Targeting better outcomes for mothers and babies
An emerging leader in the field of reproductive medicine, Dr Jonathan Paul has been internationally recognised for his work on targeting therapeutic nanoparticles to the muscle cells of the uterus.
THE DELIVERY SUITE
Dr Jonathan Paul is a member of a team of multidisciplinary researchers at the University of Newcastle's Mothers and Babies Research Centre, who work to determine the cause, and most effective therapeutic approach, to maternal, foetal and neonatal health problems in humans.
The post-doctoral scientist 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 is part of a team with a revolutionary drug delivery vector that has the capacity to increase the effectiveness of targeted therapeutics, potentially resulting in: halting pre-term 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 Presidential New Investigators Award by the Society for Reproductive Investigation at their 62nd 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 analysis of the protein changes that occur during the transition of uterine cells from quiescence to contractility. His skill in the lab has secured his involvement in many projects within the Centre.
Jonathan's primary research focus is the development of a targeted drug delivery system for the uterus, which is a successful project collaboration between the Mothers and Babies Research Centre Director, Professor Roger Smith, and Dr Susan Hua, head of the Therapeutic Targeting Research Group in the Discipline of Pharmacy. The collaboration draws upon the valuable skills of Susan in manufacturing the specialised targeted liposomes, and couples her expertise with Jonathan and Roger's research interests in reproductive medicine. Jonathan then uses his expertise in the lab to apply the drug delivery system to both human and animal models.
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 affects, 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.
A SPOONFUL OF NANOPARTICLES
Liposomes (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. We take a small section of artificial membrane, make a tiny sphere, encapsulate the drug inside that sphere, then we target that sphere to the uterus."
"What we have done is to look for a particular protein that is expressed in high abundance only on uterine cells. We've then targeted the liposomes 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 affects on other organs and tissues.
RIGHT ON TARGET
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.
Pre-term birth is the major cause of neo-natal morbidity and mortality, and is responsible for more than half the cases of cerebral palsy. Pre-term infants who survive can be left with on-going complications such as asthma, eye or hearing problems, and increased long-term risk of developing several conditions such as diabetes and heart disease.
If a pregnancy approaches 42 weeks a caesarian section will be performed to counter the increased risk of intra-uterine 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 hemorrhage 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, liposomes 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 liposomes could be loaded with medication aimed at stimulating or increasing contractility. If pre-term labour has begun, the liposomes would be loaded with medication to halt contractions.
PROGRESSING TO TERM
Jonathan has achieved great success trialing the delivery system on uterine tissue harvested during myometrium biopsies. Further research using a mouse model is underway.
A major cause of pre-term labour in women is inflammation arising from bacterial infection. Accordingly, infection is being simulated to test how effectively the targeted delivery system can work to halt contractions when pre-term labour occurs due to bacterial infection.
Progesterone withdrawal is another leading cause of pre-term labour, as it is essential to the maintenance of a pregnancy. Further research will be undertaken through a mouse model, to measure the efficacy of the targeted delivery system in the event of withdrawal of progesterone.
"The therapeutics we are looking at using target the raw mechanism of the contraction," says Jonathan.
"Regardless of what signaling events are occurring upstream, if we can disable that pathway and eliminate the ability of the cell to undergo the fundamentals of contractility, we should be able to block pre-term labour."
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.
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 it has a specific marker. In this case, Roger, Susan and I have used it to target the uterus, but it certainly has a much bigger 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 liposomes to those cancer cells."
Another area of research that is currently moving forward using the targeted delivery system is a project to fight ovarian cancer.
"I'm working with another post-doc, Dr Jorge Tolosa, with input from Roger Smith on this project. Susan Hua, who manufactures the liposomes, also has her own applications for targeted liposomes that are specific for her field of interest," explains Jonathan.
Completed trials suggest that the drug delivery vector is an acutely superior system when it comes to concentrating medication in the goal area.
Whether the targeted liposomes are stopping pre-term labour or attacking uterine cancer cells, this new system has the potential to save countless lives, and revolutionise the way therapeutics are delivered.