Placental Payloads
Tumor cells and phages inspire a new drug delivery method targeting the placenta
More than 10 percent of pregnant women develop serious complications such as preeclampsia (PE) and fetal growth restriction (FGR), both of which are caused by a poorly functioning placenta. Though a number of potential therapeutics have been identified that enhance placental growth and function in animal models, there are no drugs that can be used to treat PE or FGR. Instead, doctors have to induce early delivery, which puts the infant at increased risk of cerebral palsy in the short term and heart disease and diabetes later in life. Part of the problem is that pregnant women and developing fetuses are particularly vulnerable to drug side effects – making them a high-risk, low-return cohort for pharma companies.
To address this, an international group of researchers have developed a method to safely deliver drugs directly to the placenta (1). The inspiration for the research? Parallels with cancer biology, and a visit from a colleague. We spoke with Erkki Ruoslahti, co-author of the study, and Distinguished Professor at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, and the University of California, Santa Barbara, to find out more.
How did you become interested in this area?
From the outset, I was interested in tumor cells. My interest in the mechanisms of metastasis led me to hypothesize that the reason tumor cells metastasize into certain tissues is because they have a specific affinity for the blood vessels of that tissue. The corollary of this hypothesis was that the blood vessels of different tissues would have to be different at the molecular level. That is what we set out to study more than 20 years ago, and we are still working on it today, although we now focus on the vessels of diseased, rather than normal, tissues.
We realized that we could probe the vasculature of different tissues by injecting libraries of a billion or so peptides – expressed on a bacteriophage – into mice. We could then rescue the phage that had ended up in the tissue we were interested in. By repeating the process a few times, we could select for phages with a specific affinity for the target tissue – its blood vessels in particular.
The phage screening could also be used to probe disease-specific vascular changes – and we have identified a number of new tumor vessel markers in this manner (and used the peptides to deliver anti-cancer drugs). We have also targeted wounds, atherosclerotic plaques, inflammatory lesions and, recently, the placenta.
What inspired you to apply the technique to the placenta?
We had not considered using phage screening to target the placenta until Lynda Harris, Lecturer in Pharmaceutics at the University of Manchester, UK, paid us a visit and suggested it. Given the many similarities between the placenta and tumors – they both grow very fast and invade – it wasn’t a big step to think that our tumor-homing peptides could also home in on the placenta. In many ways, the placenta is like a malignant tumor under control. Lynda proposed doing a sabbatical in my laboratory to use our technology to target the placenta; and in our recent study, we showed that some of those peptides work very well in placental targeting (1).
What were the main findings?
We used targeted liposomes to deliver cargoes of carboxyfluorescein and insulin-like growth factor 2 to the mouse placenta; the latter significantly increased mean placental weight when administered to healthy animals and significantly improved fetal weight distribution in a well-characterized model of fetal growth restriction.
What are the challenges of delivering drugs to the placenta?
The placenta is readily accessible from circulation, so there is no problem in that regard. The challenge, however, is that you have to be very careful because the pregnant mother and the fetus are so vulnerable – thalidomide, and lately the Zika virus, are terrible illustrators of that. Only one drug for use during pregnancy has been licensed in the last 20 years.
What are the next steps?
We have, in no way, exhausted the potential of phage screening and peptide targeting in the pregnancy field. It may be possible to find peptides that are more effective and have a more restricted specificity than the tumor-homing peptides we have used so far. For example, targeting specific parts of the placenta may be possible – and I believe Lynda is currently working on that.
- A King et al., “Tumor-homing peptides as tools for targeted delivery of payloads to the placenta”, Science Advances, 2 (2016).
Over the course of my Biomedical Sciences degree it dawned on me that my goal of becoming a scientist didn’t quite mesh with my lack of affinity for lab work. Thinking on my decision to pursue biology rather than English at age 15 – despite an aptitude for the latter – I realized that science writing was a way to combine what I loved with what I was good at.
From there I set out to gather as much freelancing experience as I could, spending 2 years developing scientific content for International Innovation, before completing an MSc in Science Communication. After gaining invaluable experience in supporting the communications efforts of CERN and IN-PART, I joined Texere – where I am focused on producing consistently engaging, cutting-edge and innovative content for our specialist audiences around the world.
