Preventing preterm births with targeted drug delivery  

Using groundbreaking nanomaterials, a new targeted drug therapy has been developed to prevent preterm labour.

Pregnancy and the approaching birth of a baby are life-changing times of transition which can bring both joy and stress. When a pregnancy continues to full term (around 40 weeks) and mother and baby are both healthy, new mums and their support people often express great relief as well as delight. Yet if labour begins early (before 37 weeks), there can be distress and potential health challenges and complications. More than 26,000 Australian babies are born premature every year. Enter Dr Jonathan Paul, a University of Newcastle Senior Research Fellow on a mission to ensure more pregnancies reach full term. Paul’s work has been supported by a NSW Health Office for Health and Medical Research Early Mid-Career grant which was awarded in 2021.

Pausing contractions that cause preterm labour

Working within the Hunter Medical Research Institute as Co-Director of the Mothers and Babies Research Program (MBRP), Paul has undertaken detailed analyses of gene expression and protein changes that occur when a woman goes into labour. “During this transition, the uterus shifts from a relaxed, non-contractile state to a contractile state,” Paul explains. “This transition is associated with increased expression, or ‘switching on’, of genes that promote uterine contractions, and reduced expression, when the genes ‘switch off’, and promote relaxation of the uterus. If this process is dysregulated during pregnancy, the smooth muscle cells of the uterus can be activated too early, leading to preterm birth.”  

Paul credits his Early-Mid Career grant with assisting him to make many advances in this work and helping him to secure an NHMRC Investigator Grant. Since 2013, Paul has been part of the team developing a novel drug delivery approach to prevent preterm labour. In recognition of his groundbreaking research, he was awarded the Presidential New Investigator Award at the Annual Meeting of the Society of Reproductive Investigation in San Francisco. 

Understanding the uterus during pregnancy

Smooth muscle is found in different human organs, such as the stomach, bladder, and uterus. Hormones and other receptors influence its contractions and in the uterus, those contractions can trigger labour. “If this occurs too early, contraction-blocking drugs are usually administered to the pregnant woman to help relax the uterus,” Paul explains. “But these drugs can be taken up by other organs and cross the placenta, causing unwanted side effects for both mother and baby.” This is why Paul and his team developed a more targeted delivery system to increase the proportion of the drug that reaches the pregnant uterus, where it’s needed.” 
 
A novel nanoparticle delivery system

A major challenge in Paul’s work has been developing the best method to ensure these targeted drugs go directly to the uterus. Producing a novel nanoparticle delivery system solved the problem. In the past decade, the therapeutic applications of nanomaterials in medicine have created great interest, especially in the area of pharmacology. Lipid-based nano-materials (LNPs) are on the radar because they show particular promise for enhancing drug delivery in the human body.  

“Each cell within our body has a membrane made of lipids, which are a type of fat molecule,” Paul explains. “The LNPs we use are similar to this cell membrane. They are tiny spheres approximately 100 nanometres in diameter and made up of synthetically manufactured lipids and cholesterol. These tiny spheres encapsulate the drug therapy we are administering to the pregnant woman.” The spheres then circulate around the body via the bloodstream. As they pass through the pregnant uterus, they exit the bloodstream and bind to a particular protein. “We identified this protein as being expressed in high abundance on the surface of smooth muscle cells in the uterus during pregnancy,” Paul explains.  

Targeting the drug cargo to the uterus

In short, this novel drug delivery system uses nanomedicines to act like a truck to deliver a cargo of medicine directly to targeted cells and to a protein in the uterus. “That drug cargo contains nucleic acids which are a new class of therapeutics,” Paul explains. “They have amazing future potential as their effects are precise, efficient and stable. Nucleic acid therapeutics change the expression of genes. So we are using them to switch off genes that encourage labour contractions and switch on genes that discourage labour, by relaxing the uterus.”  
 
Paul has already experienced great success trialling this approach using pregnant human uterine cell lines, and tissue biopsied from the uterus of pregnant women who have given birth via caesarean section. Paul has also used computational models to investigate and better understand how these lipid-based nanomaterials react with the drugs they have on board. His pre-clinical work in this area has helped to predict the effectiveness and impacts of this new drug delivery system. 
 
Causes and complications of preterm labour

When a baby is born prematurely its arrival may be late preterm (34-36 weeks), moderately preterm (24-32 weeks), very preterm (28-32 weeks) or extremely preterm (born before 28 weeks of pregnancy). Though not all preterm babies experience health issues, the earlier the birth, the higher the level of potential complications for the newborn. These may range from impacts on heart function, hearing, vision and breathing, to impacts such as developmental delays and feeding problems. The greater the complications, the more pressures and stresses for the parents/carers.  

Globally, preterm birth is the biggest cause of death and disability in children under five. Maternal risk factors can include medical conditions, inflammation, infections and high blood pressure as well as carrying multiple babies, such as twins, having a prior preterm birth and a short time span of six months or less between pregnancies. Yet despite ongoing advances to ensure safer pregnancy and labour, the proportion of pre-term births, has dropped only slightly from 8.3% in 2011 to 8.2% in 2021. “This is why we have been working on our new drug delivery system which we hope will save thousands of lives by helping more mothers to carry their baby to full term, setting the baby on a trajectory for a healthier life”. 
 
Other applications 

In the future this drug delivery approach could be used to administer medication to increase contractions to bring on labour when a pregnancy continues past 42 weeks. “It could also be used to deliver contraction-blocking therapies to alleviate period pain or menstrual cramps,” says Paul. Beyond pregnancy and labour, this drug delivery method may also be adapted to target cells in other areas of the body for other health conditions. “For example, if a particular form of cancer exhibits high-level expression of a certain protein on the surface of the cells, then this could give us an avenue to target cancer killing agents to those cells,” Paul points out.