# Nanocarriers-Assisted Nose-to-Brain Delivery of Levodopa: Current Progress and Prospects
## 2 Levodopa (L-DOPA)  
Levodopa (3,4-dihydroxypropylalanine) is the natural direct precursor of dopamine in many living species, including by us, humans. Biochemically, the molecule originates from the essential aromatic amino acid phenylalanine and is obtained upon biotransformation by hydroxylation [25]. From its immediate forerunner, tyrosine, L-DOPA is distinguished by the presence of a second hydroxyl radical on _ortho_-position in the benzene ring (Figure 1); indeed, a highly efficient method for synthetic production of levodopa is considered the enzyme-catalyzed _ortho_-hydroxylation of tyrosine [26]. Unlike dopamine, L-DOPA is capable of crossing the blood-brain barrier (BBB) and, in terms of a deficit, serves as a source for the production of the neurotransmitter by enzymatic decarboxylation on site [27]. The story of L-DOPA as a drug candidate begins in the second decade of the 20 th century with the first synthetic approach by [PERSON] in 1911 and the first successful isolation of the pure L-DOPA enantiomer from Vicia faba by [PERSON] in 1913. However, its clinical recognition for the treatment of PD takes place many years later, in the 1960s, as a result of the following discoveries of [PERSON], [PERSON], and [PERSON] [28]. The extensive research on the subject ever since has led to the understanding that L-DOPA acts as a blood-to-brain penetrable dopaminergic agonist; the molecule gets converted to dopamine by the neuronal Aromatic L-Amino Acid Decarboxylase (AADC) in the brain, and, in the short term, after administration, is able to compensate for the reduced levels of this endogenous neurotransmitter in PD patients [29; 30; 31]. Clinically, the therapeutic activity of L-DOpa manifests as an improvement in motor functions [29]. Upon oral intake, L-DOPA undergoes most of the biotransformation in the peripheral bloodstream before bypassing the BBB, and only 1% of the applied dose reaches the target [32]. Responsible for this are the dopa-decarboxylase (AADC/DDC) which prematurely converts the molecule of L-DOPA to dopamine making it unable to reach the cerebral circulation, and the catechol-O-methyltransferase transferase (COMT), whose activity yields 3-O-methyldopa [33]. Because of the competitive drug interactions with L-DOPA for transportation across the BBB and the inhibitory activity on dopamine release, the latter metabolite is considered to possess a controversial role in PD therapy, mostly in a negative aspect. Moreover, unlike the short persisting L-DOPA (t\({}_{1/2}\) of L-DOPA is about 1-1.30 h), 3-O-methyldopa possesses a biological half-life of 15 h and tends to cumulate [34]. In accordance with the above, the oral administration of L-DOPA is provided in combination with various DDC and COMT inhibitors with carbodopa (a DDC inhibitor) being the most commonly and successfully utilized [33,35]. Table 1 summarizes levodopa-containing products approved for per os medication of PD patients. Common side effects and shortcomings of the oral L-DOPA combined therapies are the various types of dyskinesia frequently occurring after long-term use [36,37]; particularly, the reoccurrence of motor and non-motor symptoms in between the dosing intervals is referred to as the wearing-off phenomenon [38]. Also recognized is the on-off phenomenon presenting as unpredictable fluctuations in the response to levodopa treatment [39]. The general concepts for the reduction of these adverse reactions and improvement of the therapy's efficacy are