An Israeli breakthrough in the world of medicine: researchers at the Hebrew University succeeded in developing tiny drug carriers that can travel through the bloodstream to the cancerous tumor and release the drug locally, without further harming the patient.
An international team of researchers led by Prof. Ofra Bani and PhD student Arnon Fluxman from the School of Pharmacy in the Faculty of Medicine at the Hebrew University succeeded in developing nanometric particles that are capable of delivering medicine directly to the tumor site, controlling the rate of its release and even heating the tiny particles. All this through a revolutionary innovation: coating the drug-carrying particles with a thin layer of iron, so that the particles react to external energy sources such as a magnetic field and infrared light.
The ability to target the drug in the tumor area is one of the biggest challenges in modern medicine. Scientists and medical teams have been trying for a long time to develop effective methods of drug delivery to improve the quality of care. “For a decade we have been conducting multidisciplinary research that combines materials engineering in the field of pharmaceuticals with engineering in a biological context, and are developing tools aimed at providing better treatments to cancer patients,” explains Prof. Benny, head of the Laboratory for Nanomedicine and the Cancer Microenvironment.
“A lot of our efforts are focused on developing methods that allow drugs to be much more targeted, especially against cancerous tumors. One of our goals is to take drugs and optimize them so that they harm the tumor but not the rest of the body. If we make them reach the right place and work only there, we will reduce the exposure of the tissues Health is medicine. When drugs reach healthy tissue, they cause damage and severe side effects. That’s why our effort is focused on efficiently transporting the drugs to the site of the disease even when the tumors are located in areas of the body that are difficult to reach during surgery.”
Benny grew up in the field of biotechnology engineering. After her academic training at the Technion, she went to Harvard Medical School in Boston, for a post-doctorate, and got a research position there in the laboratory of Prof. Yehuda Folkman, one of the leaders in cancer and cancerous blood vessels research. About a decade ago, after returning to Israel, she established the laboratory for cancer research and nanomedicine at the Hebrew University School of Pharmacy.
Prof. Ofra Bani: “We said to ourselves: Wait, we can create a metal-coated particle, and that way it will be able to do many other things besides carrying medicine. Our eyes were opened because we realized that this is a technology that can be played with.”
The laboratory is located at the end of a long and gray corridor, and today 14 students work there. “Each one of them gets up in the morning and their goal is to promote research,” Fluxman describes the everyday. “The hardest thing the PhD teaches you is that most experiments fail and most hypotheses are disproved. We learn how to deal with disappointment and how to find new solutions anyway.” “It requires a lot of mental strength from the students,” adds Benny. “It’s also not easy technical work in the laboratory, the students spend many hours in calibrations. It’s an exact science. We go through thousands of formulations before we arrive at what we’re looking for.”
The first step in this kind of research is to study the cancer and its mechanisms of action. “Over the years we have learned to look at cancer tumors as something that is part of the body and even mobilizes the body for its needs,” says Benny. “A cancer tumor actually behaves like another organ in the body; it builds an environment of cells that protect it and produces a blood vessel network that connects it to the rest of the body in order to nourish itself with food and oxygen. We study its structures and, moreover, its weaknesses, in order to exploit them against it.”
For example, she explains, the blood vessels that the tumor produces are not perfect: they leak, “that is, the connection between the blood cells is not ideal, and the blood vessels are similar to a perforated tube. We know how to produce nanometer drug carriers that can penetrate through this perforated tube but not through blood vessels ordinary”. Nanometric drug carriers are tested in a multi-year study in Benny’s laboratory, and over time she discovered that even when you “get smart” with the tumor and direct the drugs to the “leaking” blood vessels, it is still not enough and the body is exposed to the harmful drugs.
Fluxman is one of the doctoral students currently working in her laboratory: an outstanding graduate of the School of Pharmacy and a pharmacist by profession. His research focuses on the active domestication of carriers for cancer treatment. “It is not enough to give the patient only one drug or to attack the tumor with a single mechanism of action,” he explains. “We were able to produce particles and program them so that we can apply a variety of manipulations on them so that they actively reach the tumor and undergo local activation in its area only. That is, instead of the cancerous tumor looking for them, the particles themselves will look for the cancerous tumor inside the body.”
Unlike drugs that are injected directly into the bloodstream, drug-carrying particles make it possible to concentrate the drug in a kind of capsule. The particles are produced in the laboratory from polymeric materials dissolved in oil, in a method known as “encapsulation” – the creation of tiny drops of oil in water, and will be stabilized with a medicine they carry inside. “It’s all a game of controlling the phases of oil and water,” Benny explains.
The next step was the hardening of the droplets to form particles that can be coated with a thin layer of iron. Here, the collaboration of the laboratory with a team of Spanish researchers led by Dr. Borja Sepulveda from the Institute of Microelectronics in Barcelona proved to be particularly fruitful. The Spaniards, who come from a background of materials engineering and deal with metals, developed the possibility of adding metal on top of materials. “When we saw what they were able to do with metals , suddenly the idea dawned on us that we could do something new with it,” Benny describes. “We said to ourselves: Wait, we can create a metal-coated particle, and that way it can do many more things besides carrying medicine. Our eyes were opened because we realized that this is a technology that can be played with.”
The researchers decided to take the particles they had developed, and coat them in a very thin layer of metal. “We chose to work with iron because it has several properties: it reacts to a magnet, which will help lead the particles to the tumor area, it serves as an excellent contrast agent, and it can also be heated from the outside using laser rays. Another advantage that the iron coating provides is that thanks to it, the particles can be seen in an MRI examination and even track the particles.” The body can contain iron, says Benny, almost without a problem. “All the contrast agents given today for various tests contain iron oxide, for example,” she explains.
The particle created in this way, Benny says, is versatile: it carries medicine, so it treats; It is coated with metal, so it can be transported in the bloodstream; It is possible to instruct him to release the medicine only in the infected area, thus avoiding damage to healthy tissues; And you can also heat it, and heating helps kill cancer cells.
To test the drug in animals, the researchers chose the chemotherapy drug paclitaxel, which works on breast cancer. A human breast cancer tumor was “induced” in a mouse. The researchers injected the drug-carrying particles, wrapped in a thin layer of iron, into the blood stream of the mouse. Using a magnet placed in the area of the tumor, they aimed the particles at the cancerous tumor: when the particles passed through the bloodstream, they stopped in the area of the magnetic field.
“After the particles reached the tumor area, the medicinal substance was gradually released from the disintegrating polymer,” Benny explains. “Today we know how to plan or schedule the breakdown of the polymer, and release the drug in a way that controls the release dose, its rate and its nature. For example, it is possible for the drug to come out in large quantities in the first few days, and in the following days slowly and in small quantities. This way, the drug is released in the damaged tissue with minimal damage to the healthy tissue Time the polymer so that the drug is released from the particle over the course of a week, with most of the material being released in the first 24-36 hours. The advantage is that if we bring the particles closer to the tumor area with a magnet, within two hours they will all be there, there will be a peak of very effective release, and then the particles will continue to release the drug over time.”
She qualifies that the road to treating humans is still long; And besides that, at the moment the development is suitable for the treatment of superficial tumors, up to a depth of 7 cm under the skin, and not for deeper tumors. “A stronger magnet could also be effective for deep tumors, but this is something that will need to be developed in the future. Another treatment method that can be thought of as effective for deeper tumors is to use a magnet through an invasive procedure – for example, to insert a tube with a magnetic tip that will move the particles to the tumor area.” When the treatment is approved for use in humans, patients will require much fewer injections of chemotherapy; and besides that, she adds My son, attacking the tumor with greater precision and efficiency will prevent damage to healthy tissue, and reduce the side effects.
“It’s an amazing and important field, and people are not aware of it,” says Prof. Benny. “The field of oncology is changing a lot, and is moving towards personalized treatments. The prevailing approach to cancer treatment, which was more common in the past, is to give high doses of medicine to patients in a short period of time, an approach that causes great suffering to patients. Today, when people fortunately live longer and are diagnosed at earlier stages, the cancer In many cases, it behaves like a chronic disease. If once they only thought about the patient’s survival, today they also think about their quality of life.”
The research findings, in collaboration with the group of Spanish experts, were published in the prestigious journal ACS Nano. This is the first time that a drug treatment system is presented that is actually a platform for additional treatments: “We can use it with almost any drug, and add functions as we wish,” Benny explains. “We showed in mice that within two weeks there is a complete disappearance of the tumor, and only a small scar remains where the laser beam passed.”
The team at Benny’s lab is not stopping: these days a study led by Fluxman is about to be published that shows many more options that can make the drug treatment more efficient. “We show that it is possible to use gold and copper instead of iron,” explains Floxman, “and thus enable new applications – for example, the prevention of bacterial infections, or the ability to control the formation of tissue. Gold heats up more efficiently than iron, and copper has antibacterial properties – so we can To improve the activity of antibiotics given in a nanoparticle, and to reduce the amount of antibiotics given to the patient. This development allows flexibility.”
It’s amazing that this is happening in a small laboratory in Jerusalem. What are the implications of your research for the world?
Benny: “Like any basic research, we must now go through all the regulatory pathways regarding safety and go through the entire approval pathway of the American Food and Drug Administration, the FDA. It’s a matter of years, it’s hard to know how long it will take, and it requires large budgets. We have already managed to bring some of the developments in the laboratory very close to the first phase of a clinical trial in humans. If we have the budget, within a few years we will reach the first clinical trial in patients.”
Can we ever beat cancer?
“You have to look at cancer as several diseases. We can already say that we are winning some of the types today. I am optimistic. Many types of cancer will disappear, simply because new diagnostic technologies have come into operation in the very initial stages – for example through the detection of DNA in the bloodstream, which will make it possible to detect tumors in a blood test Simple, and to also determine in which organ of the body they are.” The treatment will therefore take place in the early stages, she says, and will help save lives.
Apart from this, there is the field of personalized medicine, and a third component is computational medicine: “There are today advanced computational tools of machine learning and artificial intelligence, which make it possible to identify biological behaviors that we have not yet been able to identify and interpret. In my opinion, in twenty years we will be in a completely different place in terms of the fight against cancer. I I tell my students more than once – we are in a time of change. We see the horizon and the change, the beginning of directions for treatment and healing that until today were not possible.”
According to her, the optimistic horizon is made possible thanks to the maturation of many technologies at the same time. “There was a perception that as soon as some technologies matured, there would be faster and bigger breakthroughs, and now this is being realized. Just as the invention of the Internet revolutionized the field of information sharing: every few years we see innovations of a similar magnitude in medicine. Suddenly we can see the genomics of individual cells within the tumor, Which is amazing in itself. We now manage to control materials and particles of tiny sizes, we have powerful microscopes, and suddenly we have computational tools that know how to decipher ‘big data’ – these are just some of the technologies that are brewing together.”