Use of nanoparticles to deliver growth signals to the placenta

During pregnancy, the placenta transfers nutrients to the developing fetus while at the same time protecting it from harmful substances present in the mother. Very early on, rapid placental growth establishes a system for nutrient extraction that has the potential to meet the needs of the fetus later in pregnancy. At the same time, the protective barrier function of the placenta develops; this is achieved by interposing several cell layers between maternal and fetal circulations. These layers collaborate in a sophisticated way to detect growth signals present in maternal circulation and transmit them, together with the required nutrients, to the fetus, while at the same time making provision for the placenta itself to grow. Despite the affluence of developed countries, many fetuses fail to reach their normal growth potential. This has severe consequences: the smallest babies die, while those that survive have radically impaired health prospects both as children and adults.

There is convincing evidence that a high proportion of pregnancies with growth restriction are caused by placental growth abnormalities. However currently, there is no way to correct these defects. Drug companies shy away from developing drugs for use in pregnancy because they are fearful of harming unborn babies with their new products, and want to avoid expensive lawsuits. Instead, they invest in other areas of research, leaving doctors with few alternatives for treating pregnant women.

Nanoparticles are tiny synthetic beads - much smaller than cells in the body - which, in principle, could be injected into the mother's blood stream and directed to the placenta to deliver signals that cause it to grow. This mode of therapy should indirectly improve the growth - and hence health prospects - of the fetus, with the great advantage that the therapeutic particles would be retained within the placental barrier and so would be discarded at the end of pregnancy.

In work leading up to this proposal, we have developed methods for keeping placental tissue alive in the laboratory for a few days, and have shown that nanoparticles loaded with growth-stimulatory chemicals, can stimulate the resident cells to grow. However we now need to find a way to ensure that if the nanoparticles were injected, they'd be delivered to the placenta and not to other sites in the mother's body.

It has recently been discovered that every organ in the body has a unique combination of molecules on its surface. These proteins act like a "postcode" and can be used to "address" packages - for example, drugs - so that they are sent to the right place. Our preliminary work has identified the postcode for placenta and in this study we plan to address a package of nanoparticles carrying growth signals and then use ethically acceptable test tube methods to explore how the growth of the different types of cell within human placenta is affected. We will also investigate the molecular mechanisms involved in relaying growth signals between the different cells and will check that the package is retained by the placenta, and not passed to the fetus, by tracking what happens to the nanoparticles after they arrive. We know that other forms of nanoparticle can have adverse effects on cells, for example some cause DNA damage, so we will also investigate if our addressed packages have a similar effect and if necessary, develop ways to overcome these unwanted actions.

Development of a targeted drug delivery system will help women feel confident that any drugs they receive during pregnancy will not harm their unborn child. This project will define a framework within which nanoparticle therapies can be characterised and advanced towards clinical implementation.

Failure of placental growth causes impaired fetal growth which has effects on health in childhood and later life. We now seek funding to develop a novel approach to therapy in utero: the use of maternally administered nanoparticles to deliver a growth stimulus to the placenta. The placenta is an attractive target for nanoparticle-mediated therapies as it filters material in maternal circulation to prevent toxins from accessing fetal tissues. Enhanced placental growth would rescue defective fetal growth and particulate material would be confined to the placenta and discarded at birth.

Using an explant model of the early human placenta in which its barrier properties are maintained, we have shown that the growth factors (GF) IGF and TGF can stimulate placental cell proliferation. We also have data to suggest this stimulus can be delivered on a quantum dot (QD) but targeting GF-QD to the placenta and overcoming the adverse effects caused by some nanoparticles will be a pre-requisite for therapeutic exploitation. Here we plan to
1. (a) monitor the effect the effect of GF-QD on human placental trophoblast proliferation and differentiation in order to (b) generate formulations that retain GF activity once labelled with our recently identified placental "homing" peptides.
2. (a) track GF-QD (+/- homing peptides) through the placenta and identify key signalling mediators of altered trophoblast function; (b) investigate whether growth signals generated by trophoblast exposure to QD-GF are transduced to other cellular compartments within placenta.
3. (a) assess the potential for GF-QD to elicit damaging effects (DNA strand breaks and chromosomal abnormalities) and (b) explore ways of offsetting detrimental outcomes.

At the end of the project we will have developed an efficacious and safe strategy for manipulating placental growth and / or function that will form the basis for therapeutic intervention in pregnancy disorders characterised by placental abnormalities.

This project will reveal how the placenta senses stimuli - ligands for well established receptor systems that drive cellular growth - delivered in a novel way via nanoparticles labelled with placental homing peptides, and how it responds as an integrated system to promote fetal growth. The research offers a real possibility of improving human health by developing credible strategies for specifically delivering novel therapeutic interventions to the maternal / fetal interface in pregnancies complicated by abnormal fetal growth.

Recent research makes a powerful case that lifelong health is programmed in utero, so that, for example, risks of cardiovascular disease and diabetes, which have major impacts in ageing populations, are greatly increased in people who were growth restricted in utero, apparently because a 'stressed' metabolic programme is set in train. Prevention of fetal growth disorders would have a significant impact not only on individuals and their families but on society as a whole by relieving the financial burden associated with obstetric/neonatal care and the management of chronic disease. However currently, there are no appropriate interventions in the pipeline. Consequently we hope to begin a process of exploring ethically acceptable ways of specifically optimising growth in the human fetoplacental unit, whilst maintaining safety.

The ability to specifically target drugs to the materno-fetal interface will provide biologists with a means of manipulating placental or fetal development in vivo and aid the discovery of new therapeutic strategies to treat pregnancy complications. These outcomes will be of interest to clinicians and midwives, agencies within the Department of Health, and to the pharmaceutical industry. This research may also increase the number of drugs developed for use in pregnancy and labour by providing the pharmaceutical industry with a mechanism to safely direct drugs away from the fetus.

We believe the output from this project will be attractive to high impact journals. We will also convey our findings to the scientific and clinical communities by presenting at key national and international meetings.

The Universities of Manchester and Bristol have effective systems for early filing of patents on exploitable IP and the University of Manchester Intellectual Property (UMIP) and Bristol Research and Development Office have been established to support researchers in organizing and exploiting patentable research.

The Maternal and Fetal Health Research Centre hosts the UK's first placenta clinic which, in conjunction with the Manchester Academic Health Sciences Centre, will provide clinical maternal for testing novel treatments, and facilitate movement of our discoveries into new treatments.