A molecule with a destiny: modelling drug delivery in IBD

New DealInflammatory bowel diseasesLeave a Comment


Since a drug enters our body, it will complete a journey inside it that is full of difficulties. For example, when we take an aspirin, the analgesic molecules have to go all the way from the mouth to the pain location, facing, among other hazards, the harsh conditions of the stomach. Regardless of how the drug is administered, it must overcome several biological barriers. These natural obstacles are the research field of Prof. Dr Claus-Michael Lehr, head of the Drug Delivery group in the Helmholtz Center for Infection Research (Germany), and Dr Brigitta Loretz, a scientist working in the same research group. Both researchers are involved in the New Deal project testing different strategies to overcome these blockades.

“Biological barriers can be tissues, cell membranes, nuclear membranes or organellar membranes, but they can be also non-cellular barriers like mucus or bacterial biofilms” explains Prof. Lehr. But these barriers are there to protect the body against noxious influences from outside like pathogens. “If you want to deliver a drug to a target behind one of those barriers you must somehow cope with it and deliver your cargo across it without disturbing the barrier”, adds Prof. Lehr.

The strategies to overcome these barriers are highly dependent on how we decide to administer the drug. To go through the skin, creams need to sneak the therapeutic molecules without harming it; pills have to go across the stomach without out acids harming the active ingredient. But getting there is only the first half of the trip. Affecting only the target cells is key as well. “In IBD, we have the combination of overcoming the barrier and finding the target”, says Dr Lehr. Since IBD makes the immune system cells overreact, inflaming the intestines, most of the treatments available nowadays are based on immunosuppressive drugs that can produce severe side effects if administered systemically. “We need to find the way to target the therapeutic molecules exactly to the intestinal areas where they are needed”, comments Lehr.

The problem is that inflammation doesn’t always look the same in each IBD case, so targeting can be tricky. But Dr Loretz sees an opportunity here: “What we know from our research is that inflammation can be an option to try targeting with nanoparticles because somehow they have a tendency to accumulate at such inflammation sites”.  These two researchers consider nanoparticles as microscopic taxis that can give the drug a safe drive. “There is much profit you can gain from nanoparticles. You can protect the molecule and you can mask a drug property that is not really favourable for its delivery”, mentions Dr Loretz.

The New Deal project has a particularly sensitive passenger for these taxis: siRNA molecules. They act switching off the genes involved in inflammations. The genes remain untouched, but siRNA stops their effect. If you want to know more about this process, read our blogpost on the matter.

Packaging the siRNA inside a carrier is a heavy struggle, but worth the effort. “The nice thing is, when we manage to deliver siRNA, one single molecule can trigger much effect.”, comments Loretz. Once siRNA enters the cell, it can be amplified by enzymes so a lot of intermediate molecules can be degraded from a single siRNA molecule. Conventional chemical drugs don’t have this feature, as a single therapeutic molecule can only block or destroy a single target molecule once. This allows overcoming one of the most common limitations of drug delivery systems: the loss of drug during the journey, as nowadays it is impossible to deliver all the drug cargo to the cells. “The beauty of nucleotides is that if we have a potent one, we probably don’t need to deliver the 100% of the drug”, says Dr Loretz.

In the case of IBD, the perfect nanocarrier has to cross the mucus and go through the immune cells membrane to deliver the siRNA, while protecting the passenger from the hazards of the journey. To test that this is happening, Prof. Lehr and Dr Loretz use human-based cell tissue models. This allows them to study a drug delivery strategy under controlled conditions and see if it overcomes the biological barriers. “The idea of a model for me is trying to control the complexity. I can make a model as simple or complex as I want, but the idea is not to make it as close to the reality but just include the things I need to answer the question”, adds Dr Loretz. In fact, the process of testing a candidate carrier is a journey itself. To follow this journey, the nanocarriers are labelled with fluorescent substances and thus researchers can see how long carrier and drug stay together. Afterwards, it is essential to check on the biological effect: see that the targeted genes have reduced their expression. If so, it’s time to try the treatment and check if decreases the inflammation in the intestine.

Many diseases, like IBD. happen in a very specific body location, which makes treating them a challenge. Regardless of the administration means, the journey of a drug to the place where it is needed is an odyssey: plenty of dangers and a long road ahead. Looking for the most suitable carrier is like trying to turn the rough path into a clear highroad. Dr Loretz has it clear: “I would say almost every drug can profit from drug delivery systems. Even if a molecule is quite potent by itself, usually you still can enhance its efficacy if you put it together with a good delivery system.”

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