| liposomes |
increase drug efficacy |
Mengke Qu and co-workers
designed N-3,4-bis(pivaloyloxy)-dopamine-loaded-
29 amino-acid peptide (RVG29) functionalized liposomes for Parkinson’s
disease. In this study, this liposome formulation provided better
brain targeting comparing free N-3,4-bis(pivaloyloxy)-dopamine.
In in vivo studies, this liposome formulation demonstrated selective
distribution to brain endothelial cells.71
|
| increase
stability via encapsulation |
A leptin-functionalized
liposome formulation was developed as a drug carrier for resveratrol
and epigallocatechin gallate for Parkinson’s disease. In this
study, they demonstrated that liposome formulation has enhanced BBB
permeability, and cellular uptake into cloned cell line derived from
the SK-N-SH neuroblastoma cell line (SH-SY5Y) cells.72
|
| good delivery vehicle for
both hydrophobic and hydrophilic drugs |
In a study
conducted by Gailard et al., glutathione-conjugated PEGylated liposome
formulations were prepared to increase the therapeutic availability
of methylprednisolone in the treatment of MS. The prepared formulations
were administered intravenously to rats for which an EAE model was
developed. Prolonged plasma circulation and increased brain uptake
were obtained in rats administered glutathione-conjugated PEGylated
liposome formulations compared to rats administered free methylprednisolone.
In addition, thanks to the liposome formulations prepared in the study,
treatment effectiveness was achieved at lower doses, thus increasing
the therapeutic availability of methylprednisolone.73
|
| high compatibility |
| reduce the toxicity of the
encapsulated drug |
| reduce side effects |
| nontoxic, biocompatible,
biodegradable, and nonimmunogenic for systemic administrations |
| polymeric
nanoparticles |
ease
of production process |
Yang et al. prepared brain-targeted
peptide-functionalized chitosan nanoparticles for resveratrol delivery
to brain. The Morris water maze test was used to compare the effectiveness
of the formulations. The cognitive improvement was more evident in
mice that received treatment with functionalized chitosan nanoparticle
formulation.74
|
| biocompatible |
Gonzalez et al. investigated
intranasal polymeric nanoparticles containing Interferon-β (IFN-β)
which has a short half-life, and limited CNS access for multiple sclerosis.
In mice with the experimental autoimmune encephalomyelitis (EAE) model,
the same dose of intranasal and systemic free interferon administration
had no effect. The improvement in clinical symptoms, reduction of
inflammation, and the demyelinated area were observed in the mice
receiving the nanoparticle formulations containing IFN-β.75
|
| biodegradable |
si-RNA loaded chitosan nanoparticles
were prepared for gene delivery in HD treatment. Si-RNA treatment
reduces the expression of genes encoding the huntingtin protein, which
shows excessive accumulation in HD. However, intracerebral and intrathecal
applications, which are invasive methods in chronic treatment, negatively
affect patient compliance. si-RNA loaded chitosan nanoparticles were
prepared in the study conducted by Sava et al. to increase patient
compliance and treatment effectiveness. After the prepared formulations
were administered intranasally to transgenic mice, it was determined
that huntingtin protein expression in the brain tissues of the mice
was significantly reduced.76
|
| targetable carrier
systems |
In a study
conducted by Saleh and colleagues, berberine-loaded PLGA nanoparticle
formulations conjugated with Tet-1 peptide were designed for the treatment
of AD. Berberine is a natural compound known for its effects in mitigating
Tau hyperphosphorylation and reducing fibril formation; however, its
bioavailability is extremely low, hindering its ability to reach the
brain adequately. The formulated Tet-1 peptide-conjugated PLGA nanoparticles
aimed to achieve brain targeting of berberine and alleviate AD symptoms.
When administered to rats with an AD model, it was observed that the
group treated with berberine-loaded Tet-1 peptide-conjugated PLGA
nanoparticles exhibited significantly reduced fibril formation compared
to other groups. Additionally, substantial improvement in synaptic
activity and higher success rates in cognitive function tests were
observed in this group.77
|
| protection of encapsulated
drug from chemical and enzymatic degradation |
| solid lipid
nanoparticles |
protection
of encapsulated
drug from chemical and enzymatic degradation |
Dimethyl fumarate-loaded
solid lipid nanoparticles were evaluated for multiple sclerosis treatment.
Dimethyl fumarate has serious side effects like lymphopenia. The same
dose of oral dimethyl fumarate and subcutaneous dimethyl fumarate-loaded
solid lipid nanoparticles were compared for clinical outcomes. The
dimethyl fumarate-loaded solid lipid nanoparticles prevented disease
progression without causing any harm to lymphocytes.78
|
| low cytotoxicity |
Piperine, an antioxidant
natural alkaloid, mimics acetylcholine due to its similarity in structure,
blocks the acetylcholinesterase enzyme, and increases cholinergic
activity in the brain. When applied alone, the amount reaching the
brain is quite low due to the solubility problem and the hepatic first-pass
effect. To overcome these problems related to piperine, in a study
conducted by Yusuf et al., Polysorbate-80 coated solid lipid nanoparticle
formulations containing piperine were prepared. Positive effects were
obtained from these formulations in vitro and in vivo tests. A decrease
in cholinergic degradation, immobilization, and the presence of amyloid
plaque was observed.79
|
| increasing the bioavailability
of active substances with low solubility in aqueous media |
Chitosan coated-
dopamine loaded-solid lipid nanoparticle formulations were developed
aiming to achieve brain targeting for the treatment of PD. The studies
evaluating the in vitro uptake of the prepared formulations confirmed
a strong interaction between the developed solid lipid nanoparticle
formulation and brain endothelial cells, affirming the potential of
solid lipid nanoparticles as drug carriers.80
|
| reducing
serious side effects |
| biocompatible |
| dendrimers |
high drug loading |
In a study conducted by
Gothwal et al., PAMAM dendrimer formulation and lactoferrin-conjugated
PAMAM dendrimer formulations were prepared to increase the therapeutic
effectiveness of memantine used in the treatment of AD. When the prepared
formulations were applied to rats in which the AD model was developed,
more successful results and improving memory were obtained in behavioral
tests with the extended-release effect in the group in which memantine-loaded
lactoferrin-conjugated PAMAM dendrimers were applied.81
|
| improve bioavailability |
The BBB is an important
barrier that tightly controls the passage to the brain for drug and
gene delivery. In a study conducted by Zarebkohan et al., PAMAM dendrimers
were designed as gene carrier systems that carry Serine–Arginine–Leucine
peptide targeting the brain. Carrier systems were prepared by binding
Serine–Arginine–Leucine peptide to bifunctional PEG–PAMAM
dendrimers. When the prepared systems were administered to rats by
i.v. injection, it was observed that the amount of Serine–Arginine–Leucine
peptide that crossed the BBB and reached the brain parenchyma was
higher in the group to which Serine–Arginine–Leucine
peptide bifunctional PEG–PAMAM dendrimers were applied, compared
to the control groups. Study results show that PAMAM dendrimers are
suitable and effective nanocarriers for brain gene delivery.82
|
| protection of encapsulated
drug from chemical and enzymatic degradation |
In a study
conducted by Singh et al., donepezil-loaded-PAMAM dendrimer formulations
were prepared to increase the effectiveness of donepezil used in the
treatment of AD. Evaluation of treatment effectiveness was carried
out in vivo and in vitro studies. In in vitro acetylcholine esterase
inhibition activity measurement, it was determined that donepezil-loaded-PAMAM
dendrimer formulations provided a higher level of inhibition compared
to donepezil alone. In in vivo studies, the prepared formulations
were administered intravenously to rats. It was observed that the
amount of donepezil reaching the brain was 4 times higher in the group
where PAMAM dendrimer formulations were applied compared to the group
receiving free donepezil.83
|
| ease of production
process |
| demonstrating controlled
released effect |
| nanogels |
improving solubility of
hydrophobic drugs |
A nano gel carrier system
was developed for the delivery of albiflorin to enhance BBB permeability.
The intranasal application of nano gel system was compared to the
free drug and enhanced brain distribution and improved stability was
achieved via the nanogel system.84
|
| enhancing the
stability
of therapeutic agents against chemical/enzymatic degradation |
Dopamine-loaded
PEGylated nanogel formulations were prepared for the treatment of
AD, and the prepared formulations were modified with transferrin receptor
ligand, aiming to increase the passage through the BBB. In vivo studies
conducted on rats showed that the amount of dopamine reaching the
brain was 9 times higher in the group in which nanogel formulations
were applied, compared to the group in which free dopamine was administered.85
|
| increasing stability |
| demonstrating sustained
released effect |
| good delivery vehicle for
both hydrophilic and hydrophobic drugs |
| nanoemulsions |
enhanced long-term stability |
Pterostilbene is a molecule
with low bioavailability that has neuroprotective activity with its
antioxidant and anti-inflammatory properties. In a study conducted
by Liu et al., they prepared pterostilbene-loaded nanoemulsion formulations
to increase the bioavailability of pterostilbene for use in the treatment
of AD. When the prepared formulations were treated in mice, it was
observed that its bioavailability increased, the NRF2 pathway was
stimulated more strongly, and higher neuroprotective activity was
obtained in the group in which pterostilbene-loaded nanoemulsion formulations
were treated, compared to the group in which free pterostilbene was
treated.86
|
| simplicity for production |
In a study
conducted by Friedman-Levi et al., nanoemulsion formulations containing
grape seed oil were prepared to increase the neuroprotective activity
of grape seed oil in the treatment of HD. It was determined that when
the prepared formulations were applied to transgenic mice, disease
progression was delayed.87
|
| improved solubility |
| good delivery
vehicle for
both hydrophilic and hydrophobic drugs |
| protection of encapsulated
drug from enzymatic degredation |
| polymeric micelles |
increasing the solubility
and bioavailability of drugs with low water solubility |
A study was conducted to
develop galantamine-loaded 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-73 (DSPE-PEG2000) based micelles. Galantamine is
an approved drug for the treatment of Alzheimer’s disease.
It has poor brain penetration, low intestinal permeation. Lohan et.
al compared galantamine-loaded micelle formulation to galantamine
suspension in in vivo studies. They revealed improved bioavailability
in pharmacokinetic studies, improved cognitive improvement and good
clinical outcomes in pharmacodynamics studies.88
|
| prevention of interaction
with serum proteins |
Dexamethasone-loaded polymeric
micelle formulations for intranasal administration was prepared to
reduce the presystemic elimination of dexamethasone. Parallel artificial
membrane permeability assay and other in vitro test results showed
that this formulation has high permeability values for BBB.89
|
| prevention the degradation
of the drug |
A polydopamine-coated
micelle
formulation was prepared with the aim of increasing the bioavailability
of the phosphodiesterase inhibitor ibudilast and targeting the brain
for the treatment of MS. The micelles were administered intranasally
to mice with an experimental autoimmune encephalomyelitis (EAE) model
at different doses. Through the micelle formulations, it was demonstrated
that even in low-dose treatment regimens, a higher level of ibudilast
reached the brain compared to oral and nasal administration of free
ibudilast, leading to higher neuroprotective efficacy.90
|
| targeting specific tissues |
Apolipoprotein-modified
micelle formulations were prepared to enhance the bioavailability
of the plant-derived compounds oridonin and phillyrin, which possess
antioxidant, anti-inflammatory, and neuroprotective effects, for the
AD treatment. When these formulations were administered to mice with
an AD model, it was found that they achieved a higher level of brain
targeting compared to mice treated with free oridonin and phillyrin.
Additionally, an increased compound uptake by nerve cells, higher
levels of cognitive improvement, and decreased astrocyte-microglia
activity were observed.91
|
| inorganic nanoparticles |
compatible with various
surface modifications |
Hyperforin-loaded gold nanoparticles
were evaluated in the treatment of multiple sclerosis. This formulation
reduced inflammatory cells in the spinal cord and regulated transcription
factors. The study revealed that hyperforin-loaded gold nanoparticles
had a distinguishable effect on the EAE model in terms of clinical
and laboratory outcomes.92
|
| relatively low cytotoxicity |
Formulations of transmembrane
peptide-modified chondroitin sulfate gold nanoparticles were prepared
for AD treatment. Chondroitin sulfate is a glycosaminoglycan derivative
that inhibits tau protein accumulation and Aβ fibril formation,
but its passage through the BBB is limited due to its high molecular
weight. Formulations were prepared to enhance BBB permeability, and
evaluations of their anti-AD efficacy were conducted on SH-SY5Y cells.
The usage of gold nanoparticles increased the antioxidant activity
of chondroitin sulfate, the cellular uptake and transport ability
were also enhanced.93
|
| ability to cross the blood–brain
barrier |
Formulations
of glucosamine-conjugated gold nanoparticles were used to evaluate
the neuroprotective efficacy of glucosamine in the treatment of neurodegenerative
diseases. Studies conducted on SH-SY5Y cells demonstrated that glucosamine-conjugated
gold nanoparticle formulations significantly reduced protein aggregation
and substantially prevented cell death in nerve cells.94
|
| optical properties suitable
for conjugation of diagnostic and imaging agents |
| exosomes |
low risk of immunogenicity |
The intranasal administration
of resveratrol-loaded exosome formulations for multiple sclerosis
treatment was evaluated. The formulation reduced inflammatory responses
in CNS and augmented clinical outcomes in vivo.95
|
| high biocompatibility |
The intranasal administration
of exosome-based carrier system carrying catalase, a natural potent
antioxidant for Parkinson’s disease was investigated. In in
vivo studies, this formulation accumulated remarkably in the PD mouse
brain and accomplished neuroprotective effects.96
|
| good delivery vehicle for
both hydrophobic and hydrophilic drugs |
Plasma-derived exosomes
loaded with quercetin were prepared aiming to achieve brain targeting
and enhance the bioavailability of quercetin for the treatment of
AD. When these formulations were administered to mice with an AD model,
it was observed that the improvement in cognitive functions was higher
compared to the administration of free quercetin, indicating an increased
bioavailability of quercetin.97
|
| targeting specific
tissues |
Silibinin
encapsulated in
macrophage-derived exosomes was prepared to enhance the bioavailability
of silibinin while simultaneously reducing Aβ aggregation and
astrocyte deactivation in Alzheimer’s disease (AD) treatment.
The in vivo studies revealed that the administration of silibinin-loaded
macrophage-derived exosomes significantly reduced Aβ plaque
formation compared to mice treated with silibinin alone. Moreover,
astrocyte activation and the release of inflammatory cytokines were
markedly inhibited. Mice treated with drug loaded exosomes showed
better improvements in neuronal recovery and cognitive functions compared
to those treated with free silibinin.98
|
| provide
neural regeneration |
Formulations of coenzyme
Q10 loaded adipose stem cell-derived exosomes were evaluated for enhancing
the therapeutic efficacy of coenzyme Q10 in the neuroprotective activity
for AD treatment. These formulations were administered intraperitoneally
to rats with AD models. Evaluation of changes in memory and cognition
was performed using passive avoidance and Morris water maze tests,
revealing that rats treated with coenzyme Q10 loaded exosome formulations
achieved more successful outcomes compared to those treated with free
coenzyme Q10.99
|
| nanoparticular
systems coated with cell membrane |
targeting spesific tissue |
In a study by Rittchen et
al., PLGA nanoparticles containing leukemia inhibitory factor (LIF)
were surrounded by oligodendrocyte precursor cell membrane vesicles.
The prepared formulas were applied to mice with focal demyelination
in the corpus callosum region. When the efficacy of the treatment
was evaluated in terms of the region where remyelination was achieved
and the axon thicknesses, it was observed that the remyelination was
higher in the group treated with biomimetic nanoparticles and the
axon thicknesses in the mice in this group were close to the healthy
mice.100
|
| high biocompatibility |
Cell membrane-coated biomimetic
formulations containing Cu2-xSe were designed for the treatment of
Parkinson’s disease (PD). In PD mice model, the biomimetic
formulations successfully promoted neurite outgrowth via the p-Akt/p-CREB
signaling pathway and facilitated improvement in synaptic function.101
|
| low immunogenicity |
Erythrocyte
membrane-coated nanoparticle formulations modified with TGNYKALHPHN
peptide were designed to enhance the bioavailability of curcumin for
the treatment of AD. The biomimetic character was imparted, and functional
peptide conjugation was utilized to increase the passage of curcumin
across BBB and target the brain. After administration to rats with
an AD model for a 4-week treatment period, the amount of curcumin
reaching the brain was significantly higher in the group treated with
the biomimetic formulation compared to the group treated with free
curcumin. Moreover, the group treated with the biomimetic formulation
achieved more successful results in the evaluation of cognitive functions
using the new object recognition test.102
|
| ability
to cross the blood–brain
barrier |
| good delivery vehicle for
both hydrophobic and hydrophilic drugs |
| increased stability via
encapsulation |
