Researchers look at enhancing brain delivery of drugs to treat neurodegenerative diseases

King’s College London

New gel technology achieves enhanced brain delivery of a Parkinson’s Disease drug.

nasal spray

A team of researchers from the School of Cancer & Pharmaceutical Sciences at King’s, led by Professor Khuloud Al-Jamal, Head of Medicines Development at the Institute of Pharmaceutical Science, have been working collaboratively with researchers from the University of York to optimise the brain uptake of a new gel designed to treat Parkinson’s Disease.

Parkinson’s Disease is a debilitating and progressive neurodegenerative disease. Over 100,000 people live with the condition in the UK and it’s the fastest growing neurological condition in the world. The main symptoms of the disease are tremor, stiffness, and slowness of movement.

Currently, drug treatment for Parkinson’s Disease relies on levodopa, which is converted to dopamine in the brain. This makes up for the deficit of dopamine-producing cells in Parkinson’s patients and helps treat the symptoms of the disease. However, over time, levodopa becomes less effective, and increased doses are needed. This is because the body becomes more effective at breaking down the drug before it gets to the brain. Sometimes, in later stages of the disease, patients change from taking levodopa tablets to having the drug injected. It would be highly advantageous if enhanced delivery of the drug direct into the brain could be achieved.

One strategy for improving brain uptake is to use nasal delivery. Nasal spray drugs are an area of increasing interest as uptake through the nasal epithelium (the thin tissue inside the nose) can give effective delivery into the bloodstream but can also achieve direct brain delivery via the nerves that service the nose. However, to achieve effective nasal delivery, it is important to ensure that a drug delivered into the nose makes effective contact with the nasal epithelium.

Professor David Smith and his team from the University of York have been working on self-assembling systems based on small molecules that could form gels in water. The team realised that if they formed their gel in the presence of levodopa, it may help the drug to better adhere to the nasal epithelium and hence it could be delivered more effectively. The team optimised the gel to ensure that it had ‘self-healing’ properties so it could flow into the nose as a liquid, and then rapidly form a thin layer of gel. They then demonstrated that a gel loaded with levodopa could rapidly release the drug.

Professor Khuloud Al-Jamal, Dr Julie Wang, and Mr Mazen Aly from the School of Cancer & Pharmaceutical Sciences at King’s went on to test the performance of these gels in vivo in an animal model system. They found that the gelled version of levodopa was significantly more effective for nasal delivery than a simple solution of the drug. In particular, the drug had longer residence times in the nasal cavity because of better adhesion, and this then allowed the drug to achieve better levels of uptake into both the bloodstream and the brain. More detailed analysis indicated that drug uptake into the brain was occurring directly via both the olfactory and trigeminal nerves.

We were delighted to see that not only did the gel perform better than a simple solution, but that brain uptake was also better than that achieved using intravenous injection of the drug. This suggests that nasal delivery of Parkinson’s drugs using this type of gel may have clinical relevance.– Professor Khuloud Al-Jamal, School of Cancer & Pharmaceutical Sciences

The collaborative team are now working to further optimise the system. They intend to demonstrate therapeutic benefits while minimising toxicity. Ultimately, they plan to incorporate these materials into nasal spray devices and mix other additives into their simple system to enhance drug delivery further.

The researchers believe this self-assembled gel approach may also be relevant to drugs for treating other neurodegenerative conditions such as Alzheimer’s and Motor Neuron Disease.

The research is published Open Access in Advanced Science.

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