contractility. If preterm labour has begun, the nanoparticles would be loaded with medication to halt contractions.

Progressing to Term

Jonathan has achieved great success developing the delivery system using uterine tissue biopsied from pregnant giving birth via caesarean section, as well as in preclinical (mouse) models of preterm birth.

A major cause of preterm labour in women is inflammation. Accordingly, inflammation is being simulated to test how effectively the targeted delivery system can work to halt contractions when preterm labour occurs due to inflammation.

Progesterone withdrawal is another leading cause of preterm labour, as it is essential to the maintenance of a pregnancy. Further research will be undertaken using a mouse model to measure the efficacy of the targeted delivery system in the event of withdrawal of progesterone.

“Initially, we commenced by delivering tocolytics, which are drugs that block the contractile machinery of the uterine smooth muscle cells. This works great, but now we are also delivering nucleic acid therapies that are designed to reprogram the smooth muscle cells to a relaxed state,” says Jonathan.

Assuming the success of the mouse model trials, the next step would be to test the efficacy of the system using a primate model. Jonathan hopes to eventually work in collaboration with the University of Washington’s Infant Primate Research Laboratory within their Centre on Human Development and Disability.

Small but Versatile

It is already clear that the drug delivery vector could be adapted to target cells in other areas of the body.

“You could target any number of tissues, provided each tissue has a specific marker. In this case, we have used it to target the uterus, but it certainly has a much broader scope than that,” Jonathan explains.

“If you have a cancer, for instance, that expresses a particular protein in high abundance relative to any other tissues or organs, then you could target drug-loaded nanoparticles to the cancer cells.”

Whether the targeted nanoparticles are stopping preterm labour or attacking cancer cells, this new system has the potential to save countless lives and revolutionise the way therapeutics are delivered.