Intensified search for new ways to deliver biopharmaceuticals

Disease and treatment 6. apr 2023 3 min Assistant Professor Stine Rønholt Written by Kristian Sjøgren

Scientists would like to find ways to use pills and capsules for medicine to replace injections. The greatest challenge, however, is overcoming the barrier of the acidic environment in the stomach and getting the medicine to the intestines, where it can be absorbed. New research has identified a novel and ingenious method of transporting medicine to the correct location.

Children with type 1 diabetes or impaired growth have to inject medicine up to several times a day. The main reason is that insulin and growth hormone are protein-based biological medicine. From nature, the stomach is designed to degrade proteins into smaller amino acids, enabling the body to absorb nutrients from the food. Thus, when protein-based drugs are administered orally, such as through a tablet or capsule, the stomach acid, enzymes and bile salts will completely degrade the medicine before it can enter the intestine and be absorbed into the bloodstream.

Scientists have now discovered an ingenious way to deliver biopharmaceuticals to the intestines. In a new study, they show how nanoscale golf balls and tiny threadlike extensions can not only protect biopharmaceuticals on their journey from the mouth to the intestines, but also release the medicine in the exact location in the intestine where it can be absorbed.

The study is a proof of concept, but it is a first step on the way to being able to use two tablets and a glass of water to replace the injected medicine used by people with many types of diseases.

“We aim to deliver medicine at the site of absorption, and for many types of medicine, the target site is in the intestine. We are continually obtaining more detailed understanding of the challenges associated with oral delivery of biological medicine. Based on this, we can now begin to develop solutions as the first stepping stone towards the final goal: orally administered biopharmaceuticals as a part of the future treatment options,” explains a researcher behind the study, Stine Rønholt, Assistant Professor, LEO Foundation Center for Cutaneous Drug Delivery, Department of Pharmacy, University of Copenhagen.

The research has been published in ACS Applied Materials and Interfaces.

Nanoscale golf balls can deliver medicine reliably

The researchers get medicine past the acidic environment in the stomach through nanoscale golf balls called mesoporous silica nanoparticles that can protect biopharmaceuticals.

Just as real golf balls have indentations in the surface, the nanoscale golf balls have indentations that enable drug loading.

The medicine is protected in the indentations against stomach acid and can thereby pass to the small intestine, where it can be absorbed through the mucus layer lining the intestinal wall.

However, this solution requires the mesoporous silica nanoparticles to release the medicine at the right place in the intestine and the researchers developed an ingenious solution to achieve this.

“We can chemically design these mesoporous silica nanoparticles to release the medicine, for example, at a certain level of acidity, so that it is not released in the acidic environment of the stomach but only in the small intestine, where there is less degradation,” says Stine Rønholt.

Equipped with threadlike extensions

However, the small intestine is not a precise enough location for the release. Ideally, the medicine should be released exactly where it can be absorbed through the mucus layer of the intestinal wall, but this requires that the medicine penetrate this protective sheet covering the epithelial cells.

The mesoporous silica nanoparticles also solve this problem by being equipped with tiny threadlike extensions called dendrimers.

The dendrimers are like a screwdriver that can be fitted with different drills or bits to perform a job. If you need to drill a large hole, you insert a large drill, but if you need to screw a star screw of a certain size into a wall, you insert a bit that corresponds to that screw.

Similarly, the researchers can equip the dendrimers with different functions, including the ability to adhere to the mucus layer covering the epithelial cells and burrow into it.

The mesoporous silica nanoparticles not only ensure that the biopharmaceuticals survive the acidic environment of the small intestine but also transport them safely to the intestinal wall and release them there.

“We characterised the interaction between the dendrimers and the mucus layer covering the epithelial cells. We also showed how we can better control the process of attaching the dendrimers to our mesoporous silica nanoparticles by combining two synthesis methods. We are still early in the development phase, but we have shown how this technology can be developed and how it can achieve the potential it has,” explains Stine Rønholt.

Endless design possibilities

Stine Rønholt explains that the dendrimers and the mesoporous silica nanoparticles enable endless design possibilities.

If drug manufacturers want a drug to be released at a specific location in the gut, the dendrimers can be designed so that the mesoporous silica nanoparticles get there and that the drug is released under the right conditions.

In addition, the researchers can design a library of delivery options for manufacturers of insulin, growth hormone or other protein- or peptide-based drugs.

“Drug manufacturers are increasingly interested in producing biopharmaceuticals, and this opens the door for them to be able to deliver the drugs exactly where they need to be absorbed,” concludes Stine Rønholt.

Mucoadhesive dendrons conjugated to mesoporous silica nanoparticles as a drug delivery approach for orally administered biopharmaceuticals” has been published in ACS Applied Materials and Interfaces. The project has been funded by the Lundbeck Foundation and a 2016 Novo Nordisk Foundation Challenge Programme grant to co-author Hanne Mørck Nielsen for the Center for Biopharmaceuticals and Biobarriers in Drug Delivery.

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