Nanoparticles show promise for treating Parkinson's disease. Albumin/PLGA nanoparticles conjugated with dopamine improved motor skills in mouse models more than free L-DOPA. Liposomes coated with a peptide derived from rabies virus and carrying a dopamine derivative enhanced cellular uptake and brain penetration. Extracellular vesicles may also help by delivering protective agents, growth factors, dopamine, or silencing alpha-synuclein to reduce symptoms in mouse models. Overall, nanomedicine approaches aim to more effectively deliver drugs to the brain and slow progression of Parkinson's disease.

1. Nanomedicine in
Parkinson’s Disease

2. Parkinson’s disease
 Parkinson's disease is one of the most severe progressive
neurodegenerative disorders. The neural cells producing dopamine in
the substantia nigra of the brain die out. Parkinsonism cannot be cured,
but the symptoms can be reduced with the intervention of medicinal
drugs, surgical treatments, and physical therapies.
 The onset of PD may be due to environmental or genetic factors
 Treating the cause of PD at a genomic level may retard the
degeneration of many dopaminergic neurons.

3. Current therapeutics in PD
• Current therapies against PD are focused on restoring dopamine levels
based on dopamimetic drugs (benserazide/ levodopa, levodopa/
carbidopa, levodopa/ carbidopa/ entacapone) administered by the oral
route
• Unfortunately, these treatments are only symptomatic, with a temporary
effect, and without halting the progression of the disease
• Recent advancements in drug delivery technologies have facilitated drug
delivery to the brain without flooding the bloodstream and by directly
targeting the neurons

4. Nenotechnology /Nanomedicne
 Nanoparticles (NPs) are defined as natural or manufactured materials
comprising unbound or aggregated particles within the nano-size range of
1–100 nm.
 There are several types of NPs including natural inorganic particles,
natural polymers, polyethyleneimine derivatives, dendrimers, carbon-
based nanoparticles, liposomes, micelles, solid lipid nanoparticles
(SLNPs), and nanoemulsions.

5. NPs are ideal for developing new early diagnostic techniques and therapeutic agents for PD. The
attributes of NPs applied as diagnostics, therapeutics, and theranostics are illustrated in figure.

6. Advantages of Nanoparticles
 Overcome challenges such as poor stability, potential immunogenicity,
solubility, and reduced plasma half-life.
 Increase the therapeutics circulation time
 Ideal size and ability to be conjugated to pharmacologically active agents
assure their potential as therapeutic delivery systems
 Nanoscale particles (<100 nm) favor the passage through biological barriers,
such as those found in the nervous system, lung, and vasculature
surrounding tumors.
 Nanomaterials ensure the stability and protection of genetic materials such
as DNA, mRNA, and siRNA and enhance transfection efficacy with low
cytotoxicity.

7. Nanomedicines in Parkinson’s disease
Nanoparticles Year of study Conjugated drug Result
Albumin/ PLGA NP 2021 Dopamine albumin-coated NP, enhanced the interactions of
the NP with specific cell membrane receptors.
dopamine instead of L-DOPA reduced symptoms
in a mouse model compared to control NPs
without dopamine and mice administered with L-
DOPA
Improvements manifested as restoration of
balance, motor coordination, and sensorimotor
performance.

8. Nanoparticles Year of study Conjugated drug Result
LNPs 2020 Ropinirole
(dopamine agonist)
Increased pharmacokinetics was exhibited with respect
to the drug in the host, with more than two-fold
enhancement in oral administration, three-fold
enhancement in topical administration, and single-fold
enhancement in topical bioavailability in SLN and NLC
complexes. Pharmacodynamic studies have portrayed
increased levels of glutathione, catalase, and
dopamine with a reduction in lipid peroxidation levels.
Oil based nanocarrier 2013 Enhanced bioavailability through transdermal route
Solid lipid
nanoparticles (SLN)
2012 Suitable
Pharmacokinetc results and
no severe damage to
integrity of nasal mucosa.

9. Nanoparticle Year of study Conjugated drug Result
Liposomes
together with a brain-
targeted delivery system
made up of a 29 amino acid
peptides (RVG29) derived
from the rabies virus
glycoprotein
2018 dopamine derivative N-3,4-
bis(pivaloyloxy)-dopamine
Significantly improved
cellular uptake was noted in
both the endothelial and
dopaminergic cells, with
improved penetration of
the BBB.
enhanced therapeutic
efficacy was noted due to
the RVG29-LNPs being
selectively driven to the
substantia nigra and
striatum [93].
Biodegradable poly-meric
microspheres
2011 Levodopa-α-lipoic acid (LD-
LA
Improved pharmacokinetic
profile and motor side
effects
SLNPs 2008 Bromocriptine prolongs its half-life
maintaining suitable
pharmacodynamic
outcomes as it decreases
akinesias in 6-OHDA

10. Nanoparticle Year of study Conjugated drug Result
PLGA MS 2013 Rotigotine Showed improved
bioavailability of
rotigotine
PLGA-NPs 2013 Apomorphine, improve the physio-
chemical
characteristics of the
molecule and obtain a
sustained release
according to in vitro
studies
SLNs Apomorphine, oral administration
enhances
the brain uptake of the
drug in the striatum as
well as its bioavailability
Nanoemulsion Ginsenosides showed enhanced
bioavailability in the rat
brain

11. Nanodelivery of Restorative Treatments
 Phytobioactive compounds, Curcumin, resveratrol, ginsenosides, quercetin,
and catechin are phyto-derived bioactive compounds with important roles
in the prevention and treatment of PD.
 Several nanodelivery techniques, including solid lipid nanoparticles,
nanostructured lipid carriers, nanoliposomes, and nano-niosomes can be
used for controlled delivery of nanobioactive compounds to brain.
 Nanocompounds, such as ginsenosides synthesized using a nanoemulsion
technique, showed enhanced bioavailability in the rat brain.

12. Nanodelivery of restorative Treatments
 The effect of resveratrol, one of the most potent antioxidant, has also been enhanced after been
loaded in liposomes. The behaviors, TH+
cells, apoptotic cells, ROS level and antioxidant
capacity were determined in in vivo studies, showing for resveratrol liposome more favorable
effects than free resveratrol.
 Resveratrol has also been loaded in Vitamin E nanoemulsion to improve its pharmacological
properties. Pharmacokinetic studies showed a higher concentration of the drug in the brain
with the nanoemulsion, which was consistent with higher antioxidant activity evaluated by
DPPH (2,2-diphenyl-1-picrylhydrazyl) assay.
 A nano micellar formulation of coenzyme Q10 was developed and tested its effectiveness in a
mouse MPTP model however, results from the clinical trial have not reached evidence enough.

13. Extracellular Vesicles as Nanotherapeutics for
Parkinson’s Disease
 PD Signature Markers in EVs
 In 2006, a study from Théry and colleagues demonstrated for the first time the presence of
EVs in biological fluids, such as blood and urine. Since then, several protocols have been
developed to isolate and purify biofluid-derived EVs—which stably protect their cargoes
from degradation—for the discovery of novel vesicle-associated biomarkers. Virtually all
biofluids are considered important sources of vesicles, where also CNS-derived EVs can be
detected.
 So far, in PD studies, EVs have been isolated from cerebrospinal fluid (CSF), plasma, serum,
saliva, and urine. In addition, EVs have been isolated, in vitro, from the culture supernatant
deriving from a variety of cell types, including brain and peripheral cells.

14. Naturally occurring and engineered EVs as cell-free treatment for PD. EVs may be manipulated to deliver: (i) anti-
oxidant agents (e.g., curcumin, catalase or ApoD) which protect neurons from oxidative stress; (ii) growth factors (e.g.,
GDNF) to stimulate proliferation of DAergic neurons; (iii) DA to ameliorate behavioral parameters; (iv) siRNAs
silencing the expression of SNCA gene to decrease α-Syn levels. Different routes of administration (systemic injection,
intranasal injection and intraperitoneal injection) may be used to treat PD mouse models.