Repositioning of drugs for Parkinson’s disease and pharmaceutical nanotechnology tools for their optimization

Abstract

Parkinson’s disease (PD) significantly affects patients’ quality of life and represents a high economic burden for health systems. Given the lack of safe and effective treatments for PD, drug repositioning seeks to offer new medication alternatives, reducing research time and costs compared to the traditional drug development strategy. This review aimed to collect evidence of drugs proposed as candidates to be reused in PD and identify those with the potential to be reformulated into nanocarriers to optimize future repositioning trials. We conducted a detailed search in PubMed, Web of Science, and Scopus from January 2015 at the end of 2021, with the descriptors “Parkinson’s disease” and “drug repositioning” or “drug repurposing”. We identified 28 drugs as potential candidates, and six of them were found in repositioning clinical trials for PD. However, a limitation of many of these drugs to achieve therapeutic success is their inability to cross the blood–brain barrier (BBB), as is the case with nilotinib, which has shown promising outcomes in clinical trials. We suggest reformulating these drugs in biodegradable nanoparticles (NPs) based on lipids and polymers to perform future trials. As a complementary strategy, we propose functionalizing the NPs surface by adding materials to the surface layer. Among other advantages, functionalization can promote efficient crossing through the BBB and improve the affinity of NPs towards certain brain regions. The main parameters to consider for the design of NPs targeting the central nervous system are highlighted, such as size, PDI, morphology, drug load, and Z potential. Finally, current advances in the use of NPs for Parkinson's disease are cited.

Full text

Hernández‑Parraetal.
Journal of Nanobiotechnology (2022) 20:413
https://doi.org/10.1186/s12951‑022‑01612‑5
REVIEW
Repositioning ofdrugs forParkinson’s
disease andpharmaceutical nanotechnology
tools fortheir optimization
Héctor Hernández‑Parra1,2, Hernán Cortés3, José Arturo Avalos‑Fuentes4, María Del Prado‑Audelo5,
Benjamín Florán4*, Gerardo Leyva‑Gómez2*, Javad Sharifi‑Rad6* and William C. Cho7*
Abstract
Parkinson’s disease (PD) significantly affects patients’ quality of life and represents a high economic burden for health
systems. Given the lack of safe and effective treatments for PD, drug repositioning seeks to offer new medication
alternatives, reducing research time and costs compared to the traditional drug development strategy. This review
aimed to collect evidence of drugs proposed as candidates to be reused in PD and identify those with the potential to
be reformulated into nanocarriers to optimize future repositioning trials. We conducted a detailed search in PubMed,
Web of Science, and Scopus from January 2015 at the end of 2021, with the descriptors “Parkinson’s disease” and “drug
repositioning” or “drug repurposing”. We identified 28 drugs as potential candidates, and six of them were found in
repositioning clinical trials for PD. However, a limitation of many of these drugs to achieve therapeutic success is their
inability to cross the blood–brain barrier (BBB), as is the case with nilotinib, which has shown promising outcomes
in clinical trials. We suggest reformulating these drugs in biodegradable nanoparticles (NPs) based on lipids and
polymers to perform future trials. As a complementary strategy, we propose functionalizing the NPs surface by adding
materials to the surface layer. Among other advantages, functionalization can promote efficient crossing through the
BBB and improve the affinity of NPs towards certain brain regions. The main parameters to consider for the design of
NPs targeting the central nervous system are highlighted, such as size, PDI, morphology, drug load, and Z potential.
Finally, current advances in the use of NPs for Parkinson’s disease are cited.
Keywords: Drug repositioning, Drug repurposing, Parkinson’s disease, Nanoparticles, Nanocarriers, Pharmaceutical
nanotechnology
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Introduction
Neurological disorders are considered a leading cause
of disability [1]. Parkinson’s disease (PD) is the second
most frequent neurodegenerative disease worldwide only
after Alzheimer’s disease [2] and has overgrown in recent
years. In this respect, 6.1 million people were registered
with PD worldwide in 2016, and it caused 211,296 deaths
only in that year [3]. PD affects approximately 1% of the
population over 60years old; the prevalence is around 1.4
times higher in men than in women, increasing with the
population aging [3, 4]. Since life expectancy has been
increasing in the last years, patients with PD are expected
Open Access
Journal of Nanobiotechnology
*Correspondence: bfloran@fisio.cinvestav.mx; leyva@quimica.unam.mx;
javad.sharifirad@gmail.com; chocs@ha.org.hk
2 Departamento de Farmacia, Facultad de Química, Universidad Nacional
Autónoma de México, Ciudad de Mexico, Mexico
4 Departamento de Fisiología, Biofísica & Neurociencias, Centro de
Investigación y de Estudios Avanzados del Instituto Politécnico Nacional
(CINVESTAV‑IPN), Ciudad de Mexico, Mexico
6 Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
7 Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon,
Hong Kong
Full list of author information is available at the end of the article
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
to increase. According to a PD’s global burden study, the
number of PD patients will be approximately 13 million
in 2040 [3]. us, it is expected an enormous social and
economic burden for both health systems and the people
in charge of patient care.
Notwithstanding advances in understanding PD, cur-
rently available therapies are symptomatic but do not
stop the disease’s progression [5]. Besides, drugs used for
PD treatment produce side effects that can be very seri-
ous and disabling, such as dyskinesias. erefore, it is
necessary to implement new drug search and discovery
methods that offer more effective and safer treatment
alternatives. In addition to these worldwide efforts, drug
repositioning has been applied, which reduces costs and
research times compared to the traditional de novo drug
development strategy [6].
Currently, numerous drugs are under study, of which
promising results have been reported [7–12]. However,
despite these results, some drugs present limitations to
achieving therapeutic success, such as bioavailability
problems and reduced capacity to cross the blood–brain
barrier (BBB). is review analyzes information on drugs
proposed for repositioning in the treatment of PD in the
last six years. ose drugs with limitations in their bio-
availability and targeting to the brain are identified, and
pharmaceutical nanotechnology strategies are proposed
to optimize future repositioning studies of these drugs.
e most effective treatment is levodopa, but its benefits
are compromised by unpredictable absorption and exten-
sive peripheral metabolism, leading to motor fluctuations
and loss of efficacy [13].
Parkinson’s disease
Although the exact etiology of PD is not known, the risk
of developing it seems to be determined by biological fac-
tors (such as age), genetic factors (such as the presence of
specific polymorphisms or mutations), and environmen-
tal factors (e.g., exposure to pesticides such as rotenone
and paraquat) [14–16]. PD is characterized by causing
progressive degeneration of dopaminergic neurons of
the substantia nigra pars compacta (SNpc) that project
towards the striatum and other brain nuclei [17]. Another
of its main characteristics is the presence of Lewy bodies,
intraneuronal inclusions formed by insoluble aggregates
of abnormally folded alpha-synuclein protein [18].
e physiological basis of PD is dysfunction of the
basal ganglia due to the loss of dopamine (DA), its cen-
tral modulator [18]. DA is a neurotransmitter that is pro-
duced in the neurons of the substantia nigra; it is released
into the striatum to execute uniform and deliberate
movements [14]. In this context, the loss of DA produces
brain nerve activity abnormalities that cause impaired
movement. Degeneration of dopaminergic neurons
occurs mainly in the SNpc, in which DA is usually syn-
thesized and released to the brain regions that regulate
movement. However, some reports estimate that motor
symptoms appear when more than half (between 50 and
70%) of dopaminergic neurons of the SNpc are degraded
[19]. is delayed effect on motor symptoms is due to
the striatum downstream of the SNpc triggering com-
pensatory mechanisms, which can respond to a certain
degree, as eventually, neurons in the striatum also begin
to die [20]. Both genetic factors (in familial PD) and envi-
ronmental factors (in sporadic PD) converge on specific
pathways, including mitochondrial dysfunction, oxidative
stress, protein aggregation, impaired autophagy, and neu-
roinflammation, leading to the clinical manifestations of
PD [21, 22]. e activation of the c-Abl protein (Abelson
tyrosine kinase) is related to various pathogenic pathways
that could lead to neuronal death in response to oxidative
stress in PD. Oxidative stress has been considered a criti-
cal process in sporadic PD and familial PD. When acti-
vated, the c-Abl protein acts as an oxidative stress sensor
that can generate multiple downstream signals that
lead mainly to parkin inactivation, p38α activation, and
α-synuclein phosphorylation. e inactivation of parkin
causes the accumulation of pathogenic substrates (PARIS
and AIMP2), leading to neuronal death, p38α activation,
and α-synuclein phosphorylation, which are potentially
related to cytotoxicity and neuronal death [23]. In this
respect, the inhibition of the c-Abl protein could repre-
sent a powerful therapeutic target for PD [24, 25].
Burden ofParkinson’s disease
PD symptoms are motor and non-motor and can affect
the patient’s quality of life (QoL) since it is a highly dis-
abling disease. e disabling and progressive effect in a
patient with PD requires other people (caregivers) to
carry out daily activities. e burden for these caregiv-
ers is a broad topic since they must provide emotional,
physical, and social support, and as PD progresses, care
must be more rigorous, so much so that the QoL of car-
egivers can be seriously affected, developing stress, anxi-
ety, depression, and other health problems [26]. PD’s
economic burden is borne by the patient and their fami-
lies, although it also represents a significant burden for
each country’s health systems. In a study conducted in
the US, it is estimated that at least until 2017, PD repre-
sented a total economic burden of $51.9 billion; the total
burden includes direct medical costs of $25.4 billion and
$26.5 billion in indirect and non-medical costs [27]. In
that same study, a total economic burden is projected
for 2037, exceeding 79 billion dollars. Considering that
the greater the disease’s progression, the greater the eco-
nomic cost, we believe that new interventions are neces-
sary and urgent to delay the progression of the disease
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
and alleviate the burden of symptoms, and in this way,
the future burden of PD could be reduced.
Treatment forParkinson’s disease
At present, no treatment cures or stops PD progres-
sion; however, various therapeutic options are limited
to partially alleviating the signs and symptoms, allowing
patients to improve their QoL by less for a time, which
depends on the disease’s progression. Treatment options
include surgical and pharmacological therapies.
Surgical treatment: Deep brain stimulation; Focused
ultrasound; Cell replacement therapies. Many patients
with moderate to advanced disease resort to this type
of treatment in conditions where they do not respond
to pharmacological medication. However, in this type of
treatment, essential aspects such as cost and risk must be
considered, which are generally high. Its success depends
on the appropriate selection of patients and the surgeon’s
experience and skill to optimize results and minimize
complications [28]. In this respect, it is preferable to use
less invasive, cheaper, and less risky therapies, so phar-
macological therapies are used as first-choice treatments.
Pharmacological treatment: Most of these drugs have
focused on restoring neuronal dopaminergic transmis-
sion [18]. However, drugs targeting the glutamatergic,
noradrenergic, serotonergic, and cholinergic systems are
also being used, playing a fundamental role in the basal
ganglia circuits. Nevertheless, these do not stop the pro-
gression of the disease if they have managed to improve
the characteristic symptoms.
Treatment of motor symptoms:
Levodopa It is an oral precursor of DA and is to date
considered the “gold standard” of PD treatment [29], and
it is the most effective drug for the treatment of motor
manifestations [18].
Anticholinergics Like trihexyphenidyl and benztropine,
which antagonize acetylcholine’s effects at postsynaptic
muscarinic receptors to striatal interneurons, they are
used primarily to reduce tremor and have no effect on
bradykinesia [28].
Antiglutamatergics Amantadine (glutamate/NMDA
receptor antagonist). A prolonged-release formulation of
amantadine, administered before bedtime, improves dys-
kinesia and motor fluctuations [28].
Monoamine oxidase inhibitors (MAOIs) Include sele-
giline, rasagiline, and safinamide, which, although more
frequently used in mild and early PD, these MAOIs are
also effective in patients with moderately advanced PD
with levodopa-related motor complications [28, 30].
Dopamine agonists Like the non-ergot derivatives, the
most common of which include pramipexole, ropinirole,
rotigotine, and apomorphine, can be used as mono-
therapy for motor symptoms or add-on therapy when
symptoms are not controlled by levodopa or when motor
fluctuations are present [31].
Catechol-O-methyl transferase inhibitors (COMTI)
Like entacapone, tolcapone, and opicapone, which block
the degradation of peripheral levodopa and the central
degradation of levodopa and DA, increasing the central
levels of these [28].
Adenosine A2 receptor antagonist Istradefylline (Nouri-
anz) is an add-on treatment to levodopa/carbidopa in PD
patients who experience inactive episodes [32].
Treatment of non-motor symptoms:
ere are a wide variety of non-motor symptoms,
including depression, anxiety, apathy, psychosis, to
name a few, and each of them must be treated specifi-
cally. As an example, we cite the treatment of some of
the common non-motor symptoms. Such as donepezil,
rivastigmine, and memantine provide a modest benefit
in patients with PD-associated dementia [28]. Alterna-
tively, pimavanserin, a serotonin inverse agonist with a
high affinity for the 5-HT2A receptor, was approved by
the Food and Drug Administration (FDA) in 2016 to treat
hallucinations and delusions associated with PD [33].
Complications related todrug treatment
Currently available treatment for PD can significantly
improve symptoms. However, with prolonged use, the
efficacy of the drugs tends to decrease, and complica-
tions related to the treatment appear. Patients with PD
show significant variability in response to drugs in terms
of efficacy and adverse effects. Some studies have asso-
ciated interindividual variability in response to treat-
ment with genetic and environmental factors [34–37].
Currently, many studies focus on the genetic variability
in response to levodopa, the main drug used in clinical
practice to treat PD. Some patients have been found to
develop low toxicity at high doses of dopaminergic treat-
ment, while others have severe side effects [38]. Many
patients respond positively to treatment with levodopa
for many years, while others fail to achieve a therapeutic
effect in a few years. Evidence shows that around 40% of
patients develop motor complications within the first 4
to 6years of treatment with levodopa [39, 40]. Although
several genes have been studied, only some of them have
been investigated in large cohorts, such as the DRD2,
COMT, and SLC6A3 gene polymorphisms [34]. Some
authors associate the decreased efficacy of drugs with the
worsening of the disease and the presence of dopaminer-
gic brain lesions and underlying non-dopaminergic ones
[41]. However, it is believed that other genes and factors
could influence the variability in response to drugs and
the decrease in clinical efficacy.
Other complications related to pharmacologi-
cal treatment are motor and motor and non-motor
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fluctuations, dyskinesias, impulse control disorder
(ICD), dopaminergic dysregulation syndrome (DDS),
DA agonist withdrawal syndrome (DAWS), and levo-
dopa withdrawal syndrome [42]. These complications
associated with pharmacological treatment can be
treated specifically, as is the case of Levodopa-induced
dyskinesia (LID), which is reduced by concomitant
administration of amantadine, which is currently the
main drug for its treatment [28]. These side effects can
be even more disabling than those of the disease itself
in the early stages. Among the most recurrent adverse
effects, in general, we find; for DA agonists, drowsi-
ness, nausea, vomiting, dizziness, swelling of the legs,
and sweating; for COMTI, dyskinesias, dizziness,
nausea, vomiting, diarrhea, hallucinations, drowsi-
ness, dry mouth, and abdominal pain; for MAO-B
inhibitors, dizziness, drowsiness, heartburn, nausea,
and weight loss. Also, other drugs can have serious
adverse effects, such as amantadine (which can cause
dizziness, hallucinations, confusion, constipation, hair
loss, and possible exacerbations of heart failure) and
trihexyphenidyl (which cause cognitive impairment,
blurred vision, and urinary retention) [28].
As mentioned, levodopa remains the “gold standard”
in treatment, and response to levodopa is even used as
part of the diagnosis of PD. Unfortunately, treatment
with levodopa after several years of use loses effi-
cacy. Its prolonged use is associated with side effects,
such as response fluctuations and LID, representing
a significant disadvantage of continuous therapy [19].
Levodopa-related fluctuations have various clinical
manifestations, and non-motor fluctuations generally
precede and/or accompany motor fluctuations [43].
Among the motor fluctuations, the one with the earli-
est appearance is the “wearing-off” (end-of-dose dete-
rioration) [44] which is characterized by a progressive
shortening of the period between the intake of one
dose and another levodopa; motor complications also
include dyskinesias [42], different from those char-
acteristics of the natural progression of PD. The ICD
is pathological gambling, compulsive shopping, and
hypersexual disorders, among other behavioral disor-
ders associated with various drugs, such as levodopa,
amantadine, and rasagiline [45, 46]. It is also essential
to consider that not all clinical manifestations of PD
are dopaminergic and that non-dopaminergic symp-
toms (such as sleep disorders, pain syndromes, mood
disorders, and dementia) do not respond effectively to
therapeutic possibilities currently available [42]. It is
necessary to search for novel pharmacological options
and approaches that optimize these drugs and promis-
ing search strategies, as is drug repositioning.
Drug repositioning
e reuse of drugs already approved for different medical
indications is becoming a compelling alternative for the
scientific community and the pharmaceutical industry
[47]. In the future, it could be of even greater interest to
health financing organizations [48]. Drug repositioning
consists of providing new therapeutic use to an existing
drug and is a widely utilized strategy in recent years as
an alternative to de novo drug development [6, 49]. De
novo drug development has become increasingly chal-
lenging as approximately 90% of drugs fail during devel-
opment in phase I clinical trials, making this process very
risky, expensive, and requires a long time of experimenta-
tion [50]. Pharmaceutical companies increasingly explore
drug repositioning with these risks and the low probabil-
ity of success [49]. In recent years, it has been estimated
that roughly a third of approvals are for drug reuse, and
these repurposed drugs generate roughly around 25% of
the annual revenue of the pharmaceutical industry [51,
52].
Drug repositioning takes advantage, considering that a
single molecule can perform on multiple biological tar-
gets. is is known as polypharmacology [36]. It could be
beneficial when additional targets are relevant or part of
some other pathology for which the drug was not indi-
cated initially (Fig.1). Candidate drugs for repositioning,
because they are already approved for use in humans,
have exceeded regulatory standards, including preclini-
cal, clinical, and post-marketing pharmacovigilance stud-
ies [52]. ese studies allow the repositioning process to
be in less time, with less economic investment, and with a
greater probability of success. In this context, if the dose
required for the new indication is the same as that used
for the original symptom, part of the preclinical trials and
even phase I clinical trials can be avoided [52]. However,
new pharmacological safety studies will be necessary if
the dose is higher or lower than that used in the origi-
nal indication. Another advantage is that they can repre-
sent a desirable market for the pharmaceutical industry
because when drugs are without intellectual protection,
or their patent has expired, the possibility of obtaining a
patent for the new indication opens up [53]. However, an
ideal condition would be that the new indication requires
non-marketed concentrations or that the drug requires
a pharmaceutical reformulation, for example, in a novel
form of administration that allows optimizing its use. By
modifying the formulation of a reused drug, reformula-
tors could obtain a novel patent since the invention would
be considered a new composition of matter [54]. Histori-
cally, many drugs have been successfully repositioned;
some examples of successful repositioning are Sildenafil,
which was initially studied for use in hypertension and
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
angina pectoris but has been repositioned to treat erec-
tile dysfunction [50]. Rituxan was initially indicated for
non-Hodgkin lymphoma and later approved for chronic
lymphocytic leukemia and rheumatoid arthritis [55].
Currently, there are many candidate drugs for reposi-
tioning in multiple pathologies, which gives us hope in
the face of the difficult task of finding new therapies for
difficult-to-treat diseases, including neurodegenerative
ones such as PD, which despite multiple efforts, has not
yet developed a therapy capable of stopping or reversing
the disease.
Drug repositioning inParkinson’s disease
Some drugs have been successfully repositioned for
PD treatment, such as amantadine, an antiviral reposi-
tioned to treat LID [14]. Currently, many drugs are in
studies as candidates for repositioning for PD, some
with encouraging results, but that need to be optimized
for better efficacy. In this context, it is necessary to do
bibliographic reviews that gather all this evidence, iden-
tifying areas of opportunity to propose improvements
and solutions to possible limitations. We reviewed for
the last few years (2015-present) to identify those drugs
currently being proposed for repositioning in PD. e
search was carried out in PubMed NCBI, Scopus, and
Web of Science, with the search terms “(Parkinson’s
disease) and (drug repositioning or drug repurposing),”
and it was found that drug repositioning studies for PD
have increased in recent years (Fig.2). For example, for
the PubMed search in the first two years of this period
(2015–2017), only 41 publications were retrieved, and
in the last four years (2018–2021), up to 98 publica-
tions, indicating an increase of more than 50% in arti-
cles related to at least our search conditions. e above
demonstrates the expansion that the repositioning of
drugs in PD is taking and the growing interest in the
scientific community to communicate its results for the
public benefit and find new treatment alternatives for
PD.
Many are in early studies between the drug candidates
for repositioning in silico or invitro, and many others are
in more advanced studies such as preclinical or clinical
trials. In this analysis, 28 drugs were selected as proposed
to be reused in PD treatment. e initial therapeutic
Fig. 1 Drug repositioning and polypharmacology. A drug can have more than one active site, which allows the molecule to target different organs
and gives rise to multiple therapeutic indications; this is known as polypharmacology and is used in the repositioning of drugs since there are
drugs approved for a therapeutic indication for which its biological target is known, but with the potential to target other tissues and alleviate other
pathologies
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
indication, mechanism of action, the new suggested ther-
apeutic indication, and the proposal for its new mecha-
nism of action are highlighted in Table1.
e previous studies demonstrated conclusive evi-
dence in invitro and invivo models. In addition to these,
a search was carried out on https:// clini caltr ials. gov, and
six drugs with evidence from clinical trials were found as
possible treatments for PD.
Exenatide It is one of the most studied drugs and has
promising results for successful repositioning. At least
until the first half of 2021, three trials were found in
the recruitment status, two in an active status, one ter-
minated, and one in an unknown status (a study that
has passed its end date and has not had a status update
in more than 2 years). e study with the identifier
NCT01971242 was concluded in November 2016. Its
main objective was to compare exenatide’s effective-
ness versus placebo in the motor subscale MDS-UPDRS
(Movement Disorder Society‐Unified Parkinson’s Disease
Rating Scale) in patients with PD of moderate severity. A
phase II study (research phase to describe clinical trials
that collect preliminary data on drug efficacy and assess
the safety and short-term adverse events) with 60 par-
ticipants, with a double-blind, placebo-controlled trial.
Exenatide had positive effects on motor scores. How-
ever, it is unknown whether exenatide affects PD’s patho-
physiology or induces long-lasting symptomatic effects.
Nevertheless, exenatide represents an encouraging pro-
posal for reuse in PD.
Nilotinib We found three clinical trials registered on
https:// clini caltr ials. gov, one in an unknown state and
two in a terminated state for this drug. e most recent
completed study with identifier NCT03205488 published
its first results in July 2020; it was randomized, double-
blind, placebo-controlled, phase II, parallel-group, two
cohorts, to define the safety, tolerability, and biological
activity of chronic administration of nilotinib in partici-
pants with PD. In this study, daily oral administration
of nilotinib was evaluated as a chronic treatment of PD
symptoms. e results demonstrated acceptable safety
and tolerability of nilotinib. However, the low CSF (cer-
ebrospinal fluid) exposure combined with the trend-neg-
ative efficacy data led the authors of this clinical trial to
suggest that nilotinib should not be further tested in PD.
Recently (March 2021), Simuni etal. [66] reported that in
a phase II clinical trial, it failed to change levels of dopa-
mine and associated it with the fact that nilotinib has low
exposure to cerebrospinal fluid, indicating poor brain
penetration; therefore, these assays could be optimized
by reformulation in functionalized nanoparticles (NPs).
Considering the results of other trials where efficacy data
have been reported, we suggest that clinical trials should
continue to optimize drug delivery to the Central nerv-
ous system (CNS).
Fig. 2 The number of publications indexed in PubMed, Web of Science, and Scopus that contain the terms “(Parkinson’s disease) and (drug
repositioning or drug repurposing)” in the last years (01/2015–07/2021)
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Table 1 Drugs proposed for repositioning in PD with suggested new mechanisms of action
Drugs Initial therapeutic indication Initial mechanism of action Novel therapeutic indication
suggested Novel mechanism of action
suggested Model of evaluation References
Exenatide Type II diabetes mellitus GLP‑1 receptor agonist that
promotes glucose‑dependent
insulin secretion
Neuroprotective in PD Exerts neuroprotective effects
through GLP‑1 receptors,
resulting in motor perfor‑
mance improvements, behav‑
ior, learning, and memory
Clinical trial, single‑center,
randomized, double‑blind,
placebo‑controlled. The trial
included 60 patients
[7]
Levetiracetam Partial and generalized epilepsy The mechanism is unclear. It is
suggested that the binding to
synaptic vesicle 2A is the key
factor in its action
Neuroprotective in PD Counteracts the effect of
pathological mutant expres‑
sion of LRRK2 G2019S. It is a
specific neuroprotectant on
the mutant pathological toxic‑
ity of LRRK2
Three cell models:
Primary cortical neurons
obtained from C57BL/6 LRRK2
WT and LRRK2 G2019S BAC
mice
PC12 cells expressing doxy‑
cycline (dox) inducible LRRK2
G2019S mutant
SH‐SY5Y cells expressing the
dopamine D2 receptor‑bear‑
ing a Flag epitope
[8]
Semaglutide Type II diabetes mellitus It binds selectively to the GLP‑1
receptor and stimulates insulin
synthesis, causing a decrease
in blood glucose
Neuroprotective in PD Improves motor disturbances,
reduces the decrease in TH lev‑
els, the accumulation of α‑syn,
and increases the expression of
GDNF that protects dopamin‑
ergic neurons in the substantia
nigra and the striatum
Mouse model of chronic PD
with MPTP
Seventy‑two male C57BL/6
mice of 8 weeks of age were
used
[10]
Vitamin B12 Vitamin B12 deficiencies Cofactor for the enzyme
methionine synthase, essential
for synthesizing purines and
pyrimidines
Neuroprotective in PD AdoCbl modulates the activity
of LRRK2, which leads to altera‑
tions of protein conformation
and ATP binding in LRRK2
(inhibits kinase activity)
Mouse model. BAC LRRK2
(R1441G) and BAC LRRK2
(G2019S) transgenic mice,
male, 3 to 5 months of age,
and their non‑transgenic
littermates for LRRK2 kinase
inhibition in striatal brain slices
[11]
Pomalidomide Multiple myeloma Antineoplastic activity, inhibits
proliferation and induces
apoptosis of various tumor
cells
Neuroprotective in PD TNF‑α inhibitory activity.
In Drosophila, inhibition of
inflammatory pathways trig‑
gered by the Eiger ortholog
may be the main mechanism
LRRK2WD40 model of PD.
Drosophila melanogaster,
with LRRK2 loss‑of‑function
mutation in the WD40
domain. Adult wild type and
LRRKWD40 mutants males
were used
[47]
Dabrafenib Metastatic melanoma with the
BRAF V600E mutation Inhibits B‑Raf kinase activity
and decreases the proliferation
of tumor cells that contain a
mutated BRAF gene
Neuroprotective in PD It inhibits apoptosis and
enhances the phosphorylation
of ERK. There is a protein–pro‑
tein interaction between B‑Raf
and Rit2 (RIT2, PD risk gene)
Cellular model: SH‑SY5Y
human neuroblastoma cells
and HEK293T cells were used
Animal model: C57BL/6 J mice,
8 to 12 weeks old, 20 to 25 g,
were used
[56]
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
Table 1 (continued)
Drugs Initial therapeutic indication Initial mechanism of action Novel therapeutic indication
suggested Novel mechanism of action
suggested Model of evaluation References
Ketoconazole Fungal infections Interacts with 14‑α‑sterol dem‑
ethylase, inhibit the synthesis
of ergosterol, increasing the
permeability of fungal cells
Neuroprotective in PD Mechanism not suggested.
The increase in dopaminergic
neuron death was stopped
Drosophila transgenic model
of PD. The UAS‑alpha‑synuclein
transgenic strain was gener‑
ated using an attp40 insertion
site strain and the Drosophila
PhiC31 system
[57]
Felodipine Mild to moderate essential
hypertension Decreases vasoconstriction by
inhibiting the entry of calcium
ions through voltage‑gated
L‑type calcium channels
Neuroprotective in PD Eliminates mutant α‑syn in the
brain of mice Zebrafish model and murine.
The atg7 mutant fish line
(atg7sa14768) and two differ‑
ent neurodegenerative disease
mouse models (HD‑N171–82Q
mice and SNCA (A53T) G2‑3
mice) and an mRFP‑GFP‑LC3
reporter line were used
[58]
Raloxifene Osteoporosis in postmenopau‑
sal women SERM, increases the expression
of proteins in the bone matrix Neuroprotective in PD It prevents the loss of
dopaminergic neurons in the
myenteric plexus, avoiding the
increase in pro‑inflammatory
macrophage density
Mouse model of PD with MPTP.
Male C57BL/6 mice, ten weeks
old, divided into 6 groups of 8
to 9 mice
[59]
Omarigliptin Type II diabetes mellitus Inhibitor of DPP‑4 Neuroprotective in PD Increasing GLP‑1 and other
hormone levels by inhibiting
the degrading enzyme DPP‑4
Murine model. Twenty‑four
rats were used, weighing
200 g ± 25, randomly assigned
into four groups (n = 6)
[60]
Triflusal Prophylaxis of thromboembolic
disorder Acetylation of the active group
of COX‑1 prevents the forma‑
tion of thromboxane‑B2 in
platelets
Neuroprotective in PD It increases endogenous FGF20
production both in the nigros‑
triatal tract and in the ventral
mesencephalic
6‑OHDA lesioned rat model.
120 adult male Sprague Daw‑
ley rats, 250 to 280 g
[61]
Candesartan High blood pressure, heart
failure AT1 receptor antagonist. The
antihypertensive action is due
to the decrease in systemic
peripheral resistance
Neuroprotective in PD AT1 blockers lead to a decrease
in the number of OX6‑ir micro‑
glial cells, expression of CD68
mRNA, NADPH activity, expres‑
sion of markers of the M1
phenotype, and α‑syn‑induced
dopaminergic neuronal death
α‑syn overexpression model,
in AAV9‑α‑syn vector. Adult
male Sprague–Dawley rats,
8 to 10 weeks old, n = 220.
Subgroup B1 (n = 28) was
treated with vehicle, subgroup
B2 (n = 24) with candesartan,
and subgroup B3 (n = 24) with
telmisartan
[62]
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
Table 1 (continued)
Drugs Initial therapeutic indication Initial mechanism of action Novel therapeutic indication
suggested Novel mechanism of action
suggested Model of evaluation References
Telmisartan Hypertension AT1 receptor antagonist. It
binds selectively, blocking
their effects and decreasing
systemic vascular resistance
Neuroprotective in PD AT1 blockers lead to a decrease
in the number of OX6‑ir micro‑
glial cells, expression of CD68
mRNA, NADPH activity, expres‑
sion of markers of the M1
phenotype, and α‑syn‑induced
dopaminergic neuronal death
α‑syn overexpression model,
in AAV9‑α‑syn vector. Adult
male Sprague–Dawley rats,
8 to 10 weeks old, n = 220.
Subgroup B1 (n = 28) was
treated with vehicle, subgroup
B2 (n = 24) with candesartan,
and subgroup B3 (n = 24) with
telmisartan
[62]
Nitazoxanide Gastrointestinal infections Cell membrane injury in
parasites and depolarizes the
mitochondrial membrane
Neuroprotective in PD Loss in OCR and ATP produc‑
tion are improved. It confers
protection against the loss of
TH‑positive neurons of the SN
Mouse model of acute PD with
MPTP. Male C57BL‑6 J mice, 6
to 8 weeks old, 22 to 25 g, in 6
groups of 6 animals
[63]
Metformin Type II diabetes mellitus It inhibits the activity of
mitochondrial complex I.
Lowers blood glucose levels
by decreasing gluconeogen‑
esis and decreasing intestinal
glucose absorption
Neuroprotective in PD It rescued TH‑positive neurons,
restored DA depletion and
behavioral disturbances. Neu‑
roprotection could be medi‑
ated by inhibition of α‑syn
phosphorylation and induction
of neurotrophic factors
Protects rotenone‑induced
dopaminergic neurodegen‑
eration by reducing lipid
peroxidation
Mouse model of subchronic
PD with MPTP. Adult male
C57BL/6 mice, 10 weeks old,
20 to 25 g, in 4 groups with
6 mice
Mouse model of PD with
rotenone. C57BL/6 mice were
given an injection of saline or
rotenone (2.5 mg/kg/day, ip)
for 10 days
[64]
[65]
Nilotinib Chronic myelogenous leuke‑
mia It inhibits the tyrosine kinase
activity of the BCR‑ABL
protein (oncogene that causes
myelogenous leukemia)
Neuroprotective in PD Inhibits the enzyme c‑Abl.
In PD, this protein loses its
original shape and forms
aggregates that the brain
cannot discard and damage
neurons
Clinical trial. Single‑center,
phase 2, randomized, double‑
blind, placebo‑controlled trial
with 75 patients randomized
1:1:1 to placebo; nilotinib
150 mg; or nilotinib 300 mg
[9, 50]
Exemestane Advanced breast cancer in
postmenopausal women It binds irreversibly to the
aromatase active site, reduces
estrogen concentrations. This
delays tumor growth and
disease progression
Neuroprotective in PD It activates the Nrf2 signaling
pathway, induces the gene
expression of NQO1, HO‑1,
and GCL, and suppresses
inflammatory responses. By
elevating antioxidant enzymes,
it appears to protect nigral
dopaminergic neurons
Cell cultures. BV‑2 murine
microglial cells and CATH.
Murine dopaminergic neu‑
ronal cells were cultured
Murine model. Male C57BL/6 J
mice, 23 to 25 g, 8 weeks old,
four groups (n = 10); vehicle‑
treated; MPTP; MPTP plus
1 mg/kg exemestane; MPTP
plus 10 mg/kg exemestane
[67]
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
Table 1 (continued)
Drugs Initial therapeutic indication Initial mechanism of action Novel therapeutic indication
suggested Novel mechanism of action
suggested Model of evaluation References
Salbutamol Bronchospasm and other
chronic bronchopulmonary
disorders
Activation of β2AR in airway
smooth muscle leads from
cAMP activation to muscle
relaxation
Neuroprotective in PD
Associated with a lower risk
of PD
It increases endogenous FGF20
production in the nigrostri‑
atal tract and can potentially
impact the survival of dopa‑
minergic neurons
The β2AR ligands modulate
the α‑syn gene’s transcription
(SNCA) through the acetylation
of histone 3 lysine 27 from its
promoter
6‑OHDA lesioned mouse
model. 120 adult male Sprague
Dawley rats, 250 to 280 g. 80
rats in the in vivo screening
and 40 in the neuroprotection
study with 6‑OHDA
The effects of β2AR activation
were evaluated in a mouse
model of human parkinsonism
induced by MPTP and in a neu‑
ronal culture system derived
from induced pluripotent stem
cells
[61]
[68]
Pentamidine Pneumocystis carinii pneu‑
monia The exact mechanism is
unclear. It is believed to inter‑
fere with nuclear metabolism
Improves motor performance
in PD It produces inhibition of S100B,
which inhibits the RAGE/NF‑κB
pathway in the nigrostriatal
circuit, giving an improvement
in motor performance
Mouse model of PD with MPTP.
Male C57Bl/6 J mice, 8 weeks
old
[69]
Ceftriaxone Bacterial infections (antibiotic) The beta‑lactam fraction
binds to carboxypeptidases,
endopeptidases, and trans‑
peptidases in the bacterial
cytoplasmic membrane;
bacteria produce defective
cell walls
Anti‑ LID Can attenuate the loss of TH
together with an increase in
glutamate uptake and the
expression of the glutamate
transporter GLT‑1, this increase
could reach the threshold of
the expression level of GLT‑ 1
needed to prevent or reduce
LID
Rat model of 6‑OHDA. Male
Sprague Dawley rats (N = 38), 4
to 9 months old. The study was
carried out in replicas in the
three participating institutions
[12]
Vilazodone Antidepressant The exact mechanism
is unclear. It is known to
selectively inhibit serotonin
reuptake and act as a partial
agonist at 5HT‑1A receptors
Anti‑ LID It selectively inhibits L‑DOPA‑
induced gene regulation in
the direct pathway of the
dopamine‑depleted striatum
Hemiparkinsonian rat model
injured with 6‑OHDA
Mice were randomly divided
into four experimental groups
(n = 8 each). A subacute model
of MPTP toxicity induced
experimental parkinsonism
in mice
[54, 55]
Methylene blue Acquired methemoglobinemia It reacts within red blood cells,
converts the ferric ion (Fe3+)
to its oxygen‑bearing ferrous
state (Fe2+)
Anti‑ LID Antidyskinetic effects are likely
to occur through inhibition of
sGC in the CNS
6‑OHDA lesioned rat model.
Adult male Wistar rats, 200 to
250 g
[70]
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
Table 1 (continued)
Drugs Initial therapeutic indication Initial mechanism of action Novel therapeutic indication
suggested Novel mechanism of action
suggested Model of evaluation References
Nalbuphine Analgesic (moderate to severe
pain) The exact mechanism of action
is unknown, but it is believed
to interact with an opiate
receptor site in the CNS
Anti‑ LID Striatum analyzes showed that
nalbuphine co‑therapy blocks
several molecular pathways
of LID
Model of PD in non‑human
primates treated with MPTP.
Macaques with advanced
parkinsonism and reproducible
LID received subcutaneous
treatment as monotherapy,
acute coadministration with
levodopa, and chronic coad‑
ministration for 1 month
[71]
Ketamine General anesthetic It interacts with N‑methyl‑D‑
aspartate (NMDA) receptors,
opioid receptors, muscarinic,
monoaminergic, and voltage‑
sensitive Ca ion channels
Anti‑ LID The effect is mediated by the
release of BDNF in the striatum,
followed by activation of ERK1
/ 2 and mTOR signaling. This
leads to a reduction in the
mushroom spines’ density, a
phenotype highly correlated
with LID
LID rodent model
Two Sprague–Dawley rats,
male, adult, and about 225 g
The severity of the LID was
evaluated by an investigator
blinded to the experimental
conditions
[72]
Dimethyl fumarate Multiple sclerosis It is not very well known. It is
believed to upregulate the
Nrf2 pathway that is activated
in response to oxidative stress
PD‑associated synucleinopa‑
thy Activates NRF2 in the basal
ganglia, protects nigral
dopaminergic neurons against
α‑syn toxicity, and decreases
astrocytosis and microgliosis
Nrf2 − / − and Nr f2 + / + mice.
An adeno‑associated pseudo‑
type 6 (rAAV6) viral vector was
used to express human α‑SYN
under the neuron‑specific
human Synapsin 1 promoter
[73]
Kanamycin Bacterial infections (antibiotic) It binds to four nucleotides of
the 16S rRNA, which interferes
with the initiation complex
PD‑associated synucleinopa‑
thy It effectively inhibits the solu‑
tion phase and lipid‑induced
aggregation of α‑syn
The effect of Kanamycin on
the binding affinities of Α‑Syn
towards both the model and
mimic SUVs was studied using
a specific lipid‑staining fluores‑
cent probe DiIC‑18 (DiD)
[74]
Incyclinide o CMT‑3 Reduced antibiotic activity They have been used in trials
to treat HIV infection, among
others, for which the specific
mechanisms are not yet
known
PD‑associated synucleinopa‑
thy Inhibits α‑syn amyloid aggre‑
gation. Disassembles α‑syn
fibrils into smaller fragments
that cannot be seeded in sub‑
sequent aggregation reactions
(fibril extraction mechanism)
Cell cultures in SH‑SY5Y.
SH‑SY5Y cells were incubated
with α‑synuclein oligom‑
ers prepared in the absence
or the presence of CMT‑3,
and an LDH assay measured
cytotoxicity
[75]
Doxycycline Bacterial infections (broad‑
spectrum antibiotic) It inhibits translation by bind‑
ing to the 16S rRNA portion
of ribosome 9, preventing the
binding of tRNA to the 30S
subunit
PD‑associated synucleinopa‑
thy It reforms the oligomers of
α‑syn and inhibits their aggre‑
gation, thus avoiding cytotox‑
icity in dopaminergic cells
Human neuroblastoma cell
culture. SH‑SY5Y cells were
grown in DMEM supple‑
mented with fetal bovine
serum
[76]
AdoCbl Adocobalamina, AT1 Angiotensin II type 1, BDNF Brain‑derived neurotrophic factor, cAMP Cyclic adenosine monophosphate, CMT-3 Tetracycline 3 modied chemically, CNS Central nervous system, COX‑1
Cyclooxygenase‑1, DA Dopamine, DPP‑4 Dipeptidyl peptidase‑4, ERK Extracellular Signal–Regulated Kinase, FGF20 Fibroblast growth factor 20, GCL Ganglion cell layer, GDNF Glial cell line–derived neurotrophic factor,
GLP‑1 Glucagon‑like peptide 1, HO‑1 Heme oxygenase‑1, LID L‑DOPA‑induced dyskinesia, LRRK2 Leucine‑rich repeat kinase 2, mTOR Mammalian target of rapamycin, MPTP 1‑methyl‑4‑phenyl‑1, 2, 3, 6‑tetrahydropyridine,
NF‑kB Factor nuclear‑kappa B, NQO1 NADPH: quinone oxidoreductase 1, OCR Oxygen consumption rate, PD Parkinson’s disease, RAGE Receptor for advanced glycation end products, SERM Selective estrogen receptor
modulator, sGC Soluble guanylyl cyclase, TH Tyrosine hydroxylase, TNF‑α Tumor necrosis factor α, α‑syn α‑Synuclein, 6‑OHDA 6‑Hydroxydopamine
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
Levetiracetam (LEV) This drug currently presents
three clinical trials in the terminated phase, one in the
suspended phase, one in the recruiting phase, and one
in the unknown phase. The three completed trials are
on the anti-LID activity of LEV in PD, and no conclu-
sive results have been published. A phase IV trial, with
identifier NCT00307450, was concluded in July 2009,
conducted as a randomized, double-blind, placebo-
controlled, parallel-group pilot study in PD patients
with moderate to severe LID on stable dopaminer-
gic treatment. This study aimed to evaluate the effi-
cacy, safety, and tolerability of LEV for the treatment
of LID in PD, and it was observed that LEV had mild
antidyskinetic effects without worsening parkinsonian
symptoms or compromising the efficacy of levodopa.
B12 vitamin A clinical trial of vitamin B12 for PD
has been found. This study with the ClinicalTrials.gov
identifier: NCT00208611 was a phase III trial, and its
objective was to evaluate the status of cobalamin and
the response to supplementation in patients with PD.
However, this trial was unsuccessful and terminated
because funding ended, and patient enrollment was
not completed within the specified time frame. This
study could also provide critical pilot data to evalu-
ate treatment efficacy for patients considered to have
below-normal serum vitamin B12 levels.
Ceftriaxone This drug is currently in a clinical trial
under the ClinicalTrials.gov identifier: NCT03413384.
It is in recruitment status and is a phase II trial, with
an estimated study completion date of May 2022. This
study evaluates the efficacy and safety of ceftriaxone in
patients with mild PD dementia. The effects observed
in the animal model of PDD (Parkinson’s disease
dementia) have suggested that ceftriaxone is a poten-
tially promising medical treatment for PDD patients to
improve cognitive and motor function defects.
Semaglutide This drug is one of those recently pro-
posed for reuse in PD that has reached clinical trials; it
is currently in a trial with the ClinicalTrials.gov iden-
tifier: NCT03659682. This study is in a state of “not
yet recruiting,” with an estimated completion date of
December 2024 to test the neuroprotective and anti-
inflammatory properties of semaglutide in PD.
These clinical trials expose us to how promising drug
repositioning could be in PD. There are drugs with sat-
isfactory results to suggest more comprehensive stud-
ies, such as exenatide, levetiracetam, and nilotinib, on
the right path to repositioning. On the other hand,
some trials have remained in an “unknown” state,
which has not been given continuity and for which it
is necessary to carry out a more detailed review of the
possible causes of not reporting the findings.
Pharmaceutical nanotechnology strategies
foroptimizing drug repositioning inParkinson’s
disease
Pharmaceutical nanotechnology enables novel approaches
to drug delivery [77]. One promising approach is NPs as
carriers for drug transport. NPs allow overcoming phar-
macological limitations such as low solubility, rapid bio-
degradation, low bioavailability, adverse effects, and low
permeability through biological barriers [78]. e main
challenges in developing a formulation to treat PD include
an efficient crossing of the drug through the BBB and con-
trolled drug release to avoid fluctuations in concentration.
e BBB has the function of protecting the CNS, restrict-
ing the entry of harmful xenobiotics, regulating the pas-
sage of endogenous molecules, and limiting therapeutic
agents’ entry [79, 80]. Because PD therapies are generally
chronic, taking medications by mouth is a comfortable
and safe option for patients; however, studies of NPs with
the ability to overcome both the BBB and the gastroin-
testinal barrier are needed. Currently, the approaches for
administering drugs through the BBB are direct injec-
tion and implantation, the temporary opening of the BBB,
intravenously (IV), and intranasally [81–86]. An effec-
tive nanocarrier of drugs for PD should ideally be capa-
ble of protecting the drug from physiological conditions,
overcoming the BBB and target neurons in the brain, and
guaranteeing a controlled release at the site of action [19,
87]. Several internalization mechanisms have been found
through the BBB that are mainly influenced by the surface
properties of NPs; these are receptor-mediated endocyto-
sis, adsorption-mediated endocytosis, macropinocytosis,
and opening of tight junctions [88–91].
Biodegradable nanoparticles
NPs can be synthesized from different materials offering
variable physicochemical characteristics, which allow dif-
ferent interactions with biological systems. We suggest
using biodegradable NPs (polymeric and lipid, Fig.3) in
drug reformulation for optimal repositioning in PD since
they offer numerous advantages over other materials (for
example, metallic or ceramic). Currently, there is plenti-
ful research on synthesis procedures and applications of
polymeric NPs, the use of biopolymers has the advantage
that there are well-established methods for their develop-
ment, and there is extensive information on their toxicity.
Also, polymers offer a high capacity to modify their phys-
icochemical properties to synthesize NPs [19]. Some of
the most successful polymeric materials in their use are
gelatin, hyaluronic acid, alginate (ALG), chitosan (CS),
polylactic-co-glycolic acid (PLGA), polylactide (PLA),
polyethylene glycol (PEG), polycaprolactone (PCL), and
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
polyanionic cellulose (PAC) [78]. Lipid nanoparticles
have certain advantages that make them attractive to be
used as nanocarriers in PD [92], mainly their composi-
tion of lipid matrix (based on phospholipids, cholesterol,
triglycerides) that is physiologically tolerable, leads to lit-
tle toxicity, scalability of production without the need for
organic solvents, and their high bioavailability [93].
Physicochemical parameters fortheoptimization ofNPs
ere is currently no consensus on the physicochemi-
cal characteristics that NPs must meet to achieve greater
drug delivery efficiency to the CNS since these charac-
teristics depend on the specific materials used in their
synthesis. Relatively large-sized NPs, but with suitable
surface coatings (e.g., non-ionic surfactants, cationic
polymers), have been found to pass through the BBB;
therefore, it is advisable to evaluate each proposed nano-
formulation invitro and invivo. However, for the design
of NPs targeting the CNS, certain parameters must be
considered in a general way, such as size, PDI, morphol-
ogy, drug load, and Z potential.
Concerning size, it has been reported that there is
greater absorption as size decreases; NPs of 100nm in
diameter are significantly more absorbed than larger par-
ticles [94, 95]. Another study showed that the smallest
NPs, between 50 and 100nm, do not exhibit a significant
difference in cell absorption [96]. On the other hand, it
has been documented that even NPs of 345nm [19] and
up to 422nm can cross the BBB (these larger-sized NPs
were functionalized with non-ionic surfactants) [97]. In
2020, Lombardo et al. conducted an extensive review,
gathering data from more than 50 articles reporting NPs
with sizes between 100 and 345nm with efficient cross-
ing through the BBB [98]. Gao and Jiang studied the
influence of particle size on the transport of methotrex-
ate through the BBB by polysorbate 80-coated polybutyl-
cyanoacrylate NPs. ey studied NPs with sizes from 70
to 345nm, finding that NPs between 170 and 345nm did
not present a significant difference in methotrexate deliv-
ery to the brain [99]. erefore, we suggest that a size of
NPs between 100 and 345nm could be used as a refer-
ence point to start testing for BBB internalization. e
PDI must be less than 0.1 for a monodisperse size distri-
bution to be considered [100].
Concerning morphology, spherical NPs are preferred
because they guarantee an adequate volume/contact
surface ratio [101]. Regarding drug loading, it is prefer-
able to transport drugs in NPs with high loading capac-
ity to ensure greater delivery of drugs with a low number
of NPs and to avoid the toxic accumulation of materials
used to synthesize NPs [19]. e drug loading capacity in
NPs is a difficult parameter to control; most of them have
the drawback of low drug loading (generally less than
10%); therefore, nanosystems with high drug loading
capacity are necessary, which reach a drug load greater
than 10% [102]. Compared to the physical encapsulation
of drug molecules in inert carriers, polymer-drug conju-
gates are good candidates for NPs with high drug load-
ing due to their limited use of carrier materials. In this
context, Shen etal. developed linear conjugates of poly-
mer-drug by conjugating one or two molecules of strong
hydrophobic camptothecin (CPT) to a very short oligoe-
thylene glycol chain, reaching a drug load content of 40
to 58% [103]. For brain-targeted drugs that need to cross
the blood–brain barrier, carrier materials are essential for
their function, and some materials allow good drug load-
ing. For example, PLGA NPs with a size of ~ 184. 6nm
have achieved a drug loading capacity of 10.21 ± 0.89%
[104]. Other PLGA NPs with a size of ~ 155nm reached
their highest drug loading capacity of 20.6% [105]. e
influence of the Z potential, on the one hand, allows
controlling the stability of NPs in solution; on the other
hand, it allows controlling the interaction with the bio-
logical environment. For greater stability of NPs only by
Fig. 3 Biodegradable nanoparticles. Nanosystems are proposed
for the optimization of drug delivery in PD. NPs based on lipids
and polymers are the most interesting since they are synthesized
based on biodegradable and biocompatible materials representing
low toxicity and a high capacity to modify their physicochemical
properties
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
electrostatic repulsion, an absolute minimum Z poten-
tial value of |30mV| is required, approximately |20mV|
provides short-term stability, and values in the range of
|5 mV| indicate low stability (rapid aggregation) [106].
In the case of a stabilization of NPs that combine elec-
trostatic repulsion and steric stabilization (electrosteric
stabilization), generally, it is required to have a minimum
value of |20mV|. e NPs are stabilized with the help of
non-ionic surfactants; therefore, the resulting steric effect
contributes substantially to the stability of NPs with zeta
potentials below |20 mV| [106, 107]. Although, due to
the negative surface charge of the endothelial cells of the
BBB, NPs with positive Z potential are preferable to pro-
mote bioadhesion (by the principle of electro-attraction)
and, consequently, the permeability of the BBB.
Upon contact with biological matrices, most materials
are immediately coated with proteins, forming a protein
crown [108]. e affinity for proteins is higher towards
hydrophobic nanomaterials or charged surfaces than
hydrophilic or neutral ones [109]. Neutrally charged NPs
have been shown to have a distinctly slower opsonization
rate than charged particles [110]. A study on the influ-
ence of the zeta potential of negatively charged polymeric
NPs showed an increase in plasma protein uptake with
increasing surface charge density [111]. Nanomaterials
with hydrophobic surfaces have an affinity for adsorb-
ing apolipoproteins, albumin, and fibrinogen, whereas
hydrophilic surfaces bind a smaller proportion of these
proteins [112]. erefore, the formation of the protein
corona cannot be completely avoided. An option is to
adhere to materials with a nearly neutral charge or highly
hydrophilic on the surface of the NPs; if the adhesion of
proteins is completely avoided, NPs could become toxic
[19].
Surface functionalization
NPs surface functionalization allows materials to be
added to the surface layer to target NPs to specific recep-
tors found on particular cell types (e.g., dopaminergic
neurons) and improve cell permeability. For this reason,
various materials such as polymers, proteins, and other
additives have been assessed [113] (Fig. 4a). In Table2,
we cite examples of potential materials used as NPs
surface linkers for drug delivery in PD. A study has sug-
gested and successfully demonstrated that membrane
factors, such as transferrin receptors (TfRs), can promote
NPs transcytosis by specific interaction with gastrointes-
tinal endothelial cells [114]. At the brain level, lactoferrin
(Lf) is a ligand that favors the absorption of NPs in the
BBB since there is an increase in the expression of lacto-
ferrin receptors (LfRs) in the substantia nigra and striatal
dopaminergic neurons, as well as in the endothelial cells
of the BBB of PD patients [115, 116]. us, the efficacy of
NPs in PD can be improved by functionalizing the sur-
face with Lf and Tf that act as ligands to promote recep-
tor-mediated transcytosis (Fig.4b).
Current advances inNPs forParkinson’s disease
Reports detailed the presentation of drugs currently
being used for PD and have been reformulated in NPs.
For instance, Zhao etal. [123] developed polymeric NPs
based on PEG–PCL. e formulation encapsulated Gink-
golide B (GB), which is believed to act in a neuroprotec-
tive way and treat PD. GB has poor oral bioavailability,
limiting its clinical application, and these NPs facilitated
sustained release, thus enhancing its ability to accu-
mulate in the brain and treat PD. e NPs had a size of
91.26 ± 1.34nm, polydispersity index (PDI) of 0.17 ± 0.01,
the zeta potential of −12.09 ± 0.97mV, load capacity of
26.93%, and encapsulation efficiency (EE) of 87.52%. A
biphasic release pattern was observed, and ~ 30% of the
total GB was released during the first two h, followed
by a more gradual sustained release of 94% until a 48h
period. is characteristic could be improved by playing
with polymer concentrations or even coating the surface
with other polymers such as CS. Bromocriptine (BRC) is
a widely used PD drug that slows down and minimizes
the motor fluctuations associated with L-DOPA. Shadab
etal. [124] developed BRC-loaded CS NPs with an aver-
age size of 161.3nm, a zeta potential of 40.3mV, load
capacity 37.8%, EE of 84.2%, and increased brain activity
uptake of BRC-NPs was observed. Gambaryan etal. [125]
developed PLGA NPs loaded with L-DOPA, with a size
of 250 ± 50nm and EE of 10 ± 2%. e authors recorded
an L-DOPA-PLGA-NPs increased motor function during
the treatment period of 112days by the intranasal route,
demonstrating a prolonged effect even one week after the
interruption of treatment with the possible reduction of
the effective drug dose and the frequency of administra-
tion. Fernandes etal. [126] developed PLGA-PEG NPs,
as carriers of coumarin, a potent drug inhibitor of mono-
amine oxidase B (MAO-B), reversible and selective, but
with suboptimal aqueous solubility, which prevents its
use invivo tests. e NPs had an average size of 105nm,
a zeta potential of −10.1mV, and EE of 50%. e PLGA
NPs inhibited P-glycoprotein (P-gp) and could cross the
intestinal and brain membranes, allowing the successful
transport of coumarin to the brain. In these reports, pol-
ymeric materials (CS, PCL, PEG, and PLGA) are attrib-
uted to the ability to have an affinity for the BBB and to
be able to permeate it effectively.
Reports of functionalized nanocarriers have also been
found, which have presented promising results for PD
use. Lopalco etal. [117] developed liposomes (LP) loaded
with dopamine hydrochloride (DA HCl) functionalized
with Tf, with a size of 181.7 ± 7.8nm, EE of 35.4 ± 1.8%,
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Page 15 of 23
Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
PDI of 0.2, and potential zeta of + 7.5mV. Stability was
evaluated by measuring their size and PDI for one month;
then, the amount of DA was determined by high-perfor-
mance liquid chromatography (HPLC), and no significant
variations were detected, so it was stated that the vesi-
cles are stable and can be used for future studies. With
these LP, an improvement of the crossing of the BBB was
achieved, increasing the benefits and reducing the com-
plications of patients undergoing chronic treatment with
L-Dopa. On the other hand, Huang etal. [127] developed
polyamidoamine (PAMAM) NPs and PEG functionalized
in the same way with Lf, with an average size of 196nm, a
zeta potential of 29.35mV, and loaded with plasmids for
neurotrophic factor derived from the human glial cell line
(hGDNF). GDNF is considered the gold standard neuro-
trophic factor for PD therapy. However, GDNF cannot
cross the BBB; thus, the formulation in NPs becomes
capable of crossing the BBB and exerting a neuroprotec-
tive effect on dopaminergic neurons.
Reformulation strategies ofNPs forParkinson’s disease
In the present review, we have identified the drugs cur-
rently being proposed for drug repositioning and the
areas of opportunity for a possible reformulation in NPs
(Table 3) that allow future repositioning studies to be
optimized. eir ability to cross the BBB was also identi-
fied, and whether they have been previously reformulated
into NPs.
Fig. 4 a Increased specificity towards BBB. The surface coating of NPs with suitable materials can increase the specificity towards the BBB; these
materials (as mentioned in Table 2) can be polymers, proteins, antibodies, peptides, and other additives. b Receptor‑mediated transcytosis. The
passage through the BBB is exemplified through receptor‑mediated transcytosis. A very frequently used pathway for the transport of NPs to the
brain, for this use, is assembled with specific receptors found in the BBB
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Page 16 of 23
Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
We found that most of the drugs proposed for repo-
sitioning in PD have been reformulated in NPs, at least
for research purposes. However, most have been refor-
mulated to overcome the gastrointestinal barrier. ere-
fore, we identified that it is necessary to test these drugs
in NPs to improve the BBB crossing and brain bioavail-
ability. e following is evidence of drugs that have been
reformulated in NPs, focusing on overcoming BBB; how-
ever, not all formulations have had the same effects on the
central nervous system. Kumar etal. [140] encapsulated
Dimethyl fumarate in solid lipid nanoparticles (SLN)
synthesized from tocopherol acetate, with a mean size of
69.70nm, PDI of 0.317, the zeta potential of −9.71mV,
EE of 90.12%, and load capacity of 20.13%. e research
confirmed higher intestinal absorption and neuronal
uptake through cell uptake studies in Caco-2 and SH-
SY5Y monolayers, and oral bioavailability increased 4.09
times. Brain bioavailability substantially improved com-
pared to the drug alone. Recently, Khanna etal. [149],
encapsulated Nalbuphine (NLB) in SLN synthesized from
phosphatidylcholine, with an average size of 170.07nm,
encapsulation efficiency of 93.6%, and loading capacity
of 26.67%. NLB-SLN brain targeting was confirmed by
noninvasive scintigraphy, reaching its maximum perme-
ability eighth h after intranasal administration. Omarch
etal. [145] conducted a comparative study; the authors
developed polymeric PCL NPs and phosphatidylcholine
LP to evaluate pentamidine in vitro transport through
the BBB. e pentamidine-loaded PCL NPs had a mean
size of 267.58 nm, PDI of 0.25, and zeta potential of
–28.1mV, while pentamidine-loaded LP had a mean size
of 119.61nm, PDI of 0.25, and zeta potential 11.78mV.
Pentamidine loading was 0.16µg/mg (w/w) and 0.17µg/
mg (w/w) in PCL NPs and LP, respectively. LP carried
87% of the dose, PCL NPs 66% of the dose, and free pen-
tamidine penetration was 63% of the dose. erefore, the
results suggested that LP are more efficient nanocarriers
for transporting pentamidine through the BBB, at least
invitro. LP were synthesized from L-phosphatidylcholine
and cholesterol and, therefore, are considered biocom-
patible, biodegradable, and less toxic; these reports offer
better brain bioavailability of drugs that can be exploited
in the better management of PD.
erefore, NPs are an attractive strategy in the repo-
sitioning of drugs for the treatment of PD that can
guarantee an adequate therapeutic treatment as an
Table 2 Examples of materials to functionalize the surface of NPs proposed for drug delivery in PD
B Borneol, CS Chitosan, C6 Coumarin 6, DA Dopamine, DGL Dendrigraft poly‑L‑lysine, GNP Gold nanoparticles, hGDNF Human glial‑derived neurotrophic factor, Lf
Lactoferrin, LP Liposomes, NGF Nerve growth factor, NPs Nanoparticles, M PEG‑b‑PCL copolymer, pDNA Plasmid DNA, PEG Polyethylene glycol, PLGA Poly Lactic‑co‑
Glycolic Acid, RHCl Ropinirole hydrochloride, Tf Transferrin, 7pep Transferrin receptor specic 7peptide
Composition of NPs Functional material Function Mechanism References
7pep‑M‑C6 Transferrin Crossing of gastrointestinal barrier Enter the cells through a specific clathrin‑
mediated mechanism [114]
DA‑Tf‑LP Transferrin Crossing of BBB BBB crossing by Tf receptor‑mediated
endogenous transcytosis [117]
B‑Lf‑PEG‑PLGA Lactoferrin Effective biological ligand to the
striatum The Lf receptor is overexpressed in epithe‑
lial cells, capillaries, and neurons in PD. Cel‑
lular uptake occurs via receptor‑mediated
transcytosis to Lf
[115]
DA‑PEG‑LP Polyethylene glycol Evasion of the immune system PEG coating is believed to increase its
biological half‑life due to reduced interac‑
tions with plasma proteins or cell surface
receptors
[118]
Selegiline‑CS Chitosan Crossing of BBB and mucosal barriers The mucoadhesive nature of QS improves
mucosal retention time, improves permea‑
bility through the BBB through endocyto‑
sis by electrostatic adhesion, and through
an opening of tight junctions
[119]
pDNA‑NGF‑GNP Nerve growth factor Improves neural uptake Enhances neuronal uptake through NGF
receptor‑mediated endocytosis [120]
hGDNF‑Angiopep‑DGL‑PEG Angiopep Crossing of BBB Angiopep is a ligand that specifically binds
to low‑density lipoprotein receptor‑
related protein (LRP that is overexpressed
on the BBB and crosses by transcytosis
[121]
RHCl‑Polysorbate 80‑CS Polysorbate 80 Crossing of BBB Coating with polysorbate 80 helps in the
adsorption of plasma proteins from blood
and thus, facilitates the entry of nanopar‑
ticles to BBB by the receptor‑mediated
endocytosis
[122]
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
Table 3 Drugs with areas of opportunity for reformulation in NPs for PD
Drug Clinical trial status Cross the BBB? Formulated in NPs? (Type/composition) Area of opportunity
Exenatide 3–Recruiting
2–Active
1–Terminated
1–Unknown
Yes Polymeric NPs/CSK‑DEX‑PLGA [128] Rapidly eliminated by glomerular filtration, reformulation in NPs
could increase its half‑life in plasma and avoid enzymatic degrada‑
tion
Levetiracetam 3–Terminated
1–Suspended
1–Recruiting
1–Unknown
Yes Polymeric NPs/PLGA [129] Reformulation in NPs could reduce the dose and administration
frequency, reducing side effects
Semaglutide 1–Not yet recruiting No Liposome/Phospholipid‑ cholesterol [130] NPs could improve stability, bioavailability, and passage through the
BBB and avoid toxic accumulation due to its half‑life of approxi‑
mately one week
Vitamin B12 1–Terminated Yes Lipid‑protein NPs/Barley protein‑α‑tocopherol‑Phospholipids [131] Reformulate in NPs with surface functionalization allows their
targeting to the brain
Pomalidomide N/I Restricted
(P‑gp substrate) N/I BCS class IV, reformulation in NPs could improve intestinal absorp‑
tion and permeability through the BBB
Dabrafenib N/I Restricted
(P‑gp substrate) N/I Reformulation in NPs with anti‑P‑gp surface functionalization could
allow passage through the BBB
Ketoconazole N/I Restricted
(P‑gp substrate) Polymeric NPs/PLGA [132] Low solubility. Reformulation in NPs could offer a controlled release,
reduce toxic effects, and achieve greater bioavailability
Felodipine N/I Yes Polymeric NPs/PLGA [133]
SLN/Glyceryl behenate [134]Variable bioavailability, poor solubility, and extensive liver metabo‑
lism. Reformulation in NPs could offer greater brain bioavailability
Raloxifene N/I Yes Polymeric NPs/CS [135]
SLN/Glyceryl behenate [136]Low oral bioavailability, poor solubility, and extensive metabolism
in the intestine (> 90%). Reformulation in NPs could improve oral
bioavailability
Candesartan N/I Yes SLN/Trimyristin‑Tripalmitin‑Tristearin [137] Low oral bioavailability, poor solubility. Reformulation in NPs could
improve oral bioavailability and target the brain
Telmisartan N/I Yes
(dose‑dependent) Polymeric NPs/PLA [138] Low oral bioavailability, poor solubility. NPs could allow greater
penetration of the BBB and target the brain
Nitazoxanide N/I Low permeability SLN/Hydrogenated palm oil‑ Hydrogenated soybean lecithin [139] Reformulation in NPs could allow more passage through the BBB,
greater control of the dosage, and avoid toxic effects
Metformin N/I Yes Polymeric NPs/Alginate [140] BCS class III, low absorption. Reformulation in NPs could facilitate
absorption and control the dosage and release at the specific site
of action
Nilotinib 1 – Active
2 – Terminated Low permeability Polymeric micelles/Styrene‑co‑maleic acid [141] Low exposure to CSF limits its use in PD. Reformulation in function‑
alized NPs could allow vectorization towards the CNS
Exemestane N/I Yes Polymeric NPs/Alginate [142] Reformulating in NPs could improve solubility and bioavailability,
control release, and decrease side effects
Salbutamol N/I Yes Polymeric NPs/PLGA, and poly(vinyl sulfonate‑co‑vinyl alcohol)‑
graft‑PLGA [143]Low oral bioavailability. Reformulation in NPs could allow the target‑
ing of the target neurons
Pentamidine N/I Low permeability Polymeric NPs/PLGA [144]
Liposome/Phosphatidylcholine
Polymeric NPs/PCL [145]
It can cause diabetes and other toxic effects. Reformulation in NPs
could improve permeation through the BBB, greater control of the
dosage, and avoiding toxic effects
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Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
Ag Silver, Au Gold, BBB Blood–brain barrier, BCS Biopharmaceutical classication system, CMT-3 Tetracycline 3 modied chemically, CNS Central nervous system, CS Chitosan, CSF Cerebrospinal uid, CSK CSKSSDYQC
peptide, DEX Dextran, N/I No information, NPs Nanoparticles, PCL Poly ɛ‐caprolactone, PD Parkinson’s disease, PEG Polyethylene glycol, P-gp P‑glycoprotein, PLA Polylactic acid, PLGA Poly lactic‑co‑glycolic acid, SiO2 Silicon
dioxide, SLN Solid lipid nanoparticles
Table 3 (continued)
Drug Clinical trial status Cross the BBB? Formulated in NPs? (Type/composition) Area of opportunity
Ceftriaxone 1 – Recruiting Yes Polymeric NPs/CS [146] It is administered parenterally. Only 1% oral bioavailability, reformu‑
lation in NPs could increase its bioavailability and allow a controlled
release
Vilazodone N/I Restricted
(P‑gp substrate) Polymeric NPs/Copolymer Soluplus®‑Polyvinylpyrrolidone [147] Low solubility. Reformulation in NPs could increase bioavailability
and permeation through the BBB
Methylene blue N/I Yes Metallic NPs/Ag [148] Rapid distribution in tissues. Severe toxicity in high doses. Refor‑
mulation in NPs could allow controlled dosage and vectorization
towards the CNS
Nalbuphine N/I Yes SLN/Phosphatidylcholine [149] They are limited to parenteral use. High concentrations can cause
sedation. Reformulation of NPs could allow oral administration and
greater dosage control
Ketamine N/I Yes Polymeric NPs/PEG‑PLGA [150] Short half‑life. Serious adverse effects. Reformulation in NPs could
increase their bioavailability and specific release in target neurons
Dimethyl fumarate N/I Low permeability SLN/Tocopherol acetate [151] Short half‑life. Reformulation in NPs could improve bioavailability,
brain permeability and reduce adverse effects
Kanamycin N/I Low permeability Metallic NPs/Au [152] Relatively insoluble in lipids. Reformulation in NPs could allow
greater oral bioavailability and permeation through the BBB
CMT‑3 N/I Yes N/I Multi‑target drug. Reformulation in NPs could allow targeting of
target neurons
Doxycycline N/I Yes Polymeric NPs/PLGA‑PCL (153) Reformulation in NPs would allow the sustained administration of
the drug, minimizing adverse effects
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Page 19 of 23
Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
adjuvant or as the main treatment, with a shorter inves-
tigation time.
Conclusion
In PD, drug delivery to affected areas of the brain is
desired; however, most molecules cannot cross the BBB,
leading to the failure of clinical trials of many drugs pro-
posed for reuse in PD. Drug repositioning in PD is a topic
of growing interest to the scientific community and the
pharmaceutical industry, as it reduces the number of
steps required for clinical development and reduces the
amount of time and costs to bring a drug to regulatory
approval. Another advantage of repositioning is that the
clinical profile of approved drugs is already well char-
acterized. us, researchers can often move directly to
Phase II evaluations for efficacy trials in the new indi-
cation of interest. In this review, we identified 28 drugs
that have been proposed as candidates for repositioning
in PD in recent years; most of them have an inability or
low ability to cross the BBB. To overcome this limita-
tion and optimize future PD repositioning studies, we
propose using lipid and polymeric nanosystems: lipid-
based NP (SLN, micelles and LP) and polymeric-based
NP (nanocapsules, nanospheres and polymeric micelles).
ese nanosystems show promise for overcoming the
pharmacokinetic limitations of conventional therapies.
Among their main advantages, they can protect the drug
from degradation, provide sustained release, facilitate
entry into the CNS, and deliver the drug to specific cells
to target particular intracellular pathways. Surface func-
tionalization with polymers, peptides, antibodies, and
surfactants, among other materials, is also proposed as a
strategy that has been shown to promote efficient cross-
ing through the BBB. Six drugs were found in reposition-
ing clinical trials for PD, of which nilotinib has shown
promising results. e current COVID-19 pandemic has
evidenced drug repositioning as a hopeful strategy for
drug development for difficult-to-treat diseases such as
PD, although it has also been evidenced that better pro-
tocols and regulations are needed to direct this activity.
Acknowledgements
Héctor Hernández‑Parra is currently a PhD student in the “Doctorado en Cien‑
cias en la Especialidad de Farmacología”, Centro de Investigación y de Estudios
Avanzados del Instituto Politécnico Nacional, and received a fellowship (CVU
1043048) from CONACYT, Mexico. Gerardo Leyva‑Gómez acknowledges
the financial support by CONACYT grant (CB A1‑S‑15759) and PAPIIT‑UNAM
IN204722. The authors thank www. Biore nder. com for the figures created.
Author contributions
HHP, HC, JAAF, MLDPA, BF, GLG, JSR, WCC made a significant contribution to
the work reported, whether that is in the conception, study design, execution,
acquisition of data, analysis, and interpretation, or in all these areas—that is,
revising or critically reviewing the article; giving final approval of the version to
be published; agreeing on the journal to which the article has been submit‑
ted; and confirming to be accountable for all aspects of the work. All authors
have read and approved the final manuscript.
Funding
No Funding received.
Availability of data and materials
Yes.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
No competing interest.
Author details
1 Depar tamento de Farmacología, Centro de Investigación Y de Estudios
Avanzados del Instituto Politécnico Nacional (CINVESTAV‑IPN), Ciudad de
Mexico, Mexico. 2 Departamento de Farmacia, Facultad de Química, Universi‑
dad Nacional Autónoma de México, Ciudad de Mexico, Mexico. 3 Laboratorio
de Medicina Genómica, Departamento de Genómica, Instituto Nacional de
Rehabilitación Luis Guillermo Ibarra Ibarra, Ciudad de Mexico, Mexico. 4 Depar‑
tamento de Fisiología, Biofísica & Neurociencias, Centro de Investigación y de
Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV‑IPN), Ciudad
de Mexico, Mexico. 5 Escuela de Ingeniería Y Ciencias, Tecnologico de Monter‑
rey, Campus Ciudad de México, C. Puente 222, 14380 Ciudad de México,
Mexico. 6 Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador.
7 Depar tment of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong
Kong.
Received: 19 May 2022 Accepted: 31 August 2022
References
1. GBD 2015 Neurological Disorders Collaborator Group. Global, regional,
and national burden of neurological disorders during 1990–2015: a
systematic analysis for the Global Burden of Disease Study 2015. Lancet
Neurol. 2017;16(11):877–97.
2. Saavedra Moreno JS, Millán PA, Buriticá Henao OF. Introducción, epi‑
demiología y diagnóstico de la enfermedad de Parkinson. Acta Neurol
Colomb. 2019;35(1):2–10. https:// doi. org/ 10. 22379/ 24224 022244.
3. GBD 2016 Neurological Disorders Collaborator Group. Global, regional,
and national burden of Parkinson’s disease, 1990–2016: a systematic
analysis for the Global Burden of Disease Study 2016. Lancet Neurol.
2018;17(11):939–53.
4. Tysnes OB, Storstein A. Epidemiology of Parkinson’s disease. J Neural
Transm. 2017;124(8):901–5.
5. Chen X, Gumina G, Virga KG. Recent Advances in drug repurposing for
Parkinson’s disease. Curr Med Chem. 2018;26(28):5340–62.
6. Parisi D, Adasme MF, Sveshnikova A, Bolz SN, Moreau Y, Schroeder M.
Drug repositioning or target repositioning: a structural perspective
of drug‑target‑indication relationship for available repurposed drugs.
Comput Struct Biotechnol J. 2020;18:1043–55.
7. Athauda D, Maclagan K, Skene SS, Bajwa‑Joseph M, Letchford D,
Chowdhury K, et al. Exenatide once weekly versus placebo in Parkin‑
son’s disease: a randomised, double‑blind, placebo‑controlled trial.
Lancet. 2017;390(10103):1664–75.
8. Rassu M, Biosa A, Galioto M, Fais M, Sini P, Greggio E, et al. Levetiracetam
treatment ameliorates LRRK2 pathological mutant phenotype. J Cell
Mol Med. 2019;23(12):8505–10.
9. Pagan FL, Hebron ML, Wilmarth B, Torres‑Yaghi Y, Lawler A, Mundel EE,
et al. Nilotinib effects on safety, tolerability, and potential biomarkers
in Parkinson disease: a phase 2 randomized clinical trial. JAMA Neurol.
2020;77(3):309–17.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 20 of 23
Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
10. Zhang L, Zhang L, Li L, Hölscher C. Semaglutide is neuroprotective
and reduces α‑synuclein levels in the chronic MPTP mouse model of
Parkinson’s disease. J Parkinsons Dis. 2019;9(1):157–71.
11. Schaffner A, Li X, Gomez‑Llorente Y, Leandrou E, Memou A, Clemente N,
et al. Vitamin B 12 modulates Parkinson’s disease LRRK2 kinase activity
through allosteric regulation and confers neuroprotection. Cell Res.
2019;29(4):313–29.
12. Chotibut T, Meadows S, Kasanga EA, McInnis T, Cantu MA, Bishop
C, et al. Ceftriaxone reduces L‑dopa–induced dyskinesia sever‑
ity in 6‑hydroxydopamine parkinson’s disease model. Mov Disord.
2017;32(11):1547–56.
13. Baskin J, Jeon JE, Lewis SJG. Nanoparticles for drug delivery in Parkin‑
son’s disease. J Neurol. 2021;268(5):1981–94. https:// doi. org/ 10. 1007/
s00415‑ 020‑ 10291‑x.
14. National Institute of Neurological Disorders and Stroke. Parkinson’s
Disease: Hope Through Research. Bethesda, Maryland; 2020. https://
www. ninds. nih. gov/ Disor ders/ Patie nt‑ Careg iver‑ Educa tion/ Hope‑ Throu
gh‑ Resea rch/ Parki nsons‑ Disea se‑ Hope‑ Throu gh‑ Resea rch. Accessed 21
Dec 2020.
15. Tanner CM, Kame F, Ross GW, Hoppin JA, Goldman SM, Korell M, et al.
Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect.
2011;119(6):866–72.
16. Nandipati S, Litvan I. Environmental exposures and Parkinson’s disease.
Int J Environ Res Public Health. 2016;13(9):881.
17. Benazzouz A, Mamad O, Abedi P, Bouali‑Benazzouz R, Chetrit J.
Involvement of dopamine loss in extrastriatal basal ganglia nuclei in
the pathophysiology of Parkinson´s disease. Front Aging Neurosci.
2014;6(87):1–5.
18. Martínez Fernández R, Gasca Salas C, Sánchez Ferro Á, Obeso JÁ.
Actualización en la enfermedad de Parkinson. Rev Med Clin Condes.
2016;27(3):363–79.
19. Leyva‑Gómez G, Cortés H, Magaña JJ, Leyva‑García N, Quintanar‑Guer‑
rero D, Florán B. Nanoparticle technology for treatment of Parkinson’s
disease: the role of surface phenomena in reaching the brain. Drug
Discov Today. 2015;20(7):824–37.
20. Zeng XS, Geng WS, Jia JJ, Chen L, Zhang PP. Cellular and molecular
basis of neurodegeneration in Parkinson disease. Front Aging Neurosci.
2018;10(109):1–16.
21. Chen Z, Li G, Liu J. Autonomic dysfunction in Parkinson’s disease: impli‑
cations for pathophysiology, diagnosis, and treatment. Neurobiol Dis.
2020;134(104700):1–18.
22. Simon DK, Tanner CM, Brundin P. Parkinson Disease epidemiol‑
ogy, pathology, genetics and pathophysiology. Clin Geriatr Med.
2020;36(1):1–12.
23. Brahmachari S, Karuppagounder SS, Ge P, Lee S, Dawson VL, Dawson
TM, et al. c‑Abl and Parkinson’s disease: mechanisms and therapeutic
potential. J Parkinsons Dis. 2017;7(4):589.
24. Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM,
Ko HS. The c‑Abl inhibitor, Nilotinib, protects dopaminergic neu‑
rons in a preclinical animal model of Parkinson’s disease. Sci Rep.
2014;4(4874):1–8.
25. Abushouk AI, Negida A, Elshenawy RA, Zein H, Hammad AM, Menshawy
A, et al. C‑Abl Inhibition; a novel therapeutic target for parkinson’s
disease. CNS Neurol Disord Drug Targets. 2017;17(1):14–21.
26. Martinez‑Martin P, Rodriguez‑Blazquez C, Forjaz MJ. Quality of life and
burden in caregivers for patients with Parkinson’s disease: concepts,
assessment and related factors. Expert Rev Pharmacoeconomics Out‑
comes Res. 2012;12(2):221–30.
27. Yang W, Hamilton JL, Kopil C, Beck JC, Tanner CM, Albin RL, et al. Current
and projected future economic burden of Parkinson’s disease in the U.S.
NPJ Park Dis. 2020;6(15):1–9.
28. Jankovic J, Tan EK. Parkinson’s disease: etiopathogenesis and treatment.
J Neurol Neurosurg Psychiatry. 2020;91(8):795–808.
29. Marsot A, Guilhaumou R, Azulay JP, Blin O. Levodopa in Parkinson’s
disease: a review of population pharmacokinetics/pharmacodynamics
analysis. J Pharm Pharm Sci. 2017;20:226–38.
30. Schapira AHV, Fox SH, Hauser RA, Jankovic J, Jost WH, Kenney C, et al.
Assessment of safety and efficacy of safinamide as a levodopa adjunct
in patients with Parkinson disease and motor fluctuations a rand‑
omized clinical trial. JAMA Neurol. 2017;74(2):216–24.
31. Latt MD, Lewis S, Zekry O, Fung VSC. Factors to consider in the selection
of dopamine agonists for older persons with Parkinson’s disease. Drugs
Aging. 2019;36(3):189–202. https:// doi. org/ 10. 1007/ s40266‑ 018‑ 0629‑0.
32. Torti M, Vacca L, Stocchi F. Istradefylline for the treatment of Parkin‑
son’s disease: is it a promising strategy? Expert Opin Pharmacother.
2018;19(16):1821–8. https:// doi. org/ 10. 1080/ 14656 566. 2018. 15248 76.
33. Cummings J, Isaacson S, Mills R, Williams H, Chi‑Burris K, Corbett
A, et al. Pimavanserin for patients with Parkinson’s disease psy‑
chosis: a randomised, placebo‑controlled phase 3 trial. Lancet.
2014;383(9916):533–40.
34. Politi C, Ciccacci C, Novelli G, Borgiani P. Genetics and treatment
response in Parkinson’s disease: an update on pharmacogenetic stud‑
ies. NeuroMolecular Med. 2018;20(1):1–17. https:// doi. org/ 10. 1007/
s12017‑ 017‑ 8473‑7.
35. Alonso‑Navarro H, Jimenez‑Jimenez F, Garcia‑Martin E, Agundez J.
Genomic and pharmacogenomic biomarkers of Parkinson’s disease.
Curr Drug Metab. 2014;15(2):129–81.
36. Jiménez‑Jiménez FJ, Alonso‑Navarro H, García‑Martín E, Agúndez JAG.
Advances in understanding genomic markers and pharmacogenetics
of Parkinsons disease. Expert Opin Drug Metab Toxicol. 2016;12(4):433–
48. https:// doi. org/ 10. 1517/ 17425 255. 2016. 11582 50.
37. Schumacher‑Schuh AF, Rieder CRM, Hutz MH. Parkinson’s disease phar‑
macogenomics: new findings and perspectives. Pharmacogenomics.
2014;15(9):1253–71.
38. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, et al.
Levodopa and the progression of Parkinson’s disease. N Engl J Med.
2004;351(24):2498–508.
39. Kalinderi K, Fidani L, Katsarou Z, Bostantjopoulou S. Pharmacologi‑
cal treatment and the prospect of pharmacogenetics in Parkinson’s
disease. Int J Clin Pract. 2011;65(12):1289–94. https:// doi. org/ 10. 1111/j.
1742‑ 1241. 2011. 02793.x.
40. Ahlskog JE, Muenter MD. Frequency of levodopa‑related dyskinesias
and motor fluctuations as estimated from the cumulative literature.
Mov Disord. 2001;16(3):448–58.
41. Nonnekes J, Timmer MHM, de Vries NM, Rascol O, Helmich RC, Bloem
BR. Unmasking levodopa resistance in Parkinson’s disease. Mov Disord.
2016;31(11):1602–9. https:// doi. org/ 10. 1002/ mds. 26712.
42. Pirtošek Z, Bajenaru O, Kovács N, Milanov I, Relja M, Skorvanek M.
Update on the management of Parkinson’s disease for general neurolo‑
gists. Parkinsons Dis. 2020;2020:1–13.
43. Pistacchi M, Gioulis M, Sanson F, Marsala S. Wearing off: A complex
phenomenon often poorly recognized in Parkinson’s disease. A study
with the WOQ‑19 questionnaire. Neurol India. 2017;65(6):1271–9.
44. Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the
treatment of Parkinson disease. Neurology. 2009;72(21 SUPPL. 4):1–136.
45. Antonini A, Chaudhuri KR, Boroojerdi B, Asgharnejad M, Bauer L,
Grieger F, et al. Impulse control disorder related behaviours during
long‑term rotigotine treatment: a post hoc analysis. Eur J Neurol.
2016;23(10):1556–65.
46. Gatto EM, Aldinio V. Impulse control disorders in Parkinson’s Disease. A
brief and comprehensive review. Front Neurol. 2019;10(351):1–19.
47. Casu MA, Mocci I, Isola R, Pisanu A, Boi L, Mulas G, et al. Neuroprotec‑
tion by the immunomodulatory drug pomalidomide in the Drosophila
LRRK2WD40 genetic model of Parkinson’s disease. Front Aging Neuro‑
sci. 2020;12(31):1–13.
48. Parsons CG. CNS repurposing ‑ potential new uses for old drugs:
examples of screens for Alzheimer’s disease, Parkinson’s disease and
spasticity. Neuropharmacology. 2019;147:4–10.
49. Athauda D, Foltynie T. Drug repurposing in Parkinson’s disease. CNS
Drugs. 2018;32(8):747–61. https:// doi. org/ 10. 1007/ s40263‑ 018‑ 0548‑y.
50. Von Eichborn J, Murgueitio MS, Dunkel M, Koerner S, Bourne PE, Preiss‑
ner R. PROMISCUOUS: a database for network‑based drug‑reposition‑
ing. Nucleic Acids Res. 2011;39(SUPPL. 1):D1060–6.
51. Naylor S, Schonfeld JM. Therapeutic drug repurposing, reposition‑
ing and rescue part i: overview. Drug Discovery World (DDW).
2014;57:49–62.
52. Talevi A, Bellera CL. Challenges and opportunities with drug repurpos‑
ing: finding strategies to find alternative uses of therapeutics. Expert
Opin Drug Discov. 2020;15(4):397–401. https:// doi. org/ 10. 1080/ 17460
441. 2020. 17047 29.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 21 of 23
Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
53. Witkowski TX. Intellectual property and other legal aspects of drug
repurposing. Drug Discov Today Ther Strateg. 2011;8(3–4):139–43.
54. Hernandez JJ, Pryszlak M, Smith L, Yanchus C, Kurji N, Shahani VM, et al.
Giving drugs a second chance: overcoming regulatory and financial
hurdles in repurposing approved drugs as cancer therapeutics. Front
Oncol. 2017;7(273):1–8.
55. Dudley JT, Deshpande T, Butte AJ. Exploiting drug‑disease rela‑
tionships for computational drug repositioning. Brief Bioinform.
2011;12(4):303–11.
56. Uenaka T, Satake W, Cha PC, Hayakawa H, Baba K, Jiang S, et al. In silico
drug screening by using genome‑wide association study data repur‑
posed dabrafenib, an anti‑melanoma drug, for Parkinson’s disease. Hum
Mol Genet. 2018;27(22):3974–85.
57. Styczyńska‑Soczka K, Zechini L, Zografos L. Validating the predicted
effect of astemizole and ketoconazole using a Drosophila model of
Parkinson’s disease. Assay Drug Dev Technol. 2017;15(3):106–12.
58. Siddiqi FH, Menzies FM, Lopez A, Stamatakou E, Karabiyik C, Ureshino R,
et al. Felodipine induces autophagy in mouse brains with pharmacoki‑
netics amenable to repurposing. Nat Commun. 2019;10(1):1817.
59. Poirier AA, Côté M, Bourque M, Morissette M, Di Paolo T, Soulet D.
Neuroprotective and immunomodulatory effects of raloxifene in the
myenteric plexus of a mouse model of Parkinson’s disease. Neurobiol
Aging. 2016;48:61–71.
60. Ayoub BM, Mowaka S, Safar MM, Ashoush N, Arafa MG, Michel HE, et al.
Repositioning of omarigliptin as a once‑weekly intranasal anti‑parkin‑
sonian agent. Sci Rep. 2018;8(1):8959.
61. Fletcher EJR, Jamieson AD, Williams G, Doherty P, Duty S. Targeted
repositioning identifies drugs that increase fibroblast growth factor 20
production and protect against 6‑hydroxydopamine‑induced nigral cell
loss in rats. Sci Rep. 2019;9(1):8336.
62. Rodriguez‑Perez AI, Sucunza D, Pedrosa MA, Garrido‑Gil P, Kulisevsky
J, Lanciego JL, et al. Angiotensin type 1 receptor antagonists protect
against alpha‑synuclein‑induced neuroinflammation and dopaminer‑
gic neuron death. Neurotherapeutics. 2018;15(4):1063–81. https:// doi.
org/ 10. 1007/ s13311‑ 018‑ 0646‑z.
63. Amireddy N, Puttapaka SN, Vinnakota RL, Ravuri HG, Thonda S, Kalivendi
SV. The unintended mitochondrial uncoupling effects of the FDA‑
approved anti‑helminth drug nitazoxanide mitigates experimental
parkinsonism in mice. J Biol Chem. 2017;292(38):15731–43.
64. Katila N, Bhurtel S, Shadfar S, Srivastav S, Neupane S, Ojha U, et al.
Metformin lowers α‑synuclein phosphorylation and upregulates
neurotrophic factor in the MPTP mouse model of Parkinson’s disease.
Neuropharmacology. 2017;125:396–407.
65. Ozbey G, Nemutlu‑Samur D, Parlak H, Yildirim S, Aslan M, Tanrio‑
ver G, et al. Metformin protects rotenone‑induced dopaminergic
neurodegeneration by reducing lipid peroxidation. Pharmacol Rep.
2020;72(5):1397–406.
66. Simuni T, Fiske B, Merchant K, Coffey CS, Klingner E, Caspell‑Garcia C,
et al. Efficacy of nilotinib in patients with moderately advanced parkin‑
son disease: a randomized clinical trial. JAMA Neurol. 2021;78(3):312–20.
67. Son HJ, Han SH, Lee JA, Shin EJ, Hwang O. Potential repositioning of
exemestane as a neuroprotective agent for Parkinson’s disease. Free
Radic Res. 2017;51(6):633–45. https:// doi. org/ 10. 1080/ 10715 762. 2017.
13536 88.
68. Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, et al.
β2‑Adrenoreceptor is a regulator of the α‑synuclein gene driving risk of
Parkinson’s disease. Science (80). 2017;357:891–8.
69. Rinaldi F, Seguella L, Gigli S, Hanieh PN, Del Favero E, Cantù L, et al.
inPentasomes: an innovative nose‑to‑brain pentamidine delivery blunts
MPTP parkinsonism in mice. J Control Release. 2019;294:17–26.
70. Bariotto dos Santos K, Padovan Neto FE, Bortolanza M, dos Santos
Pereria M, Raisman‑Vozari R, Tumas V, et al. Repurposing an established
drug: an emerging role for methylene blue in L‑DOPA‑induced dyskine‑
sia. Eur J Neurosci. 2019;49(6):869–82.
71. Potts LF, Park ES, Woo JM, Dyavar Shetty BL, Singh A, Braithwaite SP,
et al. Dual κ‑agonist/μ‑antagonist opioid receptor modulation reduces
levodopa‑induced dyskinesia and corrects dysregulated striatal
changes in the nonhuman primate model of Parkinson disease. Ann
Neurol. 2015;77(6):930–41.
72. Bartlett MJ, Flores AJ, Ye T, Smidt SI, Dollish HK, Stancati JA, et al.
Preclinical evidence in support of repurposing sub‑anesthetic ketamine
as a treatment for L‑DOPA‑induced dyskinesia. Exp Neurol. 2020;333:
113413.
73. Lastres‑Becker I, García‑Yagüe AJ, Scannevin RH, Casarejos MJ, Kügler
S, Rábano A, et al. Repurposing the NRF2 activator dimethyl fumarate
as therapy against synucleinopathy in Parkinson’s disease. Antioxidants
Redox Signal. 2016;25(2):61–77.
74. Mahapatra A, Sarkar S, Biswas SC, Chattopadhyay K. An aminoglycoside
antibiotic inhibits both lipid‑induced and solution‑phase fibrillation of
α‑synuclein: In vitro. Chem Commun. 2019;55(74):11052–5.
75. González Lizárraga F, Ploper D, Ávila CL, Socías SB, dos Santos‑Pereria M,
Machín B, et al. CMT‑3 targets different α‑synuclein aggregates mitigat‑
ing their toxic and inflammogenic effects. Sci Rep. 2020;10(1):1–17.
https:// doi. org/ 10. 1038/ s41598‑ 020‑ 76927‑0.
76. González‑Lizárraga F, Socías SB, Ávila CL, Torres‑Bugeau CM, Barbosa
LRS, Binolfi A, et al. Repurposing doxycycline for synucleinopathies:
remodelling of α‑synuclein oligomers towards non‑toxic parallel beta‑
sheet structured species. Sci Rep. 2017;7(41755):1–13.
77. Marques CSF, Machado Júnior JB, de Andrade M, Andrade LN, Dos
Santos ALS, Cruz E, et al. Use of pharmaceutical nanotechnology for the
treatment of leishmaniasis. J Braz Soc Trop Med. 2019;52:1–5.
78. Urrejola MC, Soto LV, Zumarán CC, Peñaloza JP, Álvarez B, Fuentevilla I,
et al. Polymeric nanoparticle systems: structure, elaboration methods,
characteristics, properties, biofunctionalization and self‑assembly layer
by layer technologies. Int J Morphol. 2018;36(4):1463–71.
79. Sharma G, Sharma AR, Lee SS, Bhattacharya M, Nam JS, Chakraborty C.
Advances in nanocarriers enabled brain targeted drug delivery across
blood brain barrier. Int J Pharm. 2019;559:360–72.
80. Gupta M, Lee HJ, Barden CJ, Weaver DF. The blood‑brain barrier (BBB)
score. J Med Chem. 2019;62(21):9824–36.
81. Gallardo‑Toledo E, Tapia‑Arellano A, Celis F, Sinai T, Campos M, Kogan
MJ, et al. Intranasal administration of gold nanoparticles designed
to target the central nervous system: fabrication and comparison
between nanospheres and nanoprisms. Int J Pharm. 2020;590: 119957.
https:// doi. org/ 10. 1016/j. ijpha rm. 2020. 119957.
82. Ulbrich K, Knobloch T, Kreuter J. Targeting the insulin receptor: nano‑
particles for drug delivery across the blood–brain barrier (BBB). J Drug
Target. 2011;19(2):125–32. https:// doi. org/ 10. 3109/ 10611 86100 37340
01.
83. Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino L. Nanopar‑
ticle‑mediated brain drug delivery: overcoming blood–brain barrier to
treat neurodegenerative diseases. J Control Release. 2016;235:34–47.
84. Alavian F, Shams N. Oral and intra‑nasal administration of nanoparticles
in the cerebral ischemia treatment in animal experiments: considering
its advantages and disadvantages. Curr Clin Pharmacol. 2020;15(1):20.
85. Chenthamara D, Subramaniam S, Ramakrishnan SG, Krishnaswamy S,
Essa MM, Lin F‑H, et al. Therapeutic efficacy of nanoparticles and routes
of administration. Biomater Res. 2019;23(1):1–29. https:// doi. org/ 10.
1186/ s40824‑ 019‑ 0166‑x.
86. Pires A, Fortuna A, Alves G, Falcão A. Intranasal drug delivery: how, why
and what for? J Pharm Pharm Sci. 2009;12(3):288–311.
87. Reinholz J, Landfester K, Mailänder V. The challenges of oral drug deliv‑
ery via nanocarriers. Drug Deliv. 2018;25(1):1694–705.
88. Kaiser M, Pereira S, Pohl L, Ketelhut S, Kemper B, Gorzelanny C, et al.
Chitosan encapsulation modulates the effect of capsaicin on the tight
junctions of MDCK cells. Sci Rep. 2015;5(1):1–14.
89. Lien CF, Molnár É, Toman P, Tsibouklis J, Pilkington GJ, Górecki DC, et al.
In vitro assessment of alkylglyceryl‑functionalized chitosan nanopar‑
ticles as permeating vectors for the Blood‑Brain Barrier. Biomacromol‑
ecules. 2012;13(4):1067–73. https:// doi. org/ 10. 1021/ bm201 790s.
90. Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug
delivery. Adv Drug Deliv Rev. 2007;59(8):748.
91. Joanna R, Volker O, Inge SZ, Dick H. Size‑dependent internalization of
particles via the pathways of clathrin‑ and caveolae‑mediated endocy‑
tosis. Biochem J. 2004;377(Pt 1):159–69.
92. Mendoza‑Muñoz N, Urbán‑Morlán Z, Leyva‑Gómez G, De La Luz
Z‑Z, Piñón‑Segundo E, Quintanar‑Guerrero D. Solid lipid nanoparti‑
cles: an approach to improve oral drug delivery. J Pharm Pharm Sci.
2021;24:509–32.
93. Yuan H, Huang LF, Du YZ, Ying XY, You J, Hu FQ, et al. Solid lipid
nanoparticles prepared by solvent diffusion method in a nanoreactor
system. Colloids Surfaces B Biointerfaces. 2008;61(2):132–7.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 22 of 23
Hernández‑Parraetal. Journal of Nanobiotechnology (2022) 20:413
94. Desai MP, Labhasetwar V, Amidon GL, Levy RJ. Gastrointestinal uptake
of biodegradable microparticles: effect of particle size. Pharm Res.
1996;13(12):1838–45.
95. Yu M, Yang Y, Zhu C, Guo S, Gan Y. Advances in the transepithelial trans‑
port of nanoparticles. Drug Discov Today. 2016;21(7):1155–61.
96. Bannunah AM, Vllasaliu D, Lord J, Stolnik S. Mechanisms of nanoparticle
internalization and transport across an intestinal epithelial cell model:
effect of size and surface charge. Mol Pharm. 2014;11(12):4363–73.
https:// doi. org/ 10. 1021/ mp500 439c.
97. Voigt N, Henrich‑Noack P, Kockentiedt S, Hintz W, Tomas J, Sabel BA.
Surfactants, not size or zeta‑potential influence blood‑brain bar‑
rier passage of polymeric nanoparticles. Eur J Pharm Biopharm.
2014;87(1):19–29.
98. Lombardo SM, Schneider M, Türeli AE, Türeli NG. Key for crossing the
BBB with nanoparticles: the rational design. Beilstein J Nanotechnol.
2020;11(1):866–83.
99. Gao K, Jiang X. Influence of particle size on transport of methotrexate
across blood brain barrier by polysorbate 80‑coated polybutylcy‑
anoacrylate nanoparticles. Int J Pharm. 2006;310(1–2):213–9.
100. Hughes JM, Budd PM, Tiede K, Lewis J. Polymerized high internal phase
emulsion monoliths for the chromatographic separation of engineered
nanoparticles. J Appl Polym Sci. 2015;132(1):41229. https:// doi. org/ 10.
1002/ app. 41229.
101. Del Prado‑Audelo ML, Magaña JJ, Mejía‑Contreras BA, Borbolla‑Jiménez
FV, Giraldo‑Gomez DM, Piña‑Barba MC, et al. In vitro cell uptake evalu‑
ation of curcumin‑loaded PCL/F68 nanoparticles for potential applica‑
tion in neuronal diseases. J Drug Deliv Sci Technol. 2019;52:905–14.
102. Shen S, Wu Y, Liu Y, Wu D. High drug‑loading nanomedicines: progress,
current status, and prospects. Int J Nanomedicine. 2017;12:4085.
103. Shen Y, Jin E, Zhang B, Murphy CJ, Sui M, Zhao J, et al. Prodrugs forming
high drug loading multifunctional nanocapsules for intracellular cancer
drug delivery. J Am Chem Soc. 2010;132(12):4259–65.
104. Nigam K, Kaur A, Tyagi A, Nematullah M, Khan F, Gabrani R, et al.
Nose‑to‑brain delivery of lamotrigine‑loaded PLGA nanoparticles.
Drug Deliv Transl Res. 2019;9(5):879–90. https:// doi. org/ 10. 1007/
s13346‑ 019‑ 00622‑5.
105. Deepika MS, Thangam R, Sheena TS, Vimala RTV, Sivasubramanian S,
Jeganathan K, et al. Dual drug loaded PLGA nanospheres for synergistic
efficacy in breast cancer therapy. Mater Sci Eng C. 2019;103: 109716.
106. Bhakay A, Rahman M, Dave RN, Bilgili E. Bioavailability enhancement of
poorly water‑soluble drugs via nanocomposites: formulation‑process‑
ing aspects and challenges. Pharmaceutics. 2018;10(3):86.
107. Kocbek P, Baumgartner S, Kristl J. Preparation and evaluation of nano‑
suspensions for enhancing the dissolution of poorly soluble drugs. Int J
Pharm. 2006;312(1–2):179–86.
108. Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia MA, McNeil SE.
Nanoparticle interaction with plasma proteins as it relates to particle
biodistribution, biocompatibility and therapeutic efficacy. Adv Drug
Deliv Rev. 2009;61(6):428.
109. Roach P, Farrar D, Perry CC. Interpretation of protein adsorption: surface‑
induced conformational changes. J Am Chem Soc. 2005;127(22):8168–
73. https:// doi. org/ 10. 1021/ ja042 898o.
110. Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacoki‑
netics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102.
111. Gessner A, Lieske A, Paulke BR, Müller RH. Influence of surface
charge density on protein adsorption on polymeric nanoparticles:
analysis by two‑dimensional electrophoresis. Eur J Pharm Biopharm.
2002;54(2):165–70.
112. Cedervall T, Lynch I, Lindman S, Berggård T, Thulin E, Nilsson H, et al.
Understanding the nanoparticle‑protein corona using methods to
quntify exchange rates and affinities of proteins for nanoparticles. Proc
Natl Acad Sci U S A. 2007;104(7):2050–5. https:// doi. org/ 10. 1073/ pnas.
06085 82104.
113. Pinelli F, Perale G, Rossi F. Coating and functionalization strategies for
nanogels and nanoparticles for selective drug delivery. Gels. 2020;6(1):6.
114. Du W, Fan Y, Zheng N, He B, Yuan L, Zhang H, et al. Transferrin receptor
specific nanocarriers conjugated with functional 7peptide for oral drug
delivery. Biomaterials. 2013;34(3):794–806.
115. Tang S, Wang A, Yan X, Chu L, Yang X, Song Y, et al. Brain‑targeted
intranasal delivery of dopamine with borneol and lactoferrin
co‑modified nanoparticles for treating Parkinson’s disease. Drug Deliv.
2019;26(1):700–7.
116. Leveugle B, Faucheux BA, Bouras C, Nillesse N, Spik G, Hirsch EC, et al.
Cellular distribution of the iron‑binding protein lactotransferrin in
the mesencephalon of Parkinson’s disease cases. Acta Neuropathol.
1996;91(6):566–72.
117. Lopalco A, Cutrignelli A, Denora N, Lopedota A, Franco M, Laquintana V.
Transferrin functionalized liposomes loading dopamine HCl: develop‑
ment and permeability studies across an in vitro model of human
blood‑brain barrier. Nanomaterials. 2018;8(3):178.
118. Kang YS, Jung HJ, Oh JS, Song DY. 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(10):817–23.
119. Sridhar V, Gaud R, Bajaj A, Wairkar S. Pharmacokinetics and pharmaco‑
dynamics of intranasally administered selegiline nanoparticles with
improved brain delivery in Parkinson’s disease. Nanomed Nanotechnol
Biol Med. 2018;14(8):2609–18.
120. Hu K, Chen X, Chen W, Zhang L, Li J, Ye J, et al. Neuroprotective effect of
gold nanoparticles composites in Parkinson’s disease model. Nanomed
Nanotechnol Biol Med. 2018;14(4):1123–36.
121. Huang R, Ma H, Guo Y, Liu S, Kuang Y, Shao K, et al. Angiopep‑conju‑
gated nanoparticles for targeted long‑term gene therapy of parkinson’s
disease. Pharm Res. 2013;30(10):2549–59.
122. Ray S, Sinha P, Laha B, Maiti S, Bhattacharyya UK, Nayak AK. Polysorbate
80 coated crosslinked chitosan nanoparticles of ropinirole hydrochlo‑
ride for brain targeting. J Drug Deliv Sci Technol. 2018;48:21–9.
123. Zhao Y, Xiong S, Liu P, Liu W, Wang Q, Liu Y, et al. Polymeric nanoparti‑
cles‑based brain delivery with improved therapeutic efficacy of gink‑
golide B in Parkinson’s disease. Int J Nanomedicine. 2020;15:10453–67.
124. Shadab MD, Khan RA, Mustafa G, Chuttani K, Baboota S, Sahni JK, et al.
Bromocriptine loaded chitosan nanoparticles intended for direct nose
to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy
study in mice model. Eur J Pharm Sci. 2013;48(3):393–405.
125. Gambaryan PY, Kondrasheva IG, Severin ES, Guseva AA, Kamensky
AA. Increasing the effciency of parkinson’s disease treatment using a
poly(lactic‑co‑glycolic acid) (PLGA) based L‑DOPA delivery system. Exp
Neurobiol. 2014;23(3):246–52.
126. Fernandes C, Martins C, Fonseca A, Nunes R, Matos MJ, Silva R, et al.
PEGylated PLGA nanoparticles as a smart carrier to increase the cellular
uptake of a coumarin‑based monoamine oxidase B inhibitor. ACS Appl
Mater Interfaces. 2018;10(46):39557–69.
127. Huang R, Han L, Li J, Ren F, Ke W, Jiang C, et al. Neuroprotection in a
6‑hydroxydopamine‑lesioned Parkinson model using lactoferrin‑mod‑
ified nanoparticles. J Gene Med. 2009;11(9):754–63. https:// doi. org/ 10.
1002/ jgm. 1361.
128. Song Y, Shi Y, Zhang L, Hu H, Zhang C, Yin M, et al. Synthesis of
CSK‑DEX‑PLGA nanoparticles for the oral delivery of exenatide to
improve its mucus penetration and intestinal absorption. Mol Pharm.
2019;16(2):518–32. https:// doi. org/ 10. 1021/ acs. molph armac eut. 8b008
09.
129. Kandilli B, Ugur Kaplan AB, Cetin M, Taspinar N, Ertugrul MS, Aydin IC,
et al. Carbamazepine and levetiracetam‑loaded PLGA nanoparticles
prepared by nanoprecipitation method: in vitro and in vivo studies.
Drug Dev Ind Pharm. 2020;46(7):1063–72. https:// doi. org/ 10. 1080/
03639 045. 2020. 17691 27.
130. CN104055735A. Semaglutide liposome and preparation method
thereof. 2013. p. 1–21. https:// paten ts. google. com/ patent/ CN104 05573
5A/ en. Accessed 28 Feb 2021.
131. Liu G, Yang J, Wang Y, Liu X, Guan LL, Chen L. Protein‑lipid composite
nanoparticles for the oral delivery of vitamin B 12: impact of protein
succinylation on nanoparticle physicochemical and biological proper‑
ties. Food Hydrocoll. 2019;92:189–97.
132. Sadozai SK, Khan SA, Karim N, Becker D, Steinbrück N, Gier S, et al.
Ketoconazole‑loaded PLGA nanoparticles and their synergism against
Candida albicans when combined with silver nanoparticles. J Drug
Deliv Sci Technol. 2020;56: 101574.
133. Jana U, Mohanty AK, Pal SL, Manna PK, Mohanta GP. Felodipine loaded
PLGA nanoparticles: preparation, physicochemical characterization and
in vivo toxicity study. Nano Converg. 2014;1(1):31.
134. He Y, Zhan C, Pi C, Zuo Y, Yang S, Hu M, et al. Enhanced oral bioavail‑
ability of felodipine from solid lipid nanoparticles prepared through
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Page 23 of 23
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135. Saini D, Fazil M, Ali MM, Baboota S, Ali J. Formulation, development and
optimization of raloxifene‑loaded chitosan nanoparticles for treatment
of osteoporosis. Drug Deliv. 2015;22(6):823–36. https:// doi. org/ 10. 3109/
10717 544. 2014. 900153.
136. Ravi PR, Aditya N, Kathuria H, Malekar S, Vats R. Lipid nanoparticles for
oral delivery of raloxifene: optimization, stability, in vivo evaluation and
uptake mechanism. Eur J Pharm Biopharm. 2014;87(1):114–24.
137. Dudhipala N, Veerabrahma K. Candesartan cilexetil loaded solid lipid
nanoparticles for oral delivery: characterization, pharmacokinetic and
pharmacodynamic evaluation. Drug Deliv. 2016;23(2):395–404.
138. ÖztÜrk N, Kara A, Vural İ. Formulation and in vitro evaluation of
telmisartan nanoparticles prepared by emulsion‑solvent evaporation
technique. Turkish J Pharm Sci. 2020;17(5):492–9.
139. Abbasalipourkabir R, Fallah M, Sedighi F, Maghsood AH, Javid S. Nano‑
capsulation of nitazoxanide in solid lipid nanoparticles as a new drug
delivery system and in vitro release study. J Biol Sci. 2016;16(4):120–7.
140. Kumar S, Bhanjana G, Verma RK, Dhingra D, Dilbaghi N, Kim K‑H. Met‑
formin‑loaded alginate nanoparticles as an effective antidiabetic agent
for controlled drug release. J Pharm Pharmacol. 2017;69(2):143–50.
141. Archibald M, Pritchard T, Nehoff H, Rosengren RJ, Greish K, Taurin S. A
combination of sorafenib and nilotinib reduces the growth of castrate‑
resistant prostate cancer. Int J Nanomedicine. 2016;11:179–201.
142. Jayapal JJ, Dhanaraj S. Exemestane loaded alginate nanoparticles for
cancer treatment: formulation and in vitro evaluation. Int J Biol Macro‑
mol. 2017;105(Pt 1):416–21.
143. Beck‑Broichsitter M, Gauss J, Gessler T, Seeger W, Kissel T, Schmehl T.
Pulmonary targeting with biodegradable salbutamol‑loaded nanoparti‑
cles. J Aerosol Med Pulm Drug Deliv. 2010;23(1):47–57.
144. Valle IV, Machado ME, Araujo CDCB, Da Cunha‑Junior EF, Da Silva PJ,
Torres‑Santos EC, et al. Oral pentamidine‑loaded poly(d, l‑lactic‑co‑
glycolic) acid nanoparticles: an alternative approach for leishmaniasis
treatment. Nanotechnology. 2019;30(45): 455102.
145. Omarch G, Kippie Y, Mentor S, Ebrahim N, Fisher D, Murilla G, et al. Com‑
parative in vitro transportation of pentamidine across the blood‑brain
barrier using polycaprolactone nanoparticles and phosphatidylcholine
liposomes. Artif Cells Nanomed Biotechnol. 2019;47(1):1428–36.
146. Manimekalai P, Dhanalakshmi R, Manavalan R. Preparation and charac‑
terization of ceftriaxone sodium encapsulated chitosan nanoparticles.
Int J Appl Pharm. 2017;9(6):10.
147. Gattani SG, Moon RS. Formulation and evaluation of fast dissolving
tablet containing vilazodone nanocrystals for solubility and dissolution
enhancement using soluplus: in vitro‑in vivo study. J Appl Pharm Sci.
2018;8(05):45–54.
148. Jesus VPS, Raniero L, Lemes GM, Bhattacharjee TT, Caetano Júnior PC,
Castilho ML. Nanoparticles of methylene blue enhance photodynamic
therapy. Photodiagnosis Photodyn Ther. 2018;23:212–7.
149. Khanna K, Sharma N, Rawat S, Khan N, Karwasra R, Hasan N, et al. Intra‑
nasal solid lipid nanoparticles for management of pain: a full factorial
design approach, characterization & gamma scintigraphy. Chem Phys
Lipids. 2021;236: 105060.
150. Han FY, Liu Y, Kumar V, Xu W, Yang G, Zhao CX, et al. Sustained‑release
ketamine‑loaded nanoparticles fabricated by sequential nanoprecipita‑
tion. Int J Pharm. 2020;581: 119291.
151. Kumar P, Sharma G, Kumar R, Malik R, Singh B, Katare OP, et al. Enhanced
brain delivery of dimethyl fumarate employing tocopherol‑acetate‑
based nanolipidic carriers: evidence from pharmacokinetic, biodistribu‑
tion, and cellular uptake studies. ACS Chem Neurosci. 2017;8(4):860–5.
https:// doi. org/ 10. 1021/ acsch emneu ro. 6b004 28.
152. Payne JN, Waghwani HK, Connor MG, Hamilton W, Tockstein S, Moolani
H, et al. Novel synthesis of kanamycin conjugated gold nanoparticles
with potent antibacterial activity. Front Microbiol. 2016;7(MAY):607.
https:// doi. org/ 10. 3389/ fmicb. 2016. 00607.
153. Misra R, Sahoo SK. Antibacterial activity of doxycycline‑loaded nanopar‑
ticles. Methods Enzymol. 2012;509:61–85.
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