It is said that brilliant minds think alike, and an apple falls not far from an apple tree. Zuzanna Opolska talks to professors Marek and Michał Godlewski about “nanoparticle madness”.
- Polish oncology is not in the best condition. Patients receive care too late and cancer mortality is increasing
- Professors Marek and Michał Godlewscy developed an innovative project related to the oral administration of nanoparticles
- Testing on laboratory animals and clinical trials were successful, the project received a number of diplomas, medals and awards
Necessity is said to be the mother of invention – in the case of the IFPAN and WULS-SGGW research project it was about arresting the number one killer of Poles: cancer …
Marek G .: It’s true – the statistics are shocking. According to research, every second Pole and every third Pole will develop cancer. Half of them will die. We can say that Polish oncology is dying – all by itself. This is largely due to the fact that, in most cases, patients reach their doctors too late. Therefore, great emphasis should be placed on early diagnosis. This is the biggest challenge that will allow us to lower cancer mortality without changing the way we treat it.
Let’s go back in time – when did work on early detection tags begin?
Michał G .: In 2002, we conducted research for the Oncology Center. They found that the efficacy markers used for radiotherapy have a number of disadvantages. Our goal was to find new ones.
Marek G .: The press reported about research on “miracle markers”, but it was known in advance that they could not be used due to the content of toxic heavy metals such as cadmium.
Michał G .: Most of the attempts to use nanoparticles in oncology to date have been associated with an attempt to develop the so-called targeted therapy: a marker, most often an immunological marker, was attached to the particle, which was then to bind to the antigen in the tumor. Unfortunately, the formation of nanoparticles for a specific type of tumor, or even a specific cell clone, is a dead end. First of all, because tumors are extremely plastic and changeable. As a result, it has become virtually impossible to go beyond cell line research.
So universal tags were needed?
Michał G .: Yes, those that we will be able to use in diagnostics, and ultimately in treatment as a drug carrier. Despite the enormous progress in medicine, we still do not have a method that selectively destroys neoplastic tissue. Classic chemotherapy works on all cells of the body, especially those with high metabolism, i.e. epithelium, hair bulbs or cells of the hematopoietic system. In the case of radiotherapy, we know how to direct the X-ray beam so as not to damage or minimally damage the surrounding tissue, but in practice it must be used in combination with chemotherapy.
Marek G .: In classical surgery, on the other hand, we either remove the organ, if it is a pair of organs, or excise neoplasms with a very large surrounding of healthy tissue. Only in the brain is the minimum used, and even suspicious areas are left behind if they are critical to the patient’s survival.
Michał G .: Actually, only photodynamic therapy (PTD), used in the treatment of melanomas or esophageal neoplasms, is highly selective.
This is what makes your project different from other proposed solutions in the world, it is a form of application. Not an injection, but a tablet. Where did this idea come from?
Michał G .: It began with research on the dynamics of the digestive tract remodeling. We wanted to show how the gastrointestinal epithelium changes – the mice were given nanoparticles orally, and our task was to check how quickly new cells grow on the intestinal villi after specific periods of time. It turned out that they absorbed beautifully and spread throughout the body of the mice. At that time, there were single works around the world saying that nanoparticles were absorbed into the body through the gastrointestinal tract.
Marek G .: The idea was crazy and it worked.
Why is oral administration better than a needle?
Marek G .: Injecting nanoparticles directly into the bloodstream is risky. These substances aggregate easily, hence the risk of blocking tiny blood vessels. To minimize this risk, chemical compounds are used that change the surface properties of nanoparticles, but it turned out that the compounds are eagerly phagocytosed by cells of the immune system. Therefore, any therapeutic action would destroy the cells of our immune system and possibly the area of cancerous tissue directly adjacent to them. By administering nanoparticles orally, we are able to regulate the dynamics of nanoparticles penetration into the bloodstream. In addition, it turned out that our nanoparticles easily penetrate into the tumor tissue, deposit in it, and then diffuse through it, also reaching ischemic areas, poorly supplied with blood, which are the breeding ground for the most malignant cancer cells.
Michał G .: In 2013, a very famous work by Japanese scientists was published (The link between infection and cancer: Tumor vasculature, free radicals, and drug delivery to tumors via the EPR effect. Hiroshi Maeda. Cancer Science 104 (7) https: / /doi.org/10.1111/cas.12152) that cancer deposits various types of compounds, including nanomaterials, in a completely different way than other tissues. On the one hand, the vessels in the tumor grow so quickly that the blood-tissue barrier is much looser than in a healthy organism and nanoparticles are much easier to penetrate. On the other hand, cancerous tissue has a negligible amount of lymph vessels, so nanoparticles cannot be eliminated quickly.
How quickly are nanoparticles removed from healthy tissues?
Michał G .: Quite quickly – depending on the tissue from a week to a month. The brain tissue, for example, gets rid of them very effectively, both by the way they arrived, i.e. through the blood-brain barrier, and by neuronal transport.
Marek G .: Provided that the nanoparticles have the appropriate dimensions.
The smaller the better?
Michał G .: It was very interesting. Most of the world groups went below 20 nanometers, 10 nanometers – as a result, the nanoparticles diffused through the cells, and the tissue could not get rid of them. On the other hand, larger ones in the range of 50-200 nanometers are recognized by the cell as foreign objects, they pass through it using the mechanisms of transcellular transport, and then are transported, transferred to the blood and eliminated from the body. We know that this is a receptor activation mechanism. We still don’t know which ones. This is a new part that we are trying to unravel right now.
Marek G .: By the way, it turned out that today’s carelessness in nanotechnology is disturbing. We were overwhelmed by nanoparticle madness – nanoparticles are in practically everything from the clothing and cosmetics we wear to electronic devices in everyday use. It seems that the story of asbestos, the miracle material that increases the risk of lung cancer, has taught us nothing.
Michał G .: It is true that nanoparticles have been used in industry since the 80s, but the impact of nanotechnology on our health and the environment is still relatively unknown. Metal nanoparticles are effective in killing bacteria, but selectivity is not. The sterilization of soil and water is already observed, i.e. we are destroying bacteria that are beneficial to us. This is one of the biggest problems we will have to deal with.
This research project used zinc oxide?
Marek G .: Yes, we use zirconium oxide and zinc oxide, which have passed all safety tests. Zirconium oxide has been used in medicine for 90 years and is successfully used in dental prosthetics.
Michał G .: We also found out why most of the research in the world that used zinc oxide did not work out. For the first time, we had zinc oxide, which was fluorescent due to modification with rare earth metals. This means that we were able to study the dynamics of absorption and breakdown in the body, not just the dynamics of changes in the amount of zinc in tissues as measured so far. Our research has shown that zinc in the form of nanoparticles very effectively reaches cells, and at the same time removes the zinc contained in the cells from the body. That is, the body maintains overall zinc homeostasis, whether it is nanoparticle or ionic.
At what stage is the project currently?
Michał G .: We are constantly looking for new possibilities in diagnostics, including replacement of gadolinium in magnetic resonance imaging.
Because of the toxicity?
Michał G .: Yes, the studies conducted so far have shown that gadolinium is not only toxic to the kidneys, but also accumulates in the brain tissue. That is why today gadolinium itself is not administered, but its chelates, which are much safer. Nevertheless, pure gadolinium is also released from them, which is risky if we are dealing with progressive or regressive tumor observation.
Marek G .: In the case of chemotherapy, sometimes four tests a month are needed, and this is a cumulative dose that is deposited in the body.
Michał G .: This is a very interesting direction in which nanoparticles have a chance to be implemented as quickly as possible. One possibility is to replace the gadolinium with something else, the other to hide it in the nanoparticle so that it cannot affect the body’s cells.
Testing on laboratory animals and clinical trials were successful, the project received a number of diplomas, medals and awards – when can we expect human testing?
Marek G .: This is a very difficult topic – oncologists have shown interest, but each new experimental technique requires the approval of the Bioethics Committee. And here, unfortunately, we have great conservatism …