Roughly one person in ten with a uterus suffers from endometriosis, a painful gynecological condition that is also a leading cause of infertility during childbearing years. There is no cure for the disease, although surgery can help remove the painful uterine lesions associated with it.
But now, scientists at Oregon State University and the Oregon Health and Science University are using microscopic nanoparticles to locate and treat endometriosis in an animal model. The procedure could one day lead to a non-surgical treatment for a condition that can start in adolescence and go undiagnosed for years. With us now to talk about their research is Oleh Taratula, a professor at the Oregon State University College of Pharmacy, and Ov Slayden, a reproductive biologist and a professor at Oregon Health & Science University.
The following transcript was created by a computer and edited by a volunteer.
Dave Miller: This is Think Out Loud on OPB. I’m Dave Miller. We start today with a novel approach to endometriosis. The disease affects nearly 200 million people around the world. It happens when the tissue that lines the uterus grows outside the uterus; it can cause severe pain and infertility. Despite its prevalence, doctors have been limited in their ability to diagnose and treat endometriosis. But researchers at OSU and OHSU recently announced promising new findings. They had success using nanotechnology to identify and remove endometrial lesions in mice. They published their work in the journal Small. I’m joined now by two of the researchers behind this. Oleh Taratula is a professor at the OSU College of Pharmacy. Ov Slayden is a reproductive biologist at OHSU. Welcome to both of you.
Ov Slayden: Thank you for having us.
Oleh Taratula: Good afternoon everyone, thank you for having us.
Miller: Good afternoon to you. Ov Slayden first. I gave a really short version of this disease. Can you give us a better understanding? What is endometriosis?
Slayden: Yes. Just to make sure we’re all on the same page, the inner lining of the uterus is called the endometrium. It’s the lining that bleeds each menstrual period and also supports the fetus during pregnancy. Endometriosis is a disorder where small fragments of endometrium-like tissue occur outside, most often in the abdominal cavity. These tissues undergo cyclic bleeding just like the endometrium does inside the uterus except that, unlike normal menstruation, this bleeding and regrowth causes inflammation and chronic pain and other problems associated with fertility. It’s an incredibly common disorder compared to malignancies, for instance. One in ten women are expected to have endometriosis during their lifetime. If you look at women who have pelvic pain or infertility, the rate is as high as 50 percent. A bigger problem is that a large number of cases of endometriosis are dismissed. Women are basically told that they’re supposed to have menstrual cramps, so they’re supposed to have abdominal pain. So it remains undiagnosed for many years.
Miller: What are the challenges in actually diagnosing it?
Slayden: Because the tissue is so very similar to the endometrium inside the uterus, serological tests are not very successful…
Miller: Meaning a blood test?
Slayden: A blood test is not very successful. The newest attempts have involved multiple factors where they generate a fingerprint type of an idea, but the misdiagnosis is very high.
Miller: What about treatments?
Slayden: The standard diagnosis is a laparoscopic surgery, where they identify the lesions. That also is sort of the gold standard for treatment is to surgically remove the lesions, usually through laser ablation. Medical treatments are available that manage the pain associated with the disorder. The problem with the medical treatments is that there are no medical treatments available that will permit fertility. If a woman is desiring pregnancy, then the only realistic recourse is surgery, and the recurrence after surgery is about 30%. So women are sort of set on a timetable where they have the surgery and then they hope they can get pregnant quickly while the surgery is still having an effect.
Miller: Oleh Taratula, these are all the reasons, in terms of diagnosis and treatment, why researchers would want to find better options for people suffering from endometriosis. Why did you think that nanotechnology might actually be that way?
Taratula: Well, I worked in that field for over 20 years; I used different types of nanomaterials, mostly for cancer treatment and imaging. Several years ago I was invited to give a seminar at the Oregon National Primate Center and Dr. Slayden attended my seminar. After that we started to discuss a potential application of nanomedicine for endometriosis treatment. We realized that the nanoparticles which we use for cancer treatment can be potentially used for the endometriosis treatment. Actually this is where we started.
Miller: Can you give us a sense for how small these particles are?
Taratula: Yes, sir. We are talking about 50 nanometers. Just to give you a better perception, if you imagine a speck of dust, the nanoparticles are about 1000 times smaller than the speck of dust.
Miller: What are they made of?
Taratula: In general we can make nanoparticles by using different types of materials, but for this specific application we use iron oxide. So we can say that these nanoparticles are iron based.
Miller: How do you get these nanoparticles to attach directly to the endometrial lesions?
Taratula: Actually this is the place where we learned something from cancer. Usually what happens in cancer – and apparently endometriotic lesions behave in a similar manner – in order to grow, they develop many blood vessels, and those blood vessels actually have small pores. If you inject those nanoparticles intravenously and they circulate in the bloodstream, they can escape when they reach those lesions, they can escape from those small pores in the blood vessels. Also we’ve done one more thing: we equip those nanoparticles with special molecules – we call them targeting peptides. When those peptides come to the endometriosis cells, they can attach to the surface of those cells. As a result they specifically get inside of those cells.
Miller: You can create these targeted proteins that are good enough that they’re only going to attach to these lesions as opposed to, say, a healthy endometrial lining in the uterus or any other parts of the body?
Taratula: That’s correct. Usually endometriosis cells express different receptors on the surface. If we know that receptor, we can find the targeting molecule, for example a peptide, which will bind specifically to those receptors on the endometriosis cells.
Miller: That’s how you were able to create nanoparticles that would go to these lesions. But, Ov Slayden, one of the things I learned in prepping for this show is that, in the animal model that the two of you were working with, mice, they don’t actually have a menstrual cycle, which I guess it means that mice don’t get endometriosis. How do you give a mouse endometriosis to test this nanomedicine?
Slayden: What we do is we engraft either nonhuman primate or human endometrial tissue into the mice, giving them the displaced tissue. Then we treat the mice with steroid hormones that replicate the menstrual cycle of women so that we force a menstrual cycle on the mice so that those tissues will grow and create lesions that are very similar, if not identical, to endometriosis in women.
Miller: When you did that and then you introduced this nanomedicine in these mice, what happened next?
Taratula: In this case, we used these special nanoparticles based on iron oxide and those nanoparticles are magnetic. Because of their small size and their properties, those nanoparticles can generate heat if you expose them to the alternating magnetic field. In our case, when we inject these nanoparticles intravenously into the mice and after those nanoparticles accumulate in the lesions, what we can do [is] we can use that magnetic field, external magnetic field, and we remotely can heat those lesions and destroy them.
Miller: How hot do they get?
Taratula: For this purpose we developed these special nanoparticles with high heating efficiency, and we can raise the temperature in those lesions up to 120° Fahrenheit.
Miller: And 120° Fahrenheit, which to me doesn’t sound that hot, but that’s hot enough to actually destroy the lesions?
Taratula: That’s correct. Yes. This temperature can kill those cells in the lesions.
Slayden: Thermal therapy is a very common therapy used in gynecology for other treatments. For instance, heavy menstrual bleeding. There are other devices that will use microwaves or hot water to destroy tissues, very similar to the technique that we’re proposing for endometriosis lesions. The big advancement is the ability to target the endometriotic lesion with the magnetic particles.
Miller: You were talking earlier, Ov Slayden, about the challenge in terms of diagnosis. It seems like one of the really novel aspects of this potential new therapeutic is that it’s both a diagnostic tool and a treatment tool. What could you do in terms of imaging if all this were to work out with these nanoparticles?
Slayden: These particles are very good contrast agents for MRI. Currently the use of MRI for our diagnosing endometriosis is challenging because it can see very large lesions, but it cannot see very small lesions. It would give us the opportunity to scale down MRI so that we can see the lesions that are nearly microscopic. More importantly, I think, is that we don’t really understand why endometriosis recurs after surgery. So this technique might be an add-on to a surgical procedure where it’s used to eliminate those very small lesions that are difficult to image when you’re trying to do a surgery.
Miller: Oleh Taratula, I’ve read that in the past these kinds of nanoparticles couldn’t get hot enough to burn off a lesion. What was your breakthrough? How were you and your team able to change that?
Taratula: That’s correct. The conventional nanoparticles which were previously used for magnetic hyperthermia have relatively low heating efficiency. So, in order to generate heat in the tumors, those conventional nanoparticles have to be injected directly into the tumor. Our idea was just to develop nanoparticles which can be injected systemically and go to the lesions. In order to develop these nanoparticles with high heating efficiency, we started to use all our knowledge in material science. Specifically we started to change different parameters of those nanoparticles. I can just give you an idea; one of the ways we did [that] was we changed the shape. Previously used nanoparticles had a spherical shape, and we prepared the nanoparticles which has the shape as a hexagon. Obviously the change in the shape increased the magnetic property, and as a result we were able to increase their heating efficiency.
Miller: How much do we know, Oleh Taratula, about the potential toxicity of these nanoparticles?
Taratula: Usually in our research, this is the first step, to check the toxicity of any material which we use for treatment. What we’ve done in our research, before we did this therapy, we injected mice with these nanoparticles, and we followed them. We checked on their behavior, food consumption and especially their body weight. Usually the first sign, when something is toxic to animals, they start to lose their body weight. We didn’t see any changes after injecting those nanoparticles. Also, at the end of the treatment, we collected their blood and we sent it to the lab and it was analyzed for specific markers. Usually if there is a toxicity to the spleen, to kidneys, liver; some molecule they raise in the bloodstream, and we can notice that. So again, we checked the toxicity of those nanoparticles, and those nanoparticles are pretty safe at the injected dose which we used in our studies.
Miller: How long do they stay inside a mouse’s body?
Taratula: I believe they can stay for several days, probably like up to 10 days. But we need to do more studies just to completely understand that.
Miller: But is your assumption that after that they would somehow be excreted?
Taratula: Yeah, that’s correct. The assumption is that those nanoparticles will degrade in the body and they will be excreted through the liver and kidney.
Miller: Ov Slayden, what’s next in terms of experiments?
Slayden: We’ve been very successful in treating lesions that were engrafted into these mice. I think our next step will be to try and get the particles to accumulate in lesions in a non-human primate. In order to obtain FDA approval to move to clinical studies, we need to show that they are not toxic, and we need to show that they are effective in at least two animal models. We’ve been successful in doing this in the mouse. So our next step will be to show that these particles accumulate in non-human primates that have naturally occurring endometriosis.
Miller: So how far down the line, potentially, are human clinical trials?
Slayden: I would expect that, if we are successful in showing that the particles accumulate in non-human primates next year, then we would the following year be preparing an application to the FDA.
Miller: So, Oleh Taratula, that’s just a couple of years away. But you noted that there are already examples of nanomedicines that are being used. What are they being used for right now?
Taratula: I think the best example of nanomedicine these days is the COVID vaccine prepared by Moderna and Pfizer. That vaccine is nothing else [than] lipid nanoparticles loaded with genetic material called messenger RNA. Those lipid nanoparticles, after the injections, they can deliver that messenger RNA to the cells. And other cells, they can use that messenger RNA as a template and reduce the spike protein. This is how vaccine works. Also those different types of nanoparticles are widely used for cancer treatment and some other diseases. One of the reasons those nanoparticles are so useful in medicine overall [is] because you can load them with different types of drugs, and nanoparticles can help deliver more drugs to the disease site.
Miller: Ov Slayden, what do you see as the further frontier of nanotechnology when it comes to medicine? What’s on the horizon?
Slayden: I think the next big horizon is the development of magnets, where we can control the depth at which we can penetrate tissues and have the effect on the nanoparticles to better fine tune how exactly we can excise these lesions and, for that matter, any other undesirable tissue type.
Miller: Ov Slayden and Oleh Taratula, thanks very much for joining us.
Guests: Thank you for having us.
Miller: Ov Slayden is a reproductive biologist at OHSU. Oleh Taratula is a professor at OSU’s College of Pharmacy.
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