Researchers used computer simulation models to investigate why medicines become viscous at high concentrations.
Introduction
Have you ever had to take medicine when you were sick? Designing new medicines is complex. There are many things to consider. The solution needs to be stable so it can be stored. It also needs to be produced at a large scale. Then, researchers need to figure out how to give the medicine to patients.
Sometimes medicines need to be given in high concentrations. But concentrated solutions can have high viscosity (Fig. 1). Highly viscous medicines are given to patients intravenously. This can only happen in a doctor’s office or hospital. The process is inconvenient and expensive. If these medicines were less viscous, people could take them at home using syringes. This could save money. It would also ensure that more people had access to treatment.
Understanding why some medicines become viscous isn’t easy. To study this, scientists would ideally look at every atom in a medicine. But that’s far too complex when millions of molecules interact! Instead, researchers use coarse-grained models, which simplify the molecules by grouping several atoms into simple “beads”. These simplified models make it possible to study how several molecules behave at once while still capturing the most important properties of the solutions. One important property to consider is electrostatic interactions between charged parts of the molecules.
We wanted to develop a new model to look at the viscosity of medicines. In particular, we wanted to look at medicines containing monoclonal antibodies. These concentrated and highly viscous medicines are used to treat cancer and autoimmune diseases. Antibodies are a natural part of the immune system. They recognize foreign intruders in the body so that other cells can destroy them. And monoclonal antibodies can be modified to recognize any type of cell. This is what makes them so effective!
Methods
We used computer simulations to develop three coarse-grained models (Fig. 2). Each model is represented by 9 beads. We based our models on a specific antibody that can identify viruses in the body.
Model A – Simple model with a uniform charge across the antibody. This means that the total charge of the amino acids is spread equally over the 9 beads.
Model B – Simple model with uneven charges across the antibody. We mapped the charges of the original amino acids onto our model. For each bead in our model, we averaged the charges on the amino acids that were nearby.
Model C – Complex model with uneven charges across the antibody AND ions in the solution. This is very similar to Model B but with positive and negative ions in the solution.
For each model we looked at different antibody concentrations. We compared our results to previous laboratory values. We also calculated other parameters that help describe interactions between molecules.
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Antibody Info Box:
Antibodies are collections of molecules called amino acids. Amino acids can have positive or negative charges. Or they can be neutral. These electrostatic properties help antibodies interact with foreign cells. They can also help antibodies interact with ions in solutions.
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Results
We found that the viscosity increased as the antibody concentration increased (see Fig. 3 on p.3). We also discovered that Model C matched our laboratory evidence the best.
We saw that at high concentrations, antibodies formed temporary clusters. This was because of two things:
Areas on the antibodies that had opposite charges interacted with each other.
Areas on the antibodies interacted with ions in the solutions. This stabilized the antibodies and allowed them to stay clustered for longer, even if they had the same charge.
Discussion
We found that we needed to include ions in the solution to make a realistic model. When antibodies form temporary clusters, it can increase viscosity. This happens when areas on the antibodies interact with each other. Our results suggest they do this because of electrostatic interactions with each other and with ions in the solution. Future models should make sure to include both of these interactions.
It is important to continue developing models that align with experiments in the laboratory. This gives scientists a basic framework of the medicine’s molecular properties. Then they can add or remove things from the model to see if it changes the viscosity. For example, different interactions or how internally flexible the model is. Only by combining computer simulations and laboratory experiments can researchers understand how medicines behave. Then they can make new ones. Our results suggest that antibody concentrations can change viscosity. Adding other molecules to reduce clustering and using new solvents could also make a difference.
If scientists can reduce the viscosity of monoclonal antibody medicines, it will make them cheaper and more accessible. They could be given by syringe instead of intravenously. This means that patients could take the medicine themselves at home. Our molecular model could help scientists figure out how to make this happen. Then more patients could get the life-saving treatments they need.
Conclusion
It is really hard to investigate things that are too small to see. Technological advances like the microscope have let us see into a microscopic world. Computer simulations and models can help us see processes that are too small even for a microscope.
You interact with technology every day. What are some ways that it can help you investigate things you are interested in? How can it help you solve problems in a different way? Just because you can’t see something doesn’t mean that it has to stay a mystery!
