Development of vascular homing peptides as a drug delivery system in pregnancy

Currently, there are no means of delivering drugs directly to the area of the body where they are most needed. For example, when we take a painkiller, the drug is circulated throughout the whole body, even though we may only want to treat a headache or a backache. This means that drugs are diluted and cause unwanted side effects. If we could develop a method for delivering drugs to precisely the areas where they were needed, we could reduce unwanted side effects and make drug treatments much more efficient. It has recently been discovered that every organ in the body expresses a unique combination of molecules on its surface, giving it a unique identity or molecular 'postcode' and making it distinct from any other place in the body. This means that if a vast number of small proteins, each made up of a different sequence, are injected into a host, some of them will bind to unique molecules in the heart, whereas others will bind to unique molecules in the liver or the lungs. I am interested in identifying proteins that bind to the womb and the placenta (afterbirth) so I can develop a drug delivery system for use in pregnancy. Proteins that only bind to the placenta or womb will become trapped there, making it possible to isolate them, study their structure and manufacture them. These proteins can then be used to make an 'envelope' into which drugs can be packaged. Because the envelope will bear the unique postcode of the placenta, the drugs will only be delivered to that location. I will identify unique proteins that bind to the placenta or womb in the laboratory of Professor Erkki Ruoslahti, at the Burnham Institute, CA, USA, a world expert in this area of research. I will carry out the remainder of my work in The Maternal and Fetal Health Research Group (MFHRG), University of Manchester, an internationally recognised centre of excellence for reproductive research. Initially, I will develop this strategy using pregnant mice, including some whose babies don't grow properly. My aim is to deliver drugs to the womb and placenta that will promote the growth of the baby mice, without the mother or baby experiencing any negative side effects. When this method of drug delivery has been proven to work in mice, I will adapt it for use in humans. Human placentas are readily available from the hospital in which I work, as are small pieces of womb, which are taken during routine hysterectomy operations. I will identify proteins that bind strongly to human placenta and womb tissue and use them to make new 'envelopes' for drug delivery. I will test the ability of this method to improve the growth and function of pieces of placenta or womb cultured in the laboratory. There are currently few drugs available for use in pregnancy because drug companies 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. 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, and will provide a means for drug companies to test their products more safely, by controlling exactly where they act. This research will also provide the background work necessary for the development of drug delivery systems that target every organ in the body.

The future in tailored healthcare is to direct systemically administered pharmaceuticals to their target organs. As the endothelial lining of blood vessels of each organ expresses a unique array of molecules, phage display will be used to identify 'homing peptides' that bind exclusively to particular vascular beds. In this system, a phage library engineered to express random peptides on their surface proteins is injected into a host animal. Non-specific peptide sequences are diluted within the host, whereas peptides that bind specifically to one site are enriched in that location. Peptides that bind exclusively to the placenta or the uterine spiral arteries of pregnant mice will be identified, as both locations express a unique complement of antigens, making the materno-fetal interface a good model system in which to develop targeted drug delivery strategies. Specific peptides will be enriched in rounds of selection, then incorporated into liposomes and used as molecular couriers to deliver insulin-like growth factor-I (IGF-I) or IGF-II exclusively to the placenta, or interferon-gamma or interleukin-15 (IL-15) to the spiral arteries. These molecules promote placental growth and vascular remodelling in the mouse, thus a successful drug delivery strategy will be reflected by enhanced fetal and placental development, in the absence of any maternal or fetal pathology. Once validated, this method will be used to manipulate pregnancy outcome in mouse models that exhibit impaired placental growth and reduced arterial remodelling. The affinity of the isolated peptides for human placenta and spiral arteries will also be assessed; high affinity peptides will be incorporated into liposomes and used to deliver IGFs to manipulate cell turnover in placental explants, or deliver interferon-gamma/interleukin-15 to excised spiral arteries to promote receptivity to remodelling. This will provide the basis for a targeted drug delivery system suitable for use in human pregnancy.

Development of a targeted drug delivery system will provide the mechanistic basis for delivery of drugs to defined vascular beds. This technology will advance current strategies of drug delivery and, as a consequence, will be of interest to scientists studying pharmacology, vascular biology and drug delivery, along with the R+D and pharmacokinetic arms of the pharmaceutical industry. In the longer term, this strategy could provide drug companies with a mechanism for testing new products more safely, by controlling their site of action and reducing unwanted side effects. The ability to specifically target drugs to the materno-fetal interface will provide biologists with a means of manipulating fetal or placental 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, and may increase the number of dugs developed for use in pregnancy and labour by providing the pharmaceutical industry with a mechanism to safely direct drugs away from the fetus. As suboptimal development in utero is linked to poor health in adult life, development of strategies that enhance fetal growth and placental efficiency will be a high priority in years to come. Furthermore, revolutionary changes to the ways in which drugs are administered will be of interest to the media and the general public. I will inform the scientific community of the data generated during my fellowship via presentations at key national and international conferences. I will communicate my work to the medical community by attending clinical conferences and more informal gatherings such as the regional M62 Obstetrics and Gynaecology meeting. I am required to give local seminars within St. Mary's Hospital, where our research group is located, allowing me to converse with clinicians, nurses and midwives. I will continue to participate in departmental open days to inform healthcare professionals and members of the public about my research and maintain my profile on the University's website, which I regularly update with key experimental findings and publications. As a leader of tutorials for the Maternal and Fetal Health MRes. course, I will keep the next generation of students informed about my work. Our research group is partially funded by Tommy's the Baby Charity, allowing me to interact with members of the fundraising and charity sectors. In return, Tommy's promotes our research to the public via their website, newsletters and information booklets, and through interactions with commercial companies. I regularly present my data at joint conferences with other Tommy's-funded research centres, which are attended by charity employees and freelance journalists, and participate in fundraising events which involves explaining my research to the lay community. I will ensure that the BBSRC press office and University of Manchester public relations office are informed of my key findings and will attend the BBSRC media course, along with university-led communication workshops to advance my training in public engagement. I am committed to furthering public understanding of science and I will be actively involved in seeking opportunities to present my research to the public, via as many channels as possible. To interact with the pharmaceutical industry and facilitate translation of this basic scientific research into an effective biotechnological application, the University of Manchester runs a system for the early filing of patents on exploitable findings, and houses a Research to Enterprise Centre that aids scientists with business plans and marketing strategies, and interfaces with the commercial sector. These resources will provide the support and guidance to effectively exploit my research. In addition, our research group has worked closely with Pfizer and Ardana Biosciences in the past, thus I will capitalize on these existing links when the time is right.