| dc.description.abstract | Abstract
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease known. PD is characterised by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) due to the formation of Lewy Bodies (LB). LB disturb essential cellular pathways and induce neural cell death, resulting in dopamine (DA) deficiencies which manifests itself in (non-)motor symptoms including tremors, rigidity and loss of smell. At the time of writing, no treatment exist that cures or slows down the progressivity of PD. Current treatments aim at the delivery of L-3,4-dihydrophenylalanine (L-DOPA), a DA precursor, to the brain. L-DOPA is generally taken orally as this is convenient for patients, but is poorly taken up systemically, resulting in inefficient drug delivery. Moreover, rapid enzymatic and oxidative conversion of L-DOPA systemically cause a low half-life (50 minutes), leading to the need of high and frequent drug intake. As PD progresses, the SNpc lose the ability to store L-DOPA which further increases the need of excessive L-DOPA intake. As 1% of the administered L-DOPA reaches the brain, the majority is present systemically resulting in severe side effects including dyskinesia.
To improve current treatments, L-DOPA is encapsulated in liposomes to protect against rapid degradation, lead to sustained drug release, lower the systemic concentration and result in increased (indirect) targeting. The preparation, characterisation and L-DOPA loading of the liposomes have been formulated by previous students. This report continues on the project by demonstrating the L-DOPA retention kinetics in liposomes in relevant biological media to mimic in vivo. These retention studies have been performed with an innovative method, based on the biotin and streptavidin interaction.
The retention kinetics in blood plasma demonstrated the presence of a burst release in the first 2h of incubation in which close to 40% of the original content is released. Incubation of ≥6h revealed a discontinuation in drug release. Retention study in HEPES buffered saline (HBS) (pH 6.5) revealed a smaller burst release of 27% in the first 2h, followed by a 1%/h drug release, indicating the cruciality of blood components on liposomal drug release. Unfortunately, the retention studies performed in whole blood were unconclusive as molecules closely resembled L-DOPA were present in measured samples, making the quantification of solely L-DOPA unattainable. Moreover, the results concluded that applying HBS or dialyse cassettes for retention studies can be used to create an initial indication, but no in vivo retention kinetics can be derived due to the lack of protein corona formulation.
In conclusion, the liposomal encapsulation of L-DOPA is promising for future treatments as pharmacological properties including half-life and sustained drug release are improved. Moreover, the use of the biotin-streptavidin method has shown to be advantageous in predicting the drug retention kinetics in vivo. Yet additional research is needed to improve the method. | |
