Levodopa-loaded polymeric- and lipid-based nanoparticles for the treatment of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder where formation of Lewy Bodies (LBs) in the dopaminergic neurons of the substantial nigra pars compacta (SN) cause progressive cell death, resulting in a dopamine (DA) deficiency which manifests itself in motor symptoms including tremors and bradykinesia. Current PD treatments focus on symptom reduction through oral delivery of levodopa (L-DOPA), a precursor of DA. However, L-DOPA delivery to the brain is inefficient due to low oral bioavailability, degradation in the gastrointestinal (GI) tract and the liver, short systemic half-life, systemic L-DOPA decarboxylation into DA and limited brain uptake due to the blood brain barrier (BBB). Additionally, due to the buildup of L-DOPA tolerance by the PD brain, increased dosages are required as the disease progresses, resulting in increased systemic DA concentrations causing serious side effects like dyskinesias. To improve PD treatment efficiency and to reduce side effects, recent research focuses on the encapsulation of L-DOPA in nanoparticles (NPs), the most popular of which include the polymeric- and lipid-based NPs. Both formulations are able to protect L-DOPA from systemic decarboxylation into DA and increase L-DOPA delivery to the central nervous system (CNS). Additionally, these NPs can be modified with proteins and antibodies specifically targeting the BBB, not only improving targeting to-, but also the crossing of the BBB, thereby reducing required dosages and free systemic DA. An alternative treatment strategy is to avoid the BBB altogether through direct intranasal delivery of NP encapsulated L-DOPA to the brain. Through intranasal delivery, L-DOPA can be directly delivered to the brain via the olfactory and trigeminal nerves, reducing free systemic DA and avoiding the BBB-associated problems. These polymeric- and lipid-based NPs can be additionally modified to improve mucoadhesion and cell penetration, resulting in increased therapeutic concentrations of DA in all parts of the brain. In this review I will give an overview of the recent advancements made in the field of PD treatment, regarding NP encapsulated L-DOPA delivery to the brain via either the oral and IV route, as well as the direct intranasal delivery.