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Disease and treatment

How researchers plan to design better medicine

Medicine often has difficulty in penetrating the barrier between the gut and the bloodstream, and many types of medicine therefore need to be injected subcutaneously or intravenously. Researchers from the Technical University of Denmark are working on developing new methods to enable the body to absorb medicine as pills and to develop drugs that boost the immune system.

Have you ever wondered why some medicines can be taken as pills and others need to be injected with a needle? Vaccines, insulin and most types of medicine against cancer only work if they are injected into the bloodstream, buttocks or thigh, whereas pain relievers, antibiotics and antimalarial medicine can be washed down with a glass of water.

One reason various types of medicine need to be taken differently is the barrier between the gut and the bloodstream. The gut wall is naturally designed to keep large hydrophilic (attracted to and usually dissolved in water) molecules to pass through, and many types of medicine are hydrophilic. The gut wall prevents these large molecules from passing through the intestinal tissue into the bloodstream, so instead of helping to heal the person taking these biomedicine molecules, the medicine leaves the body on a visit to the lavatory. An entirely separate problem is that many types of medicine cannot remain intact on the journey through the gut’s cocktail of chemical substances and the stomach’s relentless gastric acid attacks.

The challenge of delivering many types of medicine as pills has been a longstanding headache for the pharmaceutical industry that cannot be cured with aspirin or paracetamol. The problem may not be that great for the types of medicine that, for example, only need to be taken monthly or through vaccination. Going to the doctor and being jabbed in the arm or buttocks occasionally is not that problematic. However, the situation becomes almost unmanageable when people need injection daily. Just think of insulin, which some people must take several times daily. Fortunately, the manufacturers of insulin have developed technologies that enable people to inject their insulin at home, with minimal discomfort. Unfortunately, this does not apply to all types of medicine taken daily that must be injected with a steady hand. Most people would also rather swallow a small white pill with a glass of water than have any kind of needle inserted into their body. Some people are definitely afraid of needles, and just the thought of being vaccinated can almost make them faint.

New methods of designing more patient-friendly medicine clearly need to be developed for all kinds of diseases, and Thomas Lars Andresen, Department of Health Technology, Technical University of Denmark, is tackling this task. He has aimed throughout his research career to make medicine better, more targeted and more patient-friendly.

“There are many reasons why we would rather take medicine as a pill rather than through a needle. There is the mental aspect, with most of us probably preferring a pill to a needle, but there is also a practical aspect. Much of the medicine taken as pills is used for treating the early stages of many of the chronic lifestyle-related diseases that are increasingly common. However, treating people in the later stages of these diseases almost always requires injection. This is a major problem for many people, since these types of medicine often have to be taken daily,” explains Thomas Lars Andresen.

Focus on optimizing medicine

Thomas Lars Andresen carries out research on how the body transports medicine. One reason is that he wants to develop methods for targeting the medicine to the tissues where it is needed. Heart medicine should preferably end up in the heart, and medicine for cirrhosis of the liver should preferably not end up in the brain.

The first problem researchers encounter in designing medicine for a specific disease or to affect a specific type of tissue is the many barriers in the body. These are designed to stop various molecules from penetrating specific types of tissue or the body in general, including molecules that are currently used as medicine. One important barrier is the gut wall, which blocks unwanted molecules from food, or the blood–brain barrier, which keeps the brain free of many potentially harmful substances. These barriers also block beneficial substances.

“Getting many types of medicine to work better and more specifically means that we often must trick the body in some way and cause it to do things that it would not normally do. This is the focus of my research,” explains Thomas Lars Andresen.

Since receiving his PhD degree, Thomas Lars Andresen has carried out research on the potential to trick the body in various ways to absorb medicine it would otherwise not absorb. He was therefore exactly the type of researcher the Novo Nordisk Foundation reached out to in Denmark in 2016 to find projects aiming to develop methods for making pill or liquid versions of medicines that are currently administered through a needle.

The collaboration with Thomas Lars Andresen was very appropriate because his research has focused on this topic for many years. His research includes the following themes.

• Transport systems to move medicine to the right places. Specifically, he has developed tiny fat globules that can deliver medicine to cancer cells. The globules are currently undergoing clinical trials.

• Controlled-release systems. These are ways to direct medicine locally into tumours, so that they release the active substances in the local area over time.

• Medicines for T-cell therapy. They are being investigated in clinical trials in the United States.

“I want to develop several methods for making medicine more usable. This may involve getting medicine to function in exactly the tissues where it needs to have an effect or generally delivering medicine into the body and bypassing the natural obstacles in our bodies,” says Thomas Lars Andresen.

Making GLP-1 medicine 10 times better

In the current project supported by the Novo Nordisk Foundation Challenge Programme, Thomas Lars Andresen is attempting to design medicine ingredients with properties that enable them to penetrate the gut wall.

One example of the problem Thomas Lars Andresen is striving to solve is medicine such as glucagon-like peptide 1 (GLP-1), which is used to treat people with type 2 diabetes. GLP-1 is a small peptide that can just barely pass through the digestive system and penetrate the gut wall. However, an enormous amount is degraded along the way, and the body actually absorbs less than 1% of the peptides that started as a pill at the back of the tongue. This is a very small percentage, but it is enough for medicine based on GLP-1 to be effective. Other medicine has even greater difficulty penetrating the gut wall. This applies to insulin, for example, because the proportion of insulin absorbed is so small that the pharmaceutical companies have concluded that oral delivery is not cost effective, because the pills need a lot of insulin to be effective. In addition, the more expensive the medicine is and the greater the side-effects are, the more important it becomes to maximize the percentage of active molecules that pass unscathed through the body.

GLP-1 is one of the molecules Thomas Lars Andresen’s research specifically tackles. He wants to make GLP-1 10 times more effective so that up to 10% of the active peptides penetrate the gut wall.

“Actually, the focus of the research is not so much GLP-1 itself but rather understanding the mechanisms behind the excessive waste of biomedicine molecules as they pass through the body,” says Thomas Lars Andresen.

Zooming in on the gut wall, which for many types of medicine is the equivalent of a border wall between Mexico and the United States, there are two problems.

• First, the gut wall is like a fine mesh that does not allow molecules that are too large to pass through. This means that medicine based on large molecules will be ineffective as pills.

• Second, the permeability of the gut wall depends on the affinity of the molecules for fat or water. Some molecules are hydrophilic (attracted to water), and others are lipophilic (attracted to fat). Lipophilic substances can easily pass through the gut wall, whereas hydrophilic substances are blocked and remain in the intestine.

“Ethanol is an example of a substance that penetrates the gut wall very easily. Ethanol is a small molecule, and the chemical bonds in ethanol make large parts of the molecule lipophilic. Therefore, ethanol can pass through almost anything,” explains Thomas Lars Andresen.

Developing one of the world’s most advanced microscopes

Although researchers can speculate and even calculate whether a specific molecule can penetrate the gut wall, reality is not that simple. The entire digestive tract comprises a soup of chemical substances that can modify biomedicine molecules such that the causes of the waste between the mouth and the bloodstream cannot be determined. Researchers can measure how much medicine they put into the mouths of laboratory mice and how much ends up in the bloodstream, but they cannot yet determine where the rest goes. Has the medicine been unable to penetrate the gut wall and ended up in the stool? Has it reacted with many other substances and been transformed into something completely different? Has the gastric acid destroyed the medicine? Researchers often cannot determine how medicine penetrates the gut barrier and ends up in the bloodstream.

To answer these questions, the first thing Thomas Lars Andresen did in his project was to develop advanced microscopes that can detect the movements of molecules in tissue. This means that researchers can use the microscopes to examine intestinal tissue and very precisely see how various molecules either penetrate the gut wall or are blocked. One of the new microscopes is nearly completed, and it is so advanced that there are only two similar microscopes worldwide – both in the United States. In developing the microscope, Thomas Lars Andresen collaborated with a researcher from Harvard Medical School who is one of the world’s leaders in developing highly specialized microscopy techniques. The development of the microscope is in itself a eureka moment in Thomas Lars Andresen’s research project, because it will provide unique insight into molecular mechanisms that have been like a black box of speculation.

Since researchers have not previously had access to the type of microscope that will soon be installed at the Technical University of Denmark, they have also had difficulty in fully understanding the mechanics of what happens when a molecule either penetrates the gut wall or is blocked.

“This mechanistic understanding is essential to make molecules that more readily penetrate the gut wall. We must be able to see that they do this in real tissue. In addition, it also enables us to take medicine with known pharmaceutical effects, modify it and then investigate whether it can penetrate the gut wall more easily than before,” says Thomas Lars Andresen.

The body activates the medicine

Designing molecules is also a major part of Thomas Lars Andresen’s research project. Researchers are already improving existing biomedicine molecules in ways that will hopefully enable more of the molecules to penetrate the gut wall. This will make medicines already in pill form more effective or enable medicine that currently needs to be injected to be put into pills and taken orally.

Thomas Lars Andresen and his colleagues use various chemical tricks in redesigning biomedicine molecules.

One option they are testing is to form bonds in the molecules to make them more lipophilic. This often involves about three chemical bonds that must be formed to make the molecules lipophilic rather than hydrophilic. If the researchers can form these three bonds, the molecules can penetrate the gut wall and migrate into the bloodstream and further throughout the body. However, getting the molecules into the bloodstream is not sufficient. Once there, they also need to have an effect, and the three new bonds probably eliminate the biopharmaceutical effect. These bonds must therefore be broken again once the molecules have passed into the bloodstream.

“We are examining two options here. One is to form bonds that degrade over time, to enable the molecules to penetrate the gut wall and subsequently return to their original form within 24 hours. This is a slow chemical activation of lipophilic substances that become increasingly hydrophilic the longer they are in contact with the water in the blood, activating these biomedicine molecules. The second option is to use some of the many enzymes in blood to break the bonds. These could also be enzymes in the tissue we want to target, which will also make the medicine even more effective because it will not be activated until it reaches its target. However, this requires forming bonds that only these local enzymes recognize,” says Thomas Lars Andresen.

The second option for getting hydrophilic molecules to penetrate the gut wall is attaching a lipophilic transport molecule to them that can pull them into the bloodstream. In this situation, the transport molecule would be like a train that picks up passengers on one side of the gut wall and then drops them off on the other side. Again, a mechanism is needed to induce the transport molecule to release its grip on the biomedicine molecule and activate it.

“I have been working on activating medicine components by using enzymes for many years. This field is exciting because sometimes inactive medicine that is only activated when it encounters a specific enzyme may be useful. You might want medicine to affect cancer cells, and designing medicine that is only activated if it encounters an enzyme that is only found in cancer cells has many perspectives,” explains Thomas Lars Andresen.

The researchers in Thomas Lars Andresen’s group are currently focusing on three biomedicine molecules, but the goal is to find generic methods to get them across the gut barrier that will work for many types of medicine.

Designing medicine to boost the immune system

Once the researchers succeed in the first part of the research project, they will move to the second part, which is closer to application. Although much of what is being done initially is carried out on cells and tissues and mostly involves achieving mechanistic understanding, the second part will comprise experiments with mice. The ultimate goal is to demonstrate that the researchers’ newly developed transport mechanisms can get more active substances into the mice and thus provide better treatment.

This new mechanistic understanding opens up a whole new universe that could make many types of medicine far better than they are today.

Once medicine has entered the body, it can have different paths. It can move through the bloodstream to the liver or through the lymphatic system to the lymph nodes. If medicine ends up in the liver, this may influence its effectiveness because the liver degrades the ingredients. In contrast, the lymphatic system does not degrade the active biomedicine molecules to the same extent, and they may therefore potentially be much more effective.

Thomas Lars Andresen also focuses on the transport to the lymphatic system. The lymphatic system is basically our immune system, which affects all aspects of our health. It is integrated into all types of treatments because it helps to activate our immune cells in responding to viral and bacterial infections but also to such diseases as cancer.

Activating the immune response with medicine enables the body to actively combat almost all types of diseases. It is like equipping the immune system with fighter aircraft, tanks and warships and then leaning back and watching it perform. Conversely, medicine might also be used to suppress the immune response and thus counteract autoimmune diseases such as chronic intestinal infections, in which an overactive immune system causes problems.

The techniques developed during the research project can make the researchers much more knowledgeable about the properties that cause molecules to move to the lymphatic system or to the liver.

“Getting medicine through the gut wall and into the lymphatic system is the ultimate goal of my research. We would like to create new knowledge about how we can control the transport of medicine so that we can direct it to where it will benefit a person most,” says Thomas Lars Andresen.

In 2017, the Novo Nordisk Foundation awarded a Challenge Programme grant of DKK 60 million to Thomas Lars Andresen, Professor at Department of Health Technology, Technical University of Denmark for the Centre for Intestinal Transport of Biopharmaceuticals.

Thomas Lars Andresen
Professor
The major challenge for obtaining high drug bioavailability of peptide biopharmaceuticals is to circumvent the intestinal barrier constituted road-block where the physiochemical properties of peptides, being relatively large macromolecules with medium to high hydrophilicity, constitutes an intrinsic challenge. Modifications that can be used to change the physiochemical properties of the peptides will often render them non-active except at a few selected positions that do not interfere with their binding to target receptors. Effective delivery of peptide biopharmaceuticals requires more advanced peptide engineering strategies and/or new drug delivery technology developments, which may need to be mutually optimized, hand-in-hand, to achieve radical improvement in oral delivery efficiency. We will innovate the next generation drug delivery systems that effectively transport peptide biopharmaceuticals across the small intestine, which can successively seek out target cells and tissues, and ultimately release the carried drugs with spatial and temporal control in a radically more efficient way than current state-of-the-art. The key challenge to be addressed is to mechanistically understand how a delivery system can be designed to transport biopharmaceuticals across the intestinal barrier with a design that provides high bioavailability of the drug to the target cells and tissues within animals and humans.