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Eye.

Use of melanin binding as drug delivery strategy to the posterior eye segment

  • Health and well-being

In her doctoral thesis, Paulina Jakubiak studied the binding of drugs to natural ocular pigment, melanin, as a novel approach to achieve sustained drug delivery to the back of the eye. A computer-based model was developed for characterizing and predicting the melanin binding extent of drug candidates.

The increasing number of patients suffering from vision-threatening diseases such as age-related macular degeneration, diabetic retinopathy and glaucoma poses a serious global health problem. Although treatment is available to address the neovascular forms of retinal diseases with large-molecule proteins, the invasive intravitreal administration of these drugs is not convenient to patients. Current research and development efforts within ophthalmology focus on finding novel therapies and efficient, patient-friendly ways to deliver drugs into the eye, that would relieve the treatment burden of repeated intravitreal injections posed on patients and the healthcare system. In this respect, small drug molecules are quickly washed out from the eye and the fraction of the administered dose that reaches the retinal tissues is very limited. Thus, to overcome these challenges, long-acting drug delivery strategies are needed.

Binding of drugs to natural ocular pigment, melanin, has been proposed as a viable approach to achieve sustained drug delivery to the back of the eye. This concept relies on the generation of a drug reservoir bound to melanin that can be steadily released from the pigmented ocular tissues. However, the molecular mechanisms behind it and the translation of the prolonged duration effects to human have not been fully elucidated. Hence, Jakubiak’s thesis aimed at establishing an understanding of the main molecular properties driving the binding of small-molecule drugs to ocular melanin in the test tube and in experimental animals.

The researchers first established an experimental melanin binding assay suitable for testing large numbers of molecules and used the generated data to develop a computer-based model for characterizing and predicting the melanin binding extent of drug candidates. This systematic experimental and computational testing allowed them to recognize prominent correlations between melanin binding and the physicochemical properties of the molecules, such as ionization category, lipophilicity and aromaticity.

Experimental drug release and binding studies were performed with different concentrations of melanin and combined with mechanistic kinetic modeling to obtain the rates of drug association and dissociation as well as the drug-melanin binding parameters at steady state conditions. Ocular pharmacokinetic studies conducted in albino and pigmented rats via intravenous injections showed a substantial drug enrichment and a prolonged residence time in pigmented eyes that could be related to the extent and kinetics of drug binding in test tube systems as well as to the drug’s pharmacological properties. Moreover, high enrichment and retention of strong melanin binders were demonstrated in the pigmented ocular tissues of rabbits after administering the drug via the intravenous, intravitreal and topical routes.

Overall, the project generated a systematic understanding of the main molecular drivers for melanin binding in the test tube systems and elucidated how these attributes interplay with concurrent pharmacological processes, resulting in distinct ocular concentration-time profiles in animals. This information could help in the rational design and development of new small-molecule drugs targeting the back of the eye that could be delivered via less invasive drug administration routes.

The doctoral dissertation of Paulina Jakubiak, Master of Science (Pharmacy), entitled Use of melanin binding as drug delivery strategy to the posterior eye segment, will be examined at the Faculty of Health Sciences on 13 March 2020. The Opponent in the public examination will be Associate Professor Sara Nicoli of the University of Parma, and the Custos will be Professor Arto Urtti of the University of Eastern Finland.