Dendrimers-Based Drug Delivery System in Addressing Parkinson’s Disease

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This entry is adapted from the peer-reviewed paper 10.3390/futurepharmacol2040027

Dendrimers are potential drug delivery systems to cross blood brain barrier. Parkinson’s disease (PD) is a progressive neurodegenerative disease that is characterized by the loss of dopamine. Since dopamine has trouble entering the blood–brain barrier, the utilization of dendrimers and other nanomaterials is considered for conjugating the neurotransmitter and other PD drugs. Dendrimers are three-dimensional, hyper-branched structures that are categorized into several generations. Alpha-synuclein (ASN) is the protein involved in regulating dopaminergic functions and is the main aggregate found inside Lewy bodies. Different types of dendrimers have shown efficacy in disrupting the formation of unstable beta structures of ASN and fibrillation. The conjugation of PD drugs into nanomaterials has elicited a prolonged duration of action and sustained release of the drugs inside the BBB. The objectives of this study are to review the applications of a dendrimer-based drug delivery system in addressing the root cause of Parkinson’s disease and to emphasize the delivery of anti-Parkinson’s drugs such as rotigotine, pramipexole and dopamine using routes of administration other than oral and intravenous.

Parkinson’s disease neurodegenerative alpha-synuclein dendrimer fibrillation

1. Introduction

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease of the central nervous system that affects the initiation and execution of voluntary movements as well as cognitive impairment ^[1]. It is considered one of the most common neurodegenerative diseases second to Alzheimer’s disease. The main morphological alteration common to all forms of PD is the loss of dopamine due to neuronal degeneration and the loss of melanin-containing nerve cells of the substantia nigra pars compacta (SNpc) ^[2]. The cardinal symptoms such as tremors, problems with balance and posture, slowing of movement or bradykinesia, and stiffness of peripherals become more prominent for people beyond 60 years ^[3]. The onset of symptoms is a cascade of events. The dopaminergic pathway starts to degenerate due to a subsequent loss of SNpc neurons. This then results in a substantial decrease in the amount of dopamine that the brain normally produces.

2. The Role of Dopamine and the Dopamine Receptors

Since dopamine is not at its normal level, the natural response of the brain in circumstances such as PD is that it tries to activate the dopamine receptors to produce dopamine like what normally takes place. The conflict with PD is that the SNpc already has a problem since it started deteriorating or degrading, which is why even if the brain instructs it to produce a normal amount of dopamine, it cannot supply the same amount anymore since there is something wrong with its function. This is where anti-Parkinson’s drugs come in specifically levodopa and most of the time in combination with other active ingredients to exert the effect ^[4]. Levodopa, commonly termed L-dopa, is the lipophilic precursor of the BBB-problematic dopamine which remains to be the gold standard of PD symptomatology treatment ^[5]. In practice, levodopa is given together with Carbidopa ^[6], a peripheral dopa decarboxylase inhibitor that prevents the premature conversion of levodopa to dopamine because the latter cannot enter the blood–brain barrier ^[7]. By combining carbidopa with levodopa, the amount of L-dopa being delivered to the brain increases significantly but it is important to take note that carbidopa is not responsible for the increase in dopamine since it mainly serves as support to levodopa and does not perform any synergism ^[7]. Aside from the levodopa–carbidopa combination, some of the anti-PD drugs under study are rotigotine, selegiline, and pramipexole.

However, in a study by Li et al. ^[8], they reported that although dopamine is unable to cross the BBB, the input of dopamine in addressing PD is a better option instead of administering levodopa. This is primarily because the receptor responsible for converting levodopa to dopamine can only do so much, especially if the PD case is still in its early phase. Administering dopamine, the primary neurotransmitter lacking in PD, is a direct solution to a progressive problem. Conversely, it is known that dopamine releases reactive oxygen species (ROS) when oxidized that in turn causes further degeneration to an already deteriorating dopaminergic pathway. However, this phenomenon only happens when dopamine is left outside the BBB waiting to be oxidized by monoamine oxidase and not all metabolites of dopamine cause oxidation. To solve this dilemma, there is a possibility of utilizing a nanomaterial to identify and select specifically the beneficial neuroprotective dopamine metabolite to target the receptors.

3. Anti-Parkinson’s Drugs and Dopamine

3.1. Rotigotine

In the study of Choudhury et al. ^[9], the primary objective is to formulate a stable nanoemulsion version of rotigotine, a non-ergot dopamine agonist which is famously marketed as a Neupro skin patch ^[10]. The main goal is to successfully prepare an adhesive to be applied to a mucosal surface of the body as a manner of drug delivery. In this study, the technique performed in preparing the rotigotine mucoadhesive nanoemulsion is via an aqueous titration method where the active drug, rotigotine, is solubilized in Capryol 90. Supposedly, a rule in formulating nanoemulsions is that the selected solubilizing agent should be the material where the API is most soluble. In this case, the solubilizing agent is Transcutol HP. However, this study found out that although rotigotine is most soluble in Transcutol HP, it will not yield a stable nanoemulsion for the long run, hence the selection of Capryol 90 as an alternative. Moreover, the selection of a suitable rotigotine-loaded nanoemulsion (RNE) to be prepared as a mucoadhesive nanoemulsion is based on the droplet size, polydispersity index (PDI), and most importantly thermodynamic assessment. After subjecting the chosen rotigotine nanoemulsion (RNE) to various stress tests, it was found that the prepared rotigotine mucoadhesive nanoemulsion final preparation (RMNEF) which is derived from the RNE is capable of releasing the API slowly while yielding a very high mucoadhesive strength.

3.2. Pramipexole

In the study by Raj et al. ^[11], the role of chitosan in a nano-sized anti-Parkinson’s drug has been highlighted immensely. The technique of incorporating chitosan with pramipexole is via the ionic gelation method wherein the cation amino group in chitosan interacts with the presence of the negatively charged components of sodium tripolyphosphate (STPP). Chitosan imparted a cationic charge to the formulated pramipexole nanoparticle (P-CN). Since the cell membrane that it attaches to is negatively charged (anion), this gives the advantages of prolonged duration inside the body and improved absorbance. After the morphological evaluation using the transmission electron microscope (TEM), it was revealed that P-CN had a spherical shape which is also beneficial for its improved flow along the bloodstream and during its perfusion to the BBB. According to Okura et al. ^[12], the uptake of pramipexole into the BBB is via a so-called organic cation-sensitive transporter. Since chitosan has a cationic charge and the manner by which pramipexole is being transported to the BBB is via a cationic transporter, this only proves the advantage that chitosan imparted to the formulation because of the similarity of their charges. In this study, the antioxidant activity of pramipexole was also discussed via the measurement of reduced glutathione (GSH) levels. GSH is one of the major antioxidants naturally found in the body and plays a major role in terms of analyzing neurodegenerative diseases such as PD ^[13]. Raj et al. ^[11] finally reported that the administration of P-CN on rotenone-damaged cells has prevented the decline of GSH in the brain cells of the rats via a postmortem analysis. Interestingly, it was previously established in this study that intranasal administration of the formulated P-CN yielded the most improved increase in dopamine levels. However, as far as the antioxidant effect of pramipexole is concerned, the oral version of pramipexole caused the highest improvement in the GSH levels.

3.3. Dopamine

Two research articles specific to dopamine were included to emphasize the assistance of a nanoparticle on the crossing of dopamine to the BBB whilst avoiding oxidation in the periphery. Kang et al. ^[14] have utilized immunoliposomes and polyethylene glycol-assisted (PEGylated) immunoliposome. To demonstrate whether dopamine has been successfully delivered through the BBB, pharmacokinetics testing needs to be performed because clinically speaking, the most optimal way to measure whether the drug is working or not is to observe the very same parameters that can declare its effect.

References

Ding, W.; Ding, L.J.; Li, F.; Han, Y.; Mu, L. Neurodegeneration and cognition in Parkinson’s disease: A review. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 2275–2281.
Moreau, C.; Rolland, A.S.; Pioli, E.; Li, Q.; Odou, P.; Barthelemy, C.; Lannoy, D.; Demailly, A.; Carta, N.; Deramecourt, V.; et al. Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson’s disease. Neurobiol. Dis. 2020, 139, 104846.
Sontheimer, H. Diseases of the Nervous System; Academic Press: Cambridge, MA, USA, 2015; pp. 133–164.
Aradi, S.D.; Hauser, R.A. Medical Management and Prevention of Motor Complications in Parkinson’s Disease. Neurotherapeutics 2020, 17, 1339–1365.
Haddad, F.; Sawalha, M.; Khawaja, Y.; Naijar, A.; Karaman, R. Dopamine and Levodopa Prodrugs for the Treatment of Parkinson’s Disease. Molecules 2018, 23, 40.
Giladi, N.; Gurevich, T.; Djaldetti, R.; Adar, L.; Case, R.; Leibman-Barak, S.; Sasson, N.; Caraco, Y. ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson’s disease and motor response fluctuations: A randomized, placebo-controlled phase 2 study. Parkinsonism Relat. Disord. 2021, 91, 139–145.
Carvey, P.M. Dopa-decarboxylase inhibitors. In Encyclopedia of Movement Disorders; Academic Press: Cambridge, MA, USA, 2010; pp. 313–316.
Li, H.; Yang, P.; Knight, W.; Guo, Y.; Perlmutter, J.S.; Benzinger, T.; Morris, J.; Xu, J. The interactions of dopamine and oxidative damage in the striatum of patients with neurodegenerative diseases. J. Neurochem. 2019, 152, 235–251.
Choudhury, H.; Zakaria, N.F.; Tilang, P.A.; Tzeyung, A.; Pandey, M.; Chatterjee, B.; Alhakamy, N.; Bhattamishra, S.; Kesharwani, P.; Gorain, B.; et al. Formulation development and evaluation of rotigotine mucoadhesive nanoemulsion for intranasal delivery. J. Drug Deliv. Sci. Technol. 2019, 54, 101301.
Thornton, P. Neupro Patch. 2019. Available online: https://www.drugs.com/neupro.html (accessed on 15 September 2020).
Raj, R.; Wairkar, S.; Sridhar, V.; Gaud, R. Pramipexole dihydrochloride loaded chitosan nanoparticles for nose to brain delivery: Development, characterization and in vivo anti-Parkinson activity. Int. J. Biol. Macromol. 2018, 109, 27–35.
Okura, T.; Ito, R.; Ishiguro, N.; Tamai, I. Blood-brain barrier transport of pramipexole, a dopamine D2 agonist. Life Sci. 2007, 80, 1564–1571.
Forman, H.J.; Zhang, H.; Rinna, A. Glutathione: Overview of its protective roles, measurement, and biosynthesis. Mol. Asp. Med. 2009, 30, 1–12.
Kang, Y.; Jung, H.; Suk Oh, J.; Song, D. Use of PEGylated Immunoliposomes to Deliver Dopamine across the Blood-Brain Barrier in a Rat Model of Parkinson’s disease. CNS Neurosci. Ther. 2016, 22, 817–823.

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Subjects: Developmental Biology

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Michaella B. Ordonio

Randa Mohammed Zaki

Amal Ali Elkordy

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Update Date: 27 Oct 2022

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