ArticlePDF AvailableLiterature Review

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems

November 2019
Current Drug Targets 20(7)

November 2019
20(7)

DOI:10.2174/1389450120666191118123151

Authors:

Gulcem Altinoglu

King's College London

Terin Adali

Near East University

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and is part of a massive and growing health care burden that is destroying the cognitive function of more than 50 million individuals worldwide. Today, therapeutic options are limited to approaches with mild symptomatic benefits. The failure in developing effective drugs is attributed to, but not limited to the highly heterogeneous nature of AD with multiple underlying hypotheses and multifactorial pathology. In addition, targeted drug delivery to the central nervous system (CNS), for the diagnosis and therapy of neurological diseases like AD, is restricted by the challenges posed by blood-brain interfaces surrounding the CNS, limiting the bioavailability of therapeutics. Research done over the last decade has focused on developing new strategies to overcome these limitations and successfully deliver drugs to the CNS. Nanoparticles, that are capable of encapsulating drugs with sustained drug release profiles and adjustable physiochemical properties, can cross the protective barriers surrounding the CNS. Thus, nanotechnology offers new hope for AD treatment as a strong alternative to conventional drug delivery mechanisms. In this review, potential application of nanoparticle based approaches in Alzheimer’s disease and their implications in therapy is discussed.

Formation of amyloid beta plaques in Alzheimer's disease pathogenesis. Abbreviations: APP, Amyloid precursor protein; AB, Amyloid beta. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

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Nano-enabled drug delivery systems for AD therapy.

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628 Current Drug Targets, 2020, 21, 628-646

REVIEW ARTICLE

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems

Gülcem Altinoglu1,2 and Terin Adali1,2,*

1Department of Biomedical Engineering, Faculty of Engineering, Near East University, P.O. Box: 99138, North Cyprus

via Mersin 10 Turkey; 2Tissue Engineering and Biomaterials Research Centre, Centre of Excellence, Near East Univer-

sity, P.O. Box: 99138, North Cyprus via Mersin 10 Turkey

A R T I C L E H I S T O R Y

Received: September 19, 2019

Revised: November 07, 2019

Accepted: November 11, 2019

DOI:

10.2174/1389450120666191118123151

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease, and is part of a

massive and growing health care burden that is destroying the cognitive function of more than 50 mil-

lion individuals worldwide. Today, therapeutic options are limited to approaches with mild sympto-

matic benefits. The failure in developing effective drugs is attributed to, but not limited to the highly

heterogeneous nature of AD with multiple underlying hypotheses and multifactorial pathology. In ad-

dition, targeted drug delivery to the central nervous system (CNS), for the diagnosis and therapy of

neurological diseases like AD, is restricted by the challenges posed by blood-brain interfaces sur-

rounding the CNS, limiting the bioavailability of therapeutics. Research done over the last decade has

focused on developing new strategies to overcome these limitations and successfully deliver drugs to

the CNS. Nanoparticles, that are capable of encapsulating drugs with sustained drug release profiles

and adjustable physiochemical properties, can cross the protective barriers surrounding the CNS.

Thus, nanotechnology offers new hope for AD treatment as a strong alternative to conventional drug

delivery mechanisms. In this review, the potential application of nanoparticle based approaches in

Alzheimer’s disease and their implications in therapy is discussed.

Keywords: Alzheimer’s disease, nanoparticles, nanotechnology, drug delivery, targeted delivery, physiochemical.

1. INTRODUCTION

Alzheimer’s Disease (AD) is the most common type of

dementia, accounting for more than 80% of reported demen-

tias around the globe [1]. The increasing prevalence of AD

stands as one of the most severe burden on socio-economy

[2]. There are currently around 50 million people suffering

from the disease, that is expected to rise over 100 million by

the year 2050 [3]. It is characterised by irreversible neurode-

generation due to a progressive loss of brain cells and their

connections [4], leading to impairments in memory, mental

functioning, thinking and behaviour. According to the Diag-

nostic and Statistical Manual of Mental Disorders V (DSM-

V), AD can be diagnosed on having a new onset memory

impairment with a gradual progression of cognitive decline

in at least one or more of other cognitive domains including

complex attention, executive function, language, perceptual-

motor, or social cognition [5]. AD combines both genetic

and environmental factors in the formation of its pathology

[6]. Advanced age is considered as the main environmental

trigger along with other metabolic and vascular conditions

such as obesity, diabetes, trauma, stroke, high cholesterol,

*Address correspondence to this author at the Department of Biomedical

Engineering, Faculty of Engineering, Near East University, P.O. Box:

99138, North Cyprus via Mersin 10 Turkey; and Tissue Engineering and

Biomaterials Research Centre, Centre of Excellence, Near East University,

P.O. Box: 99138, North Cyprus via Mersin 10 Turkey; Tel: 03926802002;

E-mail: terin.adali@neu.edu.tr

hypertension and cardiovascular disorders [7]. Genetic re-

search suggests the involvement of 5 genes that may be

linked to the pathology of AD; including mutations of amy-

loid precursor protein (APP), presenilin 1 (PS1) and preseni-

lin 2 (PS2) genes and having the apolipoprotein E (ApoE) e4

allele and/or rare variants in the triggering receptor ex-

pressed on myeloid cells 2 (TREM2) gene that have been

revealed to increase individuals’ risk of developing AD [8-

10].

The available pharmacological treatments against AD are

yet unable to prevent or slow down the progression of the

neurodegenerative process. They can only offer symptomatic

solutions, targeting the cognitive manifestations of the disor-

der with severe side effects i.e. acetylcholinesterase inhibi-

tors (rivastigmine, galantamine, donepezil and tacrine) and

N-methyl D-aspartate receptor antagonist (memantine) [11].

The lack of effective therapeutic agents highlights the impor-

tance of gaining a deeper understanding of the underlying

mechanisms of AD. There have been several hypotheses, yet

not a single theory is able to explain all aspects of this highly

heterogeneous disorder [12]. The most established underly-

ing hypotheses that have been put forward include the amy-

loid beta, tau, cholinergic and oxidative stress hypotheses

(Fig. 1), along with other secondary pathological mecha-

nisms such as the glutamate excitotoxicity and inflammation

hypotheses. Numerous candidate drugs with diverse pharma-

cological mechanisms have been tested [13]. However, de-

spite impressive progress in clinical trials, most of the thera-

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems Current Drug Targets, 2020, Vol. 21, No. 7 629

peutic approaches have failed to modify the course of the

disease irrespective of the form of therapy and/or pathologi-

cal hallmark targeted [14].

Drug delivery to the central nervous system (CNS) is

restricted due to the challenges posed by the blood-brain

barrier (BBB). Nanoparticle-mediated drug delivery repre-

sents a viable approach to facilitate the delivery of therapeu-

tic agents to the CNS bypassing the BBB. In the context of

targeting AD, different nanocarriers are being explored. The

aim of this review is to discuss the potential application of

nanoparticle based approaches in Alzheimer’s disease and

their implications in therapy.

2. ALZHEIMER’S DISEASE HYPOTHESES

2.1. Amyloid Cascade Hypothesis

One of the most established pathological hallmarks of the

disease that has been accepted as the main explanation for

AD for over 25 years is the “amyloid hypothesis”. According

to this hypothesis, there is an extracellular amyloid-beta (Aβ)

peptide accumulation, leading to the formation of Aβ

plaques, that represent an early and central event in AD pa-

thology [15]. It accepts that Aβ plaques are the causative

factor, and that other pathophysiological features of the dis-

order follow its deposition in the brain [16].

Normally, Aβ is derived from the proteolytic cleavage

of a larger transmembrane protein, amyloid precursor pro-

tein (APP), and subsequently gets degraded in the brain.

APP is sequentially cleaved by the action of β- and γ-

secretases. β- and γ-secretase yield several isoforms of the

Aβ peptide [17] but those ending at position 40 (Aβ40) and

position 42 (Aβ42) are the most pronounced Aβ species in

AD patients’ brains. Pathological Aβ accumulation is likely

the result of an altered balance between overproduction and

degradation. Spontaneous aggregation of Aβ forms small

clusters called oligomers, which develops into insoluble

fibrils with a beta-sheet structure, and eventually into senile

plaques [18] (Fig. 2). These processes trigger neurotoxicity,

neural dysfunction and ultimately neural death, leading to

neurodegeneration.

Although the majority of research in literature still sup-

ports the significance of Aβ as the main initiating trigger of

the pathogenic cascade of AD, growing evidence also sug-

gests that Aβ pathology alone is inadequate in the late stages

of the disease [19]. Advances in neuroimaging have allowed

the observation of Aβ accumulation in vivo. It has been

consistently shown that there is a lack of correlation between

Aβ aggregates and AD-related cognitive impairment [20],

with many healthy individuals having amyloid deposits, and

AD patients with very few aggregates [17, 21]. Additionally,

the failure in developing effective Aβ targeted drugs with no

significant improvements to disease symptoms and/or pro-

gression (via the blockage of Aβ aggregation, reducing its

soluble peptides or destroying already existing Aβ plaques)

formed another growing line of evidence questioning the

impact of Aβ in AD pathology. Following numerous failures

of developing Aβ targeted drugs, attention has shifted to neu-

rofibrillary tangles (NFTs), the second most established

pathological hallmark of AD, that are composed of tau pro-

tein.

2.2. Tau Hypothesis

Tau is a soluble, microtubule associated scaffolding pro-

tein modulating the cytoskeletal dynamics of neural cells

[22]. Tau hypothesis accepts tau to be the main causative

factor in AD development [18]. Under normal conditions,

tau undergoes many modifications one of which is phos-

phorylation by various kinases. In the case of AD, there is a

state of hyper-phosphorylation [23], which raises the ques-

tion as to what mechanisms trigger the abnormal phosphory-

lation state. Although the transmission mechanism leading to

tauopathy is not fully comprehended, literature suggests the

Fig. (1). Simple overview of the most established underlying hypotheses of Alzheimer’s disease. (A higher resolution / colour version of this

figure is available in the electronic cop y of the article).

630 Current Drug Targets, 2020, Vol. 21, No. 7 Altinoglu and Adali

involvement of damage signals such as Aβ oligomers (as

stated by the amyloid cascade hypothesis), iron overload,

oxygen free radicals, cholesterol levels in the neural raft and

the involvement of innate immune system through microglial

cell activation [24]. Once hyper-phosphorylated, tau starts to

dissociate from microtubules and pair with other threads of

tau, leading to its aggregation into oligomers [25]. Eventu-

ally, they form intracellular NFTs, destroying the structure of

the neural cytoskeleton and ultimately resulting in neu-

ronal/synaptic dysfunction and cell death (Fig. 3). Although

most of the efforts have failed in clinical trials, tau-targeting

treatment strategies focus on blocking tau aggregation,

modulating tau modifications and stabilizing microtubules

[11].

2.3. Oxidative Stress Hypothesis

Increasing evidence supports the hypothesis that oxida-

tive stress, triggered by different mechanisms, may play a

causative role in initiating neurodegeneration [26, 27]. Oxi-

dative stress indicates an imbalance between anti-oxidants

and oxidants, in favor of oxidants, and have been associated

with triggering or enhancing Aβ accumulation and NFT

deposition in AD patients. Mitochondrial dysfunction fol-

lowed by an increase in toxic free-radicals is reported to be

the biological basis of the anti-oxidant and oxidant imbal-

ance, leading to oxidative damage, which in turn can initiate

the apoptotic pathway [28]. It has also been evidenced that

there is a strong link between oxidation reactions and in-

creased local concentration of transition metals such as iron

(Fe2+), copper (Cu2+), aluminium (Al3+), and zinc (Zn2+)

that may act as the source of free radicals prior to triggering

oxidative damage and neurotoxicity [29].

2.4. Cholinergic Hypothesis

The cholinergic hypothesis of AD is based on the finding

that a dysfunction of cholinergic neurons which use acetyl-

choline (involved important physiological functions e.g.

learning and memory) as a neurotransmitter is commonly

seen in people with advanced age and AD patients, and that

it correlates with cognitive decline and memory impairments

observed in these individuals [30]. Acetylcholine (ACh) is

synthesized in the cytosol of presynaptic cholinergic neurons

from choline and Acetyl Coenzyme A (Ac CoA) by choline

acetyltransferase (ChAT) enzyme and binds to postsynaptic

cholinergic receptors to cause a response. Brains of patients

with AD revealed a reduced choline uptake and ChAT activ-

ity in ACh synthesizing neurons, in addition to impairments

in post synaptic Ach receptors (Fig. 4). Therefore, the cho-

linergic system remains a highly viable target for sympto-

matic AD treatment [31]. Cholinergic drugs that are cur-

rently on the market (acetylcholinesterase inhibitors

(AChEIs)), work by inhibiting the enzyme, acetylcho-

linesterase (AChE), that breaks down ACh in the synaptic

cleft. This improves cholinergic neurotransmission and thus

the cognitive symptoms of the disorder. This hypothesis is

supported by various findings in the literature, which illus-

trates that AD-like symptoms (e.g. memory and cognitive

decline) can be induced in young subjects by blocking cho-

linergic transmission via cholinergic antagonists and re-

versed by agonists [32, 33]. However, it is important to note

that not all early stage AD patients reveal a cholinergic dys-

function and are responsive to cholinergic drugs [12], chal-

lenging the validity of this hypothesis.

3. STRUCTURAL AND FUNCTIONAL BARRIERS

The disappointing results of AD therapy are the result of

its multifactorial pathology and the failure to detect it in its

early stages before any clinical manifestations [34]. Drug

delivery to the CNS is also limited by the challenges posed

by blood-brain interfaces, including the BBB and the blood

cerebrospinal fluid barrier (BCSFB) [35]. BBB is the major

interface between the brain and circulating blood. It is a

semi-permeable, highly selective barrier. It acts as a special-

ized gatekeeper to maintain the chemical composition of the

neuronal environment at normal physiological levels by

regulating the exchange of ions/molecules [36]. BBB con-

sists of a network of endothelial cells connected by tight

junctions, enzymatic barriers and transport proteins, and

Fig. (2). Formation of amyloid beta plaques in Alzheimer’s disease pathogenesis. Abbreviations: APP, Amyloid precursor protein; AB,

Amyloid beta. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems Current Drug Targets, 2020, Vol. 21, No. 7 631

Fig. (3). Formation on neurofibrillary tangles in Alzheimer’s disease pathogenesis. Abbreviations: AB, Amyloid beta; nAchR, Nicotinic ace-

tylcholine receptors; NMDAR, NMDA receptors on neuronal membrane. (A higher resolution / colour version of this figure is available in the

electronic cop y of the a rticle).

Fig. (4). Schematic representation of cholinergic neurotransmission in normal, mild and late stages of Alzheimer’s disease. Abbreviations:

ACh, Acetylcholine; AChE, Acetylcholinesterase; ChAT, Choline acetyltransferase; Ch transporter, Choline transporter; NGF, Nerve growth

factor; M1AChR/M2AChR; Muscarinic acetylcholine receptors Type 1/2; nAChR, Nicotinic acetylcholine receptors. (A higher resolution /

colour version of this figure is available in the electronic copy of the article).

632 Current Drug Targets, 2020, Vol. 21, No. 7 Altinoglu and Adali

functionally restricts the entrance of solutes or drugs that

may be of good neuro-therapeutic value [37]. Thus, the main

obstacle for CNS drug delivery stems from the presence of

the BBB. BBB prevents the entry of “foreign” substances

into the CNS, and stops the transfer of almost all high mo-

lecular weight drugs and more than 98% of low molecular

weight drugs [38]. Lipophilicity and surface activity of

molecules are other physiochemical parameters that deter-

mine the extent to which compounds can penetrate through

this physical barrier [39]. Therapeutics or compounds having

a low molecular weight (400 Da), that are lipophilic, and not

ionized at physiological pH can transport through the BBB

by diffusion [40]. Essential compounds e.g. amino acids,

hexoses and neuropeptides, however, require specific carri-

ers to cross the BBB [40], while proteins and peptides need

saturable transport systems [41]. Consequently, the first

thing to consider during drug development is their ability to

override the BBB.

The BCSFB is another physical obstacle separating the

blood from the cerebrospinal fluid (CSF) in the subarachnoid

space, located at the choroid plexus of epithelial cells in-

volved in movement restriction [42]. Even supposing some

drugs pass these biological barriers, CNS employs other de-

fence mechanisms to reduce the potential for systemic expo-

sure [43-45]. Additionally, therapeutic agents display poor

solubility, bioavailability, and targeting potency in reaching

their pathogenic targets adding to the limitations posed by

blood-brain interfaces [34]. Therefore, it is of great impor-

tance to understand the structural and functional barriers

responsible for the failure in the treatment of CNS diseases

while designing new potential drugs and delivery mecha-

nisms [46].

Over the last decade, continuous research efforts have

been made to overcome these limitations and increase the

bioavailability of therapeutic compounds. Among these, drug

delivery systems based on nanotechnology, which combines

the fields of engineering and technology, have gained a lot of

scientific interest and offer new hope for AD treatment with

encouraging success [14] (Table 2).

4. NANOPARTICLES: DRUG DELIVERY SYSTEMS

Recent advances in nanotechnology have allowed to offer

a novel opportunity for AD treatment. Due to having a con-

trol over their shape, size, hydrophobicity, coating, chemis-

try and surface charge, nanoparticle-based approaches have

been utilized as promising tools as effective drug carriers

since their first development as carrier materials by Birren-

bach and Speiser in the 1970s [47]. By definition, nanoparti-

cles (NPs) are microscopic particles with at least one dimen-

sion below 100 nm and are able to interact with biological

systems. They are composed of a surface layer, that can be

functionalized with different molecules, and an internal core

[48]. NPs are capable of overcoming the limitations posed by

biological barriers and conventional treatment methods, al-

lowing for the encapsulation of therapeutics and their trans-

port into the CNS bypassing the BBB [49]. They can be de-

signed and modified with different surface characteristics to

optimize their pharmacokinetic and pharmacodynamic pro-

files [37]. Nano-mediated drug delivery systems offer good

stability, biocompatibility, controlled/sustained drug release

and biodegradability, as well as low toxicity and immuno-

genicity response. NPs can also provide a reduction of the

quantity and frequency of dosing, and any probably side ef-

fects (Table 1) [50].

4.1. Important NP Characteristics for Brain Drug Delivery

Biocompatible, biodegradable, non-reactive and non-

toxic nanomaterials are desired when developing nano-

particulate drug delivery systems [46]. The size, the struc-

tural conformation, the molecular weight and charge, the

encapsulating materials used, the lipophilicity, affinity for

cellular proteins, the zeta potential, the concentration gradi-

ents of encapsulated agents, the affinity of the agent and the

dosage form for the receptors are all among the important

characteristics that need to be considered while designing

NPs. Having a control over these features allows for the abil-

ity to optimize their BBB transport efficiency, drug release,

stability, and the ability to escape from their rapid circulation

clearance mechanism, the reticuloendothelial system [51-53].

Several parameters influence the passage and efficacy of

NPs across the BBB. Numerous findings have indicated an

inverse correlation between NP size and the ability to over-

come the restrictive mechanism of the BBB [54-56]. Specifi-

cally, NPs that are 50 nm – 100 nm in diameter have been

preferred for a successful transport of NPs in AD animal

models [2]. Smaller particles have also been associated with

Table 1. Potential advantages and disadvantages of nanoparticle based approaches for CNS drug delivery.!

Advantages

Disadvantages

1. Facilitates BBB transport for CNS delivery

1. BBB transport is not indicative of the biological activity

2. Good stability, biocompatibility and biodegradability

2. May influence the physiology of any cell in the body

3. Drug protection against enzymatic degradation.

3. Limited information on metabolic fate and pathway

4. Improved half-life and circulation time

4. Possible aggregation

5. Improved bioavailability

5. May cause toxicity

6. Controlled and sustained drug release

6. Possibility to further disease progression

7. Minimizes the quantity and frequency of dosage

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems Current Drug Targets, 2020, Vol. 21, No. 7 633

Table 2. Nano-enabled d rug delivery systems for AD therapy.!

Nano-delivery

Systems

Therapeutic Agent

Category

Proposed Target Hypothesis

Carrier Material

References

Nanostructured

Curcumin-donepezil

Antioxidant-AChEI

Oxidative stress and

[133]

Lipid carriers

cholinergic system

Liposomes

Galantamine

AChEI

Cholinergic system

soya phosphatidylcholine,

[175]

cholesterol, and propylene

glycol

Rivastigmine

AChEI

Cholinergic system

EPC, cholesterol,

[176-178]

DSPE-PEG-CPP

phosphatidylcho-

line/cholesterol

soya lecithin/cholesterol

Donepezil

AChEI

Cholinergic system

1,2-distearyl-sn-glycero-3-

[179]

phosphocholine (DSPC),

cholesterol (CHE), polyethylene

glycol (PEG)

Brain derived neu-

rotrophic factor

Proteins and peptides

Neuroprotective peptide

[180]

Curcumin

Polyphenols

Oxidative stress and amyloid

[181]

(Antioxidant)

cascade

Nano-emulsions

Huperzine A

Natural AChEI

Cholinergic system

[182]

Ginkgo biloba

Antioxidant

Oxidative stress

[183]

Tabernaemontana

Natural AChEI

Oxidative stress

[184]

divaricate

Beta-asarone

Neuroprotective agent

Oxidative stress

[185]

Nanocomposites

Methylene blue

Tau aggregation in-

hibitor

Tau cascade

CeNC/IONC/MSN-T807

[106]

a more uniform body distribution [57], and prolonged dura-

tion of action [58]. Drug loading and release are also influ-

enced by NP size [59]. Larger NPs with relatively large cores

allow for drug encapsulation to a greater extent per particle.

Additionally, larger NPs provide slower drug release rates

whereas smaller NPs offer faster drug release profiles. This

is due to the fact that most of the drugs encapsulated in

smaller particles would be at or near the NP surface due to

the large surface area to volume ratio of smaller NPs [60]. It

is important to note that drug loading and release efficacy is

also dependent on other important characteristics of the drug

of interest and the biomaterial of choice.

Regarding the surface characteristics, NPs can have dif-

ferent shapes varying from spherical, rod-shaped, cubic and

cylindrical models, and charges (positive, zwitterionic, and

negative). The shape of NPs influences not only BBB up-

take, but also their distribution and clearance [57]. Zeta po-

tential is another key element affecting the tendency of NPs

to penetrate through the BBB [39]. It is a measure of the

overall surface charge on the NP surface [61], and is an indi-

cator of particle stability [62]. It has been shown that most

NPs for CNS delivery have moderate or highly negative zeta

potentials, between -1 to -15 mV or -15 to -45 mV respec-

tively [63-65]. Highly positive zeta potentials are linked with

inducing BBB toxicity, yet some NPs up to 15 mV or above

have been successful in permeating through the BBB and are

used as effective delivery mechanisms [66, 67]. Being neu-

tral and zwitterionic in nature they also contribute to longer

circulation times and clearance as opposed to negative and

positive NPs [68]. The correct mechanism(s) of transport of

NPs across the BBB is not clearly established. Yet, studies

suggest the involvement of various processes including dif-

fusion, endocytosis and/or transcytosis [69], depending on

the physiochemical characteristics of NPs.

NPs can be classified into various categories. In this re-

view, we have focused on polymeric NPs, lipid-based NPs

(solid lipid NPs and nanostructured lipid carriers), liposomes

and nano-emulsions.

636 Current Drug Targets, 2020, Vol. 21, No. 7 Altinoglu and Adali

4.2. Polymeric Nanoparticles

Polymeric NPs are solid colloidal particles that can

transport therapeutic agents by encapsulating, entrapping or

bounding covalently to them [70, 52, 53]. These polymers

are the most extensively studied nano-carriers due to a sta-

ble, biocompatible and biodegradable nature with low toxic-

ity and immunogenicity [71]. Polymeric NPs may be pre-

pared from both natural polymers (e.g. polysaccharides (chi-

tosan and alginate), amino acids (poly(lysine), poly(aspartic

acid) (PASA)), or proteins (gelatin and albumin) [72], and

synthetic polymers (e.g. poly(ethylenimine) (PEI),

poly(alkylcyanoacrylates), poly(amidoamine) dendrimers

(PAMAM), poly(ε-caprolactone) (PCL), poly (lactic-co-

glycolic acid) (PLGA), polyesters (poly(lactic acid) (PLA),

or from inorganic materials, such as gold, silicon dioxide

(silica) and alumina) [2]. NPs obtained from natural poly-

mers offer the benefit of providing biological signals for

specific receptors and transporters, while expressing some

intrinsic limitations due to challenges with which they can be

modified, as opposed to synthetic NPs that can be designed

to obtain a wide range of necessary characteristics [70]. Po-

lymeric NPs are obtained by employing various preparation

techniques such as ionic gelation, polymer polymerization,

nano-precipitation, spray drying and emulsion solvent

evaporation [73], where the technique employed is deter-

mined by the characteristics of encapsulated material and the

particular polymer used [74].

4.3. Lipid-based Nanoparticles

Lipid-based nano-carriers are another type of nano-

particulate systems that offer good drug loading capacities,

protection against drug degradation, sustained and controlled

drug release and low toxicity issues. Lipid NPs are colloidal

particles that can cross the BBB via endocytosis due to their

lipophilic nature, which would also have a beneficial effect

on the ease of loading lipophilic drugs and surface function-

alization [75]. Additionally, lipid carriers have compara-

tively enhanced drug loading efficacies compared to polym-

eric NPs, allowing them to have greater control over drug

release [76]. Yet, they also express some limitations includ-

ing poor in vivo stability and poor loading of hydrophilic

agents [35].

Lipid NPs consist of solid lipid nanoparticles (SLNs) and

nanostructured lipid carriers (NLCs), both of which have been

used as drug delivery vehicles for AD treatment. SLNs are

typically composed of a solid lipid core matrix, in which the

therapeutic drugs can be dispersed or dissolved [77]. Their

nano-size (40 nm – 200 nm) offer them the ability to elude the

liver and the reticuloendothelial system, and thus penetrate

through the endothelial cells of the BBB [78]. SLNs may be

prepared from lipids, emulsifying agents, and water/solvent

that are biocompatible for application in humans. Different

preparation techniques can be utilized in their manufacture

comprising ultra-sonication/high-shear technique, high pres-

sure homogenization, solvent emulsification – diffusion,

evaporation, double emulsion and spray drying techniques

[79]. NLCs, on the other hand, are drug delivery vehicles with

both solid and liquid lipid cores, that were developed to avoid

some of the limitations of SLNs such as limited drug-loading

capacity and expulsion during storage [80].

4.4. Liposomes

Liposomes are vesicles comprising one or multiple phos-

pholipid bilayers that self-assemble around an aqueous core

[81], and are therefore categorized as uni-lamellar or multi-

lamellar [82], with sizes ranging from 50 nm to 100 µm.

Liposomes can be utilized as biocompatible and non-toxic

carriers of not only lipophilic or hydrophilic drugs [83], but

also of hydrophobic and amphiphilic agents that can be en-

trapped within the aqueous core of liposomes, due to their

phospholipid nature. Once administered, liposomes are ca-

pable of BBB transport via lipid mediated diffusion or endo-

cytosis. As with other nano-particulate systems, different

techniques can be employed to prepare liposomes including

hydration of a thin lipid film followed by agitation, sonica-

tion, high-pressure homogenization, reverse-phase evapora-

tion, and extrusion [84].

4.5. Nano-Emulsions

Nano-emulsions are nanometric-scale oil-in-water (O/W)

or water-in-oil (W/O) emulsions, typically having a droplet

size ranges of 20 nm-200nm [85], making them interesting

candidates to enhance drug delivery. They are transparent

heterogeneous mixtures comprised of oil droplets, surfac-

tant(s) as stabilizers and water or other aqueous medium

[50]. They are kinetically stable systems while being metas-

table thermodynamically [35]. They may be prepared by

different processes including high-energy input or low-

energy methods (such as high-pressure homogenizers and

spontaneous emulsification respectively), ultrasound genera-

tors and phase inversion temperature [85]. The choice of oil

employed in the preparation process has been reported to

have an effect on their uptake into the CNS. Despite posing

limitations regarding their instability during storage leading

to phase separation and burst-release effect [50, 86], several

studies have employed nano-emulsion systems to improve

drug delivery to the brain [87].

5. NANO-ENABLED ANTI-AD STRATEGIES

5.1. Nano-enabled Anti-amyloid Strategies

As discussed previously, Aβ aggregation is a commonly

reported pathological hallmark of AD. The search for new

drug candidates for AD has indicated that neuroprotective

peptides hold promise therapy-wise [2]. They can act in a

variety of ways by breaking down Aβ plaque formation, de-

grading Aβ toxic peptide and modulating Aβ cleaving en-

zymes [88]. Additionally, more futuristic neuro-regenerative

approaches aspire to rebuild the damaged tissue and reverse

the disease pathology [89, 90]. In this context, several nano-

carrier systems have been studied.

Sub-fragments of Aβ are proposed to protect brain cells

from AD. Yet, their bioavailability for in vivo applications is

restricted owing to their low permeability through the BBB.

To this end, Songjiang and Lixing synthesized chitosan NPs

loaded with Aβ sub-fragments via mechanical stirring emul-

sification methods [91]. Chitosan is a biocompatible and

biodegradable natural polymer, that has been used exten-

sively as a carrier for controlled drug delivery applications

[92]. Their results confirmed that this nano-mediated deliv-

ery has successfully carried out Aβ to the brain with a sig-

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems Current Drug Targets, 2020, Vol. 21, No. 7 637

nificant immunogenic response, underlining the importance

of research on peptide vaccines for AD [91]. iAβ5 peptide is

also a shorter anti-β-sheet peptide. Despite its significant

activity to inhibit Aβ fibrillogenesis, iAβ5 peptide is unstable

and easily degradable by proteases interrupting its use in in

vivo applications [93]. To this end, iAβ5 loaded NPs can be a

promising strategy. A research group loaded iAβ5 peptides

in PLGA NPs functionalized with two different types of an-

tibodies, an anti-transferrin receptor monoclonal antibody

OX26 (surface receptor on the brain capillary endothelium)

and anti-Aβ DE2B4 (targeting peptide for Aβ) [94].

Poly(lactic-co-glycolic acid) (PLGA) NPs are another type

of extensively studied polymeric carriers for drug delivery in

relation to their ability to offer surface functionalization,

enhanced drug loading capacity and biocompatibility with

low toxicity issues [95]. Results showed that when function-

alized, the CNS delivery of iAβ5 loaded PLGA NPs was

significantly enhanced compared to NPs with no functionali-

zation, with the purpose of increasing their bioavailability

and weakening the brain Aβ aggregates. Vasoactive intesti-

nal neuropeptide (VIP) is another neuroprotective major neu-

ropeptide found extensively in the central and peripheral

nervous system [96]. Besides possessing anti-inflammatory

effects, in vivo and in vitro studies of VIP demonstrated an

ability to inhibit excitotoxicity mediated neural death [97],

and reduce Aβ toxicity [98]. However, developing VIP-

based drug design against AD was not a success owing to its

instability and limited bioavailability. Encapsulation of VIP

by polymeric NPs has been proposed as an alternative solu-

tion by various research groups. Gao and his colleagues syn-

thesized I125 vasoactive intestinal peptide (I125VIP) loaded

poly (ethylene glycol)-poly (lactic acid) (PLA) NPs modified

with wheat germ agglutinin (WGA). Bio-distribution and

uptake of I125 VIP exhibited enhanced concentrations of the

peptide in the mice brain after intranasal administration

when loaded in WGA-conjugated and non-conjugated NPs

compared to the free drug, with an increase of 5.6–7.7-folds

and 3.5–4.7-folds, respectively [99]. Another study from

Kanwar and associates have incorporated I125 VIP into the

PEG-PLA NPs surface modified with lectins and wheat germ

agglutinin (WGA). Lectins are proteins or glycoproteins that

bind to Aβ protein. They reported a 2-fold increased uptake

of lectin modified NPs in comparison to uncoated I125 VIP

loaded NPs [100]. Zhang et al. also developed a dual-

functional anti-amyloid NP system targeting the Aβ plaques

in the brains of transgenic AD mice based on a PEGylated

PLA NPs surface functionalized with two targeting peptides;

TGN and QSH. TGN targets ligands at the BBB for BBB

penetration, while QSH has a good affinity for Aβ1-42 for

specific targeting of the plaques [29]. This study demon-

strated an enhanced and precise delivery in AD model mice,

proving effective as a valuable targeting system and improv-

ing research on disease-modifying strategies. It can be con-

cluded that surface modified polymeric NPs can serve as

promising delivery systems for carrying anti-amyloid agents

like peptides or proteins to the brain.

Besides peptides and proteins, hormones can also be

loaded in NPs that can be of good use therapeutically. There

is significant preclinical evidence that gonadal steroids (e.g.

estrogens and androgens) are key players of brain function-

ing, influencing a wide range of brain activities [101]. Addi-

tionally, estrogen has been suggested to reduce the cerebral

amyloid load and stimulate the growth and survival of cho-

linergic neurons in the brain [102]. Taking this into consid-

eration, Wang et al synthesized estradiol loaded chitosan

NPs by ionic gelation technique that was administered to

Wistar rats either intranasally or intravenously. Following

intranasal administration, plasma concentrations (32.7 ± 10.1

ng/ml) were significantly lower compared to its intravenous

administration (151.4 ± 28.2 ng/ml), whereas CSF concen-

trations after intranasal administration (76.4 ± 14.0 ng/ml)

were found to be considerably higher than those after intra-

venous administration (29.5 ± 7.4 ng/ml). Their results indi-

cate that nasal delivery could be a more optimal delivery

option targeting of drugs to the CNS directly, making it more

likely for estradiol to reach the brain [103]. Estradiol loaded

NPs have also been employed by Mittal and associates who

encapsulated estradiol in PLGA NPs for oral administration

to study the impact of polymer molecular weight and co-

polymer composition on release behavior in vivo and in vi-

tro. Fine tuning these two variables yielded a 10-fold in-

crease in the bioavailability of the drug as compared with the

free drug [104]. The same group also loaded estradiol in

PLGA NPs coated with tween-80 (T-80) via single emulsion

technique to study the effect of surface coating on the NPs.

24 h after oral administration, T-80 coated PLGA NPs re-

sulted in a significantly higher brain estradiol levels (1.969 ±

0.197 ng/g tissue) when compared to non-coated PLGA NPs

(1.105 ± 0.136 ng/g tissue). Comparing the efficacy of both

NPs also revealed a successful inhibition of Aβ42 im-

munoreactivity expression in the hippocampus area for

coated NPs as opposed to non-coated NPs, indicating the

importance of NP surface coating for brain drug delivery

[105].

5.2. Nano-enabled Anti-tau Strategies

Tau aggregation is closely linked with clinical manifesta-

tion of AD symptoms [106]. Yet, to the best of our knowl-

edge, nano-encapsulation of tau-inhibitors is still scarce.

Several approaches have employed nanoparticles and loaded

them with anti-tau agents to study their therapeutic effect.

Among them, methylene blue (MB), also known as meth-

ylthioninium chloride, is considered as a redox regulator and

a tau aggregation inhibitor. MB has been shown to delay the

progression of AD along with other tauopathies. Nonethe-

less, it suffers from limited brain availability due to its

highly hydrophilic nature [107]. Taking this into considera-

tion, glutathione coated hydrophobic poly-(lactide-co-

glycolide) (PLGA-b-PEG) NPs have been utilized to in-

crease its brain availability. These nano-carriers were found

suitable for CNS penetration. Transwell in vitro BBB model

studies revealed a greater BBB penetration of drug loaded

NPs compared to the drug solution alone over 48 hours. Syn-

thesized NPs showed a steady and sustained drug release

profile (up to 144 hrs) with no initial burst release effect.

Therapeutically, MB-NP administration was tested on two

different AD cell culture models expressing the tau protein.

According to their results, MB-NPs led to a significant re-

duction in both endogenous and over-expressed tau protein

levels, and thus could offer an alternative solution to AD

638 Current Drug Targets, 2020, Vol. 21, No. 7 Altinoglu and Adali

therapy [108]. Chen et al and colleagues have also encapsu-

lated MB in CeNC/IONC/MSN-T807 nanocomposite capa-

ble of targeting tau pathology owing to its high affinity for

the hyper-phosphorylated state of tau. In vitro and in vivo

tests showed a reduction not only in tau hyper-

phosphorylation but also in mitochondrial oxidative stress

and neuronal loss. Additionally, behavioral measures re-

vealed a considerable memory reversal of AD rats upon NP

administration, indicating its potential as a tau-focused

treatment modality [106]. Considering the involvement of

protein misfolding in protein aggregation, targeting molecu-

lar chaperones might represent a promising therapeutic ap-

proach. Among these, heat shock protein 70 (Hsp 70), which

has a crucial role in preventing protein misfolding, has re-

ceived great attention as a potential target in AD pathogene-

sis [109]. MKT-077 is one such drug that has shown promis-

ing results in AD pathology in vitro and ex vivo through a

tau-mediated pathway by targeting Hsp70. It is a highly wa-

ter soluble rhodacyanine dye previously known as FJ-776

and implicated in possessing anti-cancerous effects [110].

Yet, its potential use as an anti-AD agent is restricted due to

its limited passage across the BBB and renal toxicity. To

overcome these issues, MKT-077 loaded PEG-PLGA NPs

coated in 2% glutathione were synthesized. These NPs have

yielded a successful permeation across a Transwell in vitro

BBB model, with a higher permeability than the MKT-077

solution alone over 48 hours. Also, MKT-077 NPs demon-

strated a sustained drug release and tau reduction in in vitro

experimental models [111], holding a promise for AD and

other tau-related disorders. Similarly, Nicotinamide, the am-

ide form of vitamin B3, appears to have neuroprotective ef-

fects and has been associated with neuronal development and

survival [112]. Preclinical studies displayed an enhancement

of cognition following nicotinamide treatment. Thus, the

effectiveness of nicotinamide therapy on AD progression has

been evaluated and established as successful [113]. How-

ever, despite its ability to readily cross the BBB, nicotina-

mide suffers from a sink condition and is only available at

relatively low concentrations, making it necessary to take

multiple doses per day [114]. As a solution, a nano-based

delivery system has been employed. Nicotinamide loaded

SLNs were prepared by Vakilinezhad and associates, and

functionalized with one of the three different coatings;

polysorbate 80, phosphatidylserine or phosphatidic acid.

Their results confirmed the benefits of functionalization in

improving brain bio-distribution. In vitro cytotoxicity tests

also indicated the safety of these particles excluding the

polysorbate 80 coated NPs. Reduction in tau hyper-

phosphorylation and conservation of neuronal cells in AD

rats were demonstrated for phosphatidylserine coated

Nicotinamide-NPs in parallel with the results of spatial and

memory test [114]. Based on these reasons, these NPs can be

used as delivery vehicles to overcome the limitation of con-

ventional nicotinamide administration and target AD more

effectively.

5.3. Nano-enabled Cholinergic Strategies

As discussed earlier, the dysfunction of the cholinergic

system is considered to have a significant influence on the

learning and memory impairments of AD patients [115]. The

enhancement of cholinergic transmission via acetylcho-

linesterase (AChE) inhibition is the most established thera-

peutic approach for symptomatic AD treatment [107]. Rivas-

tigmine, an FDA-approved non-competitive and reversible

inhibitor of AChE enzyme, is one of the few drugs that are

commonly used among AD patients for long-term sympto-

matic treatment. Yet, its clinical efficacy is still limited

mostly due to poor brain uptake that leads to adverse cho-

linergic effects on peripheral organs, making it a target can-

didate for nano-encapsulation [116]. For this reason, many

studies have encapsulated rivastigmine in NPs aiming to

enhance its brain delivery and overcome the above men-

tioned limitations. Wilson et al prepared polysorbate 80-

coated Poly(n-butylcyano-acrylate) (PnBCA) NPs by emul-

sion polymerization method to improve the uptake and

bioavailability of rivastigmine via intravenous injection into

rats. A 3.82-fold increase in the uptake of the drug was ob-

served when compared with its administration as a free drug

[117]. A similar study by Joshi et al who encapsulated rivas-

tigmine not only with PnBCA NPs but also with

poly(lactide-co-glycolide) (PLGA) NPs reported improved

uptake of rivastigmine within the brain compartment. They

further observed a positive therapeutic outcome with a faster

memory regain on scopolamine-induced amnesic mice [118].

Furthermore, many studies have employed chitosan NPs to

load rivastigmine for AD therapy due to its ease of manufac-

ture and reduced cost compared to other biodegradable

polymers [119]. Fazil et al synthesized chitosan loaded ri-

vastigmine NPs using ionic gelation technique for intranasal

administration to increase drug transport efficiency across

the BBB. The findings revealed a higher transport efficiency

(355 ± 13.52%) with direct transport (71.80 ± 6.71%) in

comparison to other formulations employed [120]. Various

other experiments also showed that chitosan NPs can be em-

ployed to increase the brain concentrations of drugs via the

intranasal route [103, 121, 122]. These findings indicate the

suitability of employing AChEI-loaded NPs due to better

brain targeting efficiency. Further studies are required to

support the efficiency of such formulations in vivo.

Not only rivastigmine but many other AChE inhibitors

have also been encapsulated in NPs for the same purposes.

Tacrine, another AChE inhibitor, was the first drug to be

approved for AD treatment in 1993 [123]. However, due to

poor tolerability, tacrine use was discontinued. Nonetheless,

nano-mediated brain targeting of tacrine has been investi-

gated. Tacrine loaded PnBCA NPs were synthesized by

emulsion polymerization process by varying drug polymer

ratios. In vivo results showed that brain concentrations of

intravenously injected 1% polysorbate-80 coated tacrine NPs

were improved up to 4.07 fold compared to the free drug

[124]. Additionally, polysorbate 80 coated NPs demonstrated

a higher brain concentration of the drug in comparison to

non-coated NPs. In a similar study, Wilson et al have devel-

oped tacrine loaded chitosan NPs and tested its bio-

distribution on rats after intravenous injection. Their findings

revealed that NPs coated with 1% polysorbate 80 enhanced

brain drug concentrations, with minimal reticuloendothelial

system uptake and long half-lives [125], highlighting the

importance of this coating in brain drug delivery. According

to Sun and colleagues, brain targeting is achieved via an in-

teraction between polysorbate 80 coating and brain micro-

vessel endothelial cells making polysorbate-80 necessary for

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems Current Drug Targets, 2020, Vol. 21, No. 7 639

NP brain delivery [126]. To overcome the limitations of

BBB, AChEI drug Galantamine, has also been encapsulated

in NPs to enhance its bioavailability in the brain. Galan-

tamine was successfully delivered to the brain following its

intranasal administration in hydro-bromide incorporated chi-

tosan NPs with higher transport efficiency in comparison to

its oral administration, with no toxicity issues [119]. More

recently, galantamine loaded thiolated chitosan NPs were

successfully delivered to the brain and demonstrated a sig-

nificant recovery in amnesia induced mice [127]. Apart from

AChEIs, the effects of direct acetylcholine brain delivery

have been studied. In a recent study, Fan L et al and associ-

ates were the first to demonstrate that acetylcholine-loaded

human serum albumin nanoparticles might lead to a better

therapeutic outcome with enhanced spatial learning and

memory, while decreasing oxidative stress in mice [128].

The discussed formulations prove that nano-based delivery

of AChE inhibitors and ACh itself have the potential to be

developed as a treatment option due to better brain targeting

efficiency.

5.4. Nano-enabled Antioxidant Strategies

Another method for AD therapy is focused on the brain

delivery of antioxidants due to their ability to neutralize oxi-

dative stress mediated free radicals and association with the

prevention of neurodegenerative diseases [37]. However,

most antioxidants have limited bioavailability due to being

rapidly metabolized and eliminated from the body. One po-

tential approach is the use of antioxidant-loaded NPs for

brain-specific delivery. Curcumin, a yellow curry spice ob-

tained from the rhizome of Curcuma species, has strong neu-

roprotective, anti-oxidant and anti-inflammatory properties

besides other important medicinal values [36]. In vitro and in

vivo studies have also confirmed that curcumin has positive

effects on AD pathology. It decreases amyloid beta forma-

tion from APP protein, interacts with metal ions and inhibit

metal induced Aβ formation, inhibits the aggregation of Aβ,

and destabilize preformed Aβ fibrils [129-132]. Based on

these reasons, Sood et al have encapsulated curcu-

min/donepezil with solid lipid NPs (SLNs). Higher brain

concentrations of the drug after intranasal administration

were also supported by behavioral experiments on rats which

showed enhanced learning and memory behaviors [133].

Kakkar and associates also loaded curcumin into SLNs and

evaluated their brain targeting via the oral route in rats. Cur-

cumin loaded SLNs revealed a 2-fold increase of curcumin

concentration within the brain and improved AChE activity

when compared with the free drug [134]. Not only lipid-

based NPs but also polymeric NPs such as PnBCA NPs have

been employed to encapsulate curcumin. The encapsulation

process significantly improved the curcumin circulation time

and concentration in the brain in comparison to curcumin

alone, although its biological activity had not been evaluated

[135, 136]. Resveratrol, a natural polyphenol found in the

seeds and skins of grapes and red wine [137], is another

agent that received increased attention due to its antioxidant,

anti-inflammatory [138], and neuroprotective properties

against Aβ induced toxicity [139]. However, as with curcu-

min, resveratrol is rapidly metabolized and fails to reach the

target organs. Therefore, it is essential to stabilize resveratrol

to preserve its biological activity and to increase its bioavail-

ability in the CNS. To this end, Frozza et al developed res-

veratrol loaded SLNs to increase its brain concentration as a

result of the nano-encapsulation process. They demonstrated

a 3 to 6-fold increase in resveratrol concentration in the

brain, liver and kidneys along with improvements in memory

impairments in mouse models [140]. Lu and co-workers also

prepared a nano-particulate delivery system of resveratrol in

AD. They loaded resveratrol in PEGylated poly-caprolactone

(PCL) NPs and showed that after 48 hours, the encapsulation

process could protect PC12 cells against Aβ and were non-

toxic, as compared to the ineffective free resveratrol [141].

Another important potential antioxidant in AD therapy is

ferulic acid. It is a natural and abundant phenolic found in

plant cell walls. Bondi et al. synthesized ferulic acid-SLNs

and demonstrated that ferulic acid loaded SLNs were able to

cause a greater reduction in radical oxygen species in com-

parison to cells treated with free ferulic acid [142]. It is im-

portant to note that although the protective effects of these

antioxidant compounds are well-established, no human clini-

cal trials have been completed regarding their role in AD

therapy.

6. LIMITATIONS OF USING NANO-DELIVERY SYS-

TEMS IN AD

Despite the fact that NPs hold a significant promise as

innovative drug delivery systems, they face some issues re-

garding their use. Initially, it is important to note that in vitro

and in vivo experimental models currently used for NP stud-

ies are significant oversimplifications of real physiological

systems under study. Therefore, these models are limited to

the study of such complex NP interactions [143]. One should

be cautious of the effects of NPs on disease pathology, as a

successful delivery of drug loaded NPs across the BBB is not

predictive of their biological activity [39]. AD is a highly

heterogeneous and multi-variate disorder with multiple hy-

potheses, and testing the impact of treatment might be a

challenge across a wide range of pathways. Potentially, NPs

have the capacity to interact and influence the physiology of

any given cell in the body [144, 145]. Therefore, it is impor-

tant to develop systems that only remotely release the drug

on entering the CNS [146]. Additionally, systemic admini-

stration of NPs generates non-specific interactions between

the NP surface and biomolecules in the bloodstream leading

to their adsorption onto the NP surface, forming a layer

called the protein corona [147]. This layer may change the

morphology and surface characteristics of NPs, which has an

influence on their cellular uptake and interaction with AD

pathology [148], further complicating the use of NPs. To

overcome this limitation, further modifications at the NP

surface can be performed (e.g. PEGylating the surface). The

potential toxicity of NPs is another issue that needs to be

evaluated carefully. Clinical data on NP toxicity are still

scant, and the existing ones are primarily on non-primate

animals. The majority of these studies have focused on short-

term NP exposure, with very few reports on long-term ef-

fects and toxicity [34], that should be addressed in future

studies. Furthermore, certain NPs are not easily removed

from the body. This increases their likelihood of accumula-

tion that could interfere with blood flow or further aggravate

disease progression [149]. To this end, benefit-to-risk ratio

of using NPs as drug delivery systems for neurodegenerative

640 Current Drug Targets, 2020, Vol. 21, No. 7 Altinoglu and Adali

diseases like AD should be thoroughly assessed from a

therapeutic point of view, addressing all of these issues in

future studies.

7. AUTHORS INSIGHT ON THE TOPIC

The application of nanotechnology is increasing rapidly

by addressing the shortcomings of conventional therapy of a

wide range of chronic diseases. Alzheimer’s disease is one

such disorder that can benefit from nanoscale drug delivery

systems. Despite screening numerous drug candidates

against various biological mechanisms of AD, only a few are

currently on the market today. These treatment strategies are

also restricted due to their poor solubility, low bioavailability

and low permeability across the BBB. Therefore, one can

come to the conclusion that it may not entirely be the drugs

that are failing to target AD, but also the way they are deliv-

ered. Current advances in nanotechnology offer the potential

to overcome these limitations. Apart from drugs, other novel

therapeutic agents (e.g. peptides, hormones, antioxidants)

have also revealed significant promise in targeting AD and

thus should not be overlooked. However, extensive clinical

trials are still required to examine the effect of NPs in hu-

mans.

CONCLUSION

AD is the most common neurodegenerative disorder,

affecting the lives of approximately 50 million individuals

worldwide with a substantial impact on socio-economy. This

number is expected to double every 20 years [150], empha-

sizing the urgent need to develop new and effective treat-

ment strategies against AD. Yet, the challenges posed by the

BBB and CNS defence mechanisms significantly limit the

bioavailability of potentially effective therapeutic agents.

Nanotechnology-based approaches may provide a solution to

these limitations and thus hold a great potential as drug de-

livery mechanisms. In the context of AD, nanoparticles can

cross the BBB and establish a new frontier for drugs and

other neuroprotective molecules. Careful design of these

particles offers numerous advantages by facilitating the CNS

delivery of therapeutics with enhanced bioavailability, stabil-

ity and half-life, with controlled and sustained release pro-

files along with decreasing the frequency of dosing and ad-

verse effects [46]. Although very promising, there are still

various challenges concerning the use of NPs as drug deliv-

ery mechanisms. A crucial gap is still waiting to be filled for

improved comprehension of nano-mediated transport of

drugs to the CNS [147] and thus continuous research is es-

sential to successfully employ NPs in AD therapy.

LIST OF ABBREVIATIONS

AcCoA = Acetyl Coenzyme A

AChE = Acetylcholinesterase

AChEIs = Acetylcholinesterase Inhibitors

AD = Alzheimer’s Disease

ApoE = Apolipoprotein E

APP = Amyloid Precursor Protein

Aβ = Amyloid-beta

BBB = Blood Brain Barrier

ChAT = Choline Acetyltransferase

Ch Transporter = Choline Transporter

BCSFB = Blood Cerebrospinal Fluid Barrier

CNS = Central Nervous System

CSF = Cerebrospinal Fluid

Hsp70 = Heat Shock Protein 70

M1AChR/M2AChR = Muscarinic Acetylcholine Recep-

tors Type 1/2

MB = Methylene Blue

NFTs = Neurofibrillary Tangles

NLCs = Nanostructured Lipid Carriers

NMDAR = NMDA Receptors

nAChR = Nicotinic Acetylcholine Receptors

NPs = Nanoparticles

O/W = Oil-in-Water

PAMAM = Poly(amidoamine) Dendrimers

PASA = Poly(aspartic acid)

PCL = Poly(ε-caprolactone)

PEG = Polyethylene Glycol

PEI = Poly(ethylenimine)

PLA = Poly(lactic acid)

PLGA = Poly (lactic-co-glycolic acid)

PnBCA = Poly(n-butylcyano-acrylate)

PS1 = Presenilin 1

PS2 = Presenilin 2

SLNs = Solid Lipid Nanoparticles

T-80 = Tween-80

TREM2 = Triggering Receptor Expressed on

Myeloid Cells 2

VIP = Vasoactive Intestinal Neuropeptide

W/O = Water-in-Oil

WGA = Wheat Germ Agglutinin

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or

otherwise.

ACKNOWLEDGEMENTS

Declared none.

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Nov 2022

The incidence of Alzheimer’s disease (AD) is increasing day by day worldwide, which results in a poor quality of life. Early diagnosis and treatment of AD is necessary to suppress the progression of the disease. Conventional treatments have several limitations due to the protective blood-brain barrier. In this review, we described a nanoparticle-based approach to crossing the blood-brain barrier for AD detection and treatment. Nanoparticles encapsulate the anti-AD drug and are directed to the target tissues where controlled release of the drug takes place. There are various types of nanoparticles that are used to encapsulate drugs, including solid-based nanoparticles, liposomes, nanoemulsions, iron NPs, cerium NPs, selenium NPs, and gold NPs. In this review, we have described the use of different nanoparticles as nanomedicine. Nanoparticles are also coated with proteins and antibodies for efficient release of drugs. This review aims to provide clinical insights and the importance of nanotechnology in theranostics and describes how nanomedicine has revolutionized the drug delivery approach for AD treatment

Drug Delivery Systems as a Strategy to Improve the Efficacy of FDA-Approved Alzheimer’s Drugs

Article

Full-text available

Oct 2022

Alzheimer’s disease (AD) is the most common form of dementia, with a high impact worldwide, accounting for more than 46 million cases. The continuous increase of AD demands the fast development of preventive and curative therapeutic strategies that are truly effective. The drugs approved for AD treatment are classified into acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The therapeutic effectiveness of those drugs is hindered by their restricted access to the brain due to the blood–brain barrier, low bioavailability, and poor pharmacokinetic properties. In addition, the drugs are reported to have undesirable side effects. Several drug delivery systems (DDSs) have been widely exploited to address these issues. DDSs serve as drug carriers, combining the ability to deliver drugs locally and in a targeted manner with the ability to release them in a controlled and sustained manner. As a result, the pharmacological therapeutic effectiveness is raised, while the unwanted side effects induced by the unspecific distribution decrease. This article reviews the recently developed DDSs to increase the efficacy of Food and Drug Administration-approved AD drugs.

Bibliometric analysis of research progress on tetramethylpyrazine and its effects on ischemia-reperfusion injury

Article

May 2024
PHARMACOL THERAPEUT

Promising Nano-Carriers-Based Targeted Drug Delivery Approaches for the Effective Treatment of Alzheimer’s Disease

Chapter

Dec 2023

The book summarizes the role of multiple enzyme targets and strategies to design and develop novel drug candidates for Alzheimer's disease (AD). Insights from researchers across the globe from diverse fields are presented in a thematic volume. The chapters highlight current information scientists have unraveled about the origin, pathogenesis and prevention of AD. The contributions consider both established and emerging drug targets viz. Tau proteins, TREM, and microglia. Topics covered in the book include multi-target anti-Alzheimer's agents, epigenetic modifications, and the role of specific proteins like TMP21 and Tau in AD. A section dedicated to pharmacological treatments discusses the significance of tubulin-modifying enzymes, memantine, and glutamate antagonists. Enzymatic targets for drug discovery are thoroughly examined, focusing on cholinesterase, secretases, and other enzymes. Additionally, the book explores innovative nano-carrier-based drug delivery methods, emphasizing the crucial role of nanotechnology in effective Alzheimer's treatment. The book aims to inform students and researchers in the field of neuroscience, medicine and pharmacology about current research and biochemical nuances of AD pathogenesis and enzymatic drug targeting strategies.

Drug delivery for Alzheimer's disease using nanotechnology: Challenges and advancements

Chapter

Full-text available

Dec 2023

Alzheimer's disease (AzD) is the most common type of dementia among older adults, with a progressive disorder of brain that affect thinking ability, behavior, and memorizing capability. It is the most common cause of dementia in older adults, accounting for approximately 60%–80% of all cases of dementia. The exact cause of AzD is yet not fully understood, however several reports indicate that a combinations of genetic, environmental, and lifestyle factors contribute to the development and progression of AzD. The risk factors associated with AzD are age, family history, head injuries, high blood pressure, and high cholesterol. Moreover, the abnormal deposition of protein (β-amyloid plaques and tau tangles) in brain lead to the mortality of brain cells and gradual decline of cognitive functions. Currently, there is no complete cure for AzD available, however advancement in drug delivery system developed several treatment strategies that can help manage symptoms and slow the progression of the disease. The management strategies include medications to improve cognitive function, behavioral and environmental modifications, and support for caregivers and family members. Recently nanotechnology have gained significant attention among researcher in management of AzD although the drug diffusion to blood brain barriers presents several difficulty. Carrier-based drug delivery presents promising alternative to deliver medicament to the brain. Several carrier-based drug delivery reported such as liposomes, nanocrystals, nanoemulsions, dendrimers, polymer-protein/drug conjugates, nanoparticles, antibody conjugated drugs, nanotubes, nanogels, and micelles are included in this chapter for the management AzD. While the use of nanotechnology in AzD is still in early stages of research, it holds great promise for the fabrication of pharmaceuticals in management of this devastating disease.

The Major Hypotheses of Alzheimer's Disease: Related Nanotechnology-Based Approaches for Its Diagnosis and Treatment

Article

Full-text available

Nov 2023

Alzheimer's disease (AD) is a well-known chronic neurodegenerative disorder that leads to the progressive death of brain cells, resulting in memory loss and the loss of other critical body functions. In March 2019, one of the major pharmaceutical companies and its partners announced that currently, there is no drug to cure AD, and all clinical trials of the new ones have been cancelled , leaving many people without hope. However, despite the clear message and startling reality, the research continued. Finally, in the last two years, the Food and Drug Administration (FDA) approved the first-ever medications to treat Alzheimer's, aducanumab and lecanemab. Despite researchers' support of this decision, there are serious concerns about their effectiveness and safety. The validation of aducanumab by the Centers for Medicare and Medicaid Services is still pending, and lecanemab was authorized without considering data from the phase III trials. Furthermore, numerous reports suggest that patients have died when undergoing extended treatment. While there is evidence that aducanumab and lecanemab may provide some relief to those suffering from AD, their impact remains a topic of ongoing research and debate within the medical community. The fact is that even though there are considerable efforts regarding pharmacological treatment, no definitive cure for AD has been found yet. Nevertheless, it is strongly believed that modern nanotechnology holds promising solutions and effective clinical strategies for the development of diagnostic tools and treatments for AD. This review summarizes the major hallmarks of AD, its etiological mechanisms, and challenges. It explores existing diagnostic and therapeutic methods and the potential of nanotechnology-based approaches for recognizing and monitoring patients at risk of irreversible neuronal degeneration. Overall, it provides a broad overview for those interested in the evolving areas of clinical neuroscience, AD, and related nanotechnology. With further research and development, nanotechnology-based approaches may offer new solutions and hope for millions of people affected by this devastating disease.

Potential Neuroprotective Strategies using Smart Drug Delivery Systems for Alzheimer’s Disease

Article

Oct 2023

Background Alzheimer's disease (AD) is the most common neurological disorder, affecting more than 50 million individuals worldwide and causing gradual but progressive cognitive decline. The rising cost of medical treatment is mostly attributable to AD. There are now mainly a few slightly symptomatic therapeutic options accessible. Although this is not the primary reason, the failure to develop effective treatments for AD is often attributed to the disease's complicated pathophysiology and the wide range of underlying ideas. Objective Studies undertaken over the past decade have aimed to find novel methods of overcoming these barriers and effectively delivering drugs to the central nervous system. As a result, nanotechnology provides a promising alternative to the standard means of administering anti-amyloidosis drugs, enhancing expectations for a successful treatment of Alzheimer's disease. These therapeutic implications of using nanoparticle-based approaches for the treatment of Alzheimer's disease are discussed in this paper. Methodology Published articles from PubMed, SciFinder, Google Scholar, ClinicalTrials.org, and the Alzheimer Association reports were carefully examined to compile information on the various strategies for combating AD. That has been studied to summarize the recent advancements and clinical studies for the treatment of Alzheimer's disease (AD). Statistics is the study and manipulation of data, including ways to gather, review, analyze, and draw conclusions from data. Conclusion The biology of the BBB and its processes of penetration must be carefully taken into account while creating DDSs. If we have a better grasp of the disease's mechanism, we might be able to overcome the shortcomings of current treatments for AD. Different DDSs show interesting properties for delivering medication tailored to the brain. This review paper examines the recent applications of DDSs in diverse domains. By selecting the best targeting vectors and optimizing the combination of carriers, multifunctionalized DDS may be produced, and these DDS have a significant impact on AD therapy potential. To develop DDSs with the best therapeutic efficacy and manageable side effects, experts from a variety of fields may need to contribute their efforts. Currently, the therapeutic use of nanotechnology-based DDSs appears to be a promising prospect for AD therapy, and as the pathophysiology of AD is better understood, this strategy will develop over time.

Nanotechnology-empowered therapeutics targeting neurodegenerative diseases

Article

May 2023

Neurodegenerative diseases are posing pressing health issues due to the high prevalence among aging populations in the 21st century. They are evidenced by the progressive loss of neuronal function, often associated with neuronal necrosis and many related devastating complications. Nevertheless, effective therapeutical strategies to treat neurodegenerative diseases remain a tremendous challenge due to the multisystemic nature and limited drug delivery to the central nervous system. As a result, there is a pressing need to develop effective alternative therapeutics to manage the progression of neurodegenerative diseases. By utilizing the functional reconstructive materials and technologies with specific targeting ability at the nanoscale level, nanotechnology‐empowered medicines can transform the therapeutic paradigms of neurodegenerative diseases with minimal systemic side effects. This review outlines the current applications and progresses of the nanotechnology‐enabled drug delivery systems to enhance the therapeutic efficacy in treating neurodegenerative diseases. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies

Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer’s disease animal model by reducing Tau hyperphosphorylation

Article

Full-text available

Nov 2018
DARU

Background: Nicotinamide is considered to be effective in halting the Alzheimer's disease progression. The body could absorb a limited amount of nicotinamide at a time, requiring multiple doses through a day. To overcome such an obstacle which reduces the patient compliance, a sustained/controlled delivery system could be useful. Method: Nicotinamide loaded solid lipid nanoparticles (SLN) were prepared and functionalized with polysorbate 80 (S80), phosphatidylserine (PS) or phosphatidic acid (PA). The acquired particles were characterized and evaluated in respect of their cytotoxicity, biodistribution, and in vivo effectiveness through the different routes of administration. Results: The optimum sizes of 112 ± 1.6 nm, 124 ± 0.8 nm, and 137 ± 1.05 nm were acquired for S80-, PS-, and PA-functionalized SLNs, respectively. The in vitro cytotoxicity on SH-SY5Y cell line showed the safety of formulations except for S80-functionalized SLNs. Biodistribution study of SLNs has proved the benefits of functionalization in improving the brain delivery. The results of spatial and memory test, i.e. Morris water maze, and also histopathology and biochemical tests demonstrated the effectiveness of i.p. injection of PS -functionalized SLNs in improving the cognition, preserving the neuronal cells and reducing tau hyperphosphorylation in a rat model of Alzheimer's disease. Conclusion: The acquired PS-functionalized SLN could be a potential brain delivery system. Loaded with nicotinamide, an HDAC inhibitor, it could ameliorate the cognition impairment of rats more effectively than the conventional administration of nicotinamide, i.e. oral, in the early stage of Alzheimer's disease. Graphical abstract ᅟ.

PPARγ agonist-loaded PLGA-PEG nanocarriers as a potential treatment for Alzheimer’s disease: in vitro and in vivo studies

Article

Full-text available

Sep 2018

Objective The first aim of this study was to develop a nanocarrier that could transport the peroxisome proliferator-activated receptor agonist, pioglitazone (PGZ) across brain endothelium and examine the mechanism of nanoparticle transcytosis. The second aim was to determine whether these nanocarriers could successfully treat a mouse model of Alzheimer’s disease (AD). Methods PGZ-loaded nanoparticles (PGZ-NPs) were synthesized by the solvent displacement technique, following a factorial design using poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). The transport of the carriers was assessed in vitro, using a human brain endothelial cell line, cytotoxicity assays, fluorescence-tagged nanocarriers, fluorescence-activated cell sorting, confocal and transmission electron microscopy. The effectiveness of the treatment was assessed in APP/PS1 mice in a behavioral assay and by measuring the cortical deposition of β-amyloid. Results Incorporation of PGZ into the carriers promoted a 50x greater uptake into brain endothelium compared with the free drug and the carriers showed a delayed release profile of PGZ in vitro. In the doses used, the nanocarriers were not toxic for the endothelial cells, nor did they alter the permeability of the blood–brain barrier model. Electron microscopy indicated that the nanocarriers were transported from the apical to the basal surface of the endothelium by vesicular transcytosis. An efficacy test carried out in APP/PS1 transgenic mice showed a reduction of memory deficit in mice chronically treated with PGZ-NPs. Deposition of β-amyloid in the cerebral cortex, measured by immunohistochemistry and image analysis, was correspondingly reduced. Conclusion PLGA-PEG nanocarriers cross brain endothelium by transcytosis and can be loaded with a pharmaceutical agent to effectively treat a mouse model of AD.

The Influence of Nicotinamide on Health and Disease in the Central Nervous System

Article

Full-text available

May 2018

Nicotinamide, the amide form of vitamin B3 (niacin), has long been associated with neuronal development, survival, and function in the central nervous system (CNS), being implicated in both neuronal death and neuroprotection. Here, we summarise a body of research investigating the role of nicotinamide in neuronal health within the CNS, with a focus on studies that have shown a neuroprotective effect. Nicotinamide appears to play a role in protecting neurons from traumatic injury, ischaemia, and stroke, as well as being implicated in 3 key neurodegenerative conditions: Alzheimer’s, Parkinson’s, and Huntington’s diseases. A key factor is the bioavailability of nicotinamide, with low concentrations leading to neurological deficits and dementia and high levels potentially causing neurotoxicity. Finally, nicotinamide’s potential mechanisms of action are discussed, including the general maintenance of cellular energy levels and the more specific inhibition of molecules such as the nicotinamide adenine dinucleotide-dependent deacetylase, sirtuin 1 (SIRT1).

Alzheimer’s disease hypothesis and related therapies

Article

Full-text available

Dec 2018

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause for dementia. There are many hypotheses about AD, including abnormal deposit of amyloid β (Aβ) protein in the extracellular spaces of neurons, formation of twisted fibers of tau proteins inside neurons, cholinergic neuron damage, inflammation, oxidative stress, etc., and many anti-AD drugs based on these hypotheses have been developed. In this review, we will discuss the existing and emerging hypothesis and related therapies.

Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease

Article

Full-text available

Jan 2018

The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar amyloid β (Aβ) peptide is the primary cause of Alzheimer's disease (AD), has been the mainstream concept underlying AD research for over 20 years. However, all attempts to develop Aβ-targeting drugs to treat AD have ended in failure. Here, we review recent findings indicating that the main factor underlying the development and progression of AD is tau, not Aβ, and we describe the deficiencies of the amyloid hypothesis that have supported the emergence of this idea.

Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer’s disease

Article

Full-text available

Jan 2018
DRUG DELIV

In recent years, the incidental rate of neurodegenerative disorders has increased proportionately with the aging population. Alzheimer’s disease (AD) is one of the most commonly reported neurodegenerative disorders, and it is estimated to increase by roughly 30% among the aged population. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates – such as acetylcholinesterase inhibitors are currently utilized as an effective clinical therapy. However, targeted drug delivery of these drugs to the central nervous system (CNS) exhibits several limitations including meager solubility, low bioavailability, and reduced efficiency due to the impediments of the blood-brain barrier (BBB). Current advances in nanotechnology present opportunities to overcome such limitations in delivering active drug candidates. Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability. Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop successful therapeutics with sustained release and improved efficacy. Here, we discuss few recently updated nano-drug delivery applications that have been adapted in the field of AD therapeutics, and future prospects on potential molecular targets for nano-drug delivery systems.

Delivering the Acetylcholine Neurotransmitter by Nanodrugs as an Effective Treatment for Alzheimer's Disease

Article

Dec 2018
J BIOMED NANOTECHNOL

The current clinical symptomatic therapy for Alzheimer's disease involves increasing acetylcholine levels in the brain by inhibiting acetylcholinesterase. However, the effectiveness of acetylcholinesterase inhibitors decreases as the disease progresses, leading to many side effects including over-inhibition of other enzymes and hepatic injury. Herein, we investigate the effects of the direct delivery of a low-dose of acetylcholine via human serum albumin nanoparticles to brain. This novel nanodrug improved both spatial learning and memory capability, whereas it reduced oxidative damage in mice. More importantly, damage to the liver or interference with the inherent neurotransmitter generation due to supplementation were almost absent. Our study is the first to demonstrate that supplementation of acetylcholine-loaded nanoparticles might offer a better therapeutic option in the ease of Alzheimer's disease.

Nose to Brain Delivery of Galantamine Loaded Nanoparticles: In-vivo Pharmacodynamic and Biochemical Study in Mice

Article

Oct 2018
Curr Drug Deliv

Background: Presence of blood brain barrier is one of the major hurdle in drug delivery to brain for the treatment of neurological diseases. Alternative and more effective drug delivery approaches have been investigated for the drug targeting to brain in therapeutic range. Objective: The present investigation was carried out to improve the galantamine bioavailability in brain by intranasal drug delivery through thiolated chitosan nanoparticles and compared to nasal and oral delivery of its solution using pharmacodynamic activity as well as biochemical estimation. Method: Thiolated chitosan (modified) nanoparticles were fabricated using modified ionic gelation method and intranasal delivery is evaluated by reversal of scopolamine induced amnesia and biochemical estimation of acetylcholinesterase activity in Swiss albino mice brain. Scopolamine (0.4 mg/kg, i.p.) was used to induce amnesia. Piracetam (400mg/kg, i.p.) was used as positive control. Mice were treated with galantamine solution (4mg/kg) by oral and nasal route and formulated galantamine nanoparticles (equivalent to 4mg/kg) by intranasal administrationfor 7 successive days and the results were compared statistically. Results: Intranasal delivery of galantamine loaded thiolated chitosan nanoparticles was found significant (p<0.05) as compared oral and nasal administration of its solution, by pharmacodynamic study and biochemical estimation of acetylcholinesterase activity in Swiss albino mice brain. Conclusion: Significant recovery in amnesia induced mice model by intranasal administration of galantamine loaded thiolated chitosan nanoparticles establish the relevance of nose to brain delivery over the conventional oral therapies for the treatment of alzheimer's disease.

Application of Nanoemulsions in Drug Delivery

Chapter

Mar 2018

Nanoemulsions are being increasingly utilized as drug delivery systems for the effective administration of pharmaceuticals because of their potential advantages over other approaches. Nanoemulsions can be used to design delivery systems that have increased drug loading, enhanced drug solubility, increased bioavailability, controlled drug release, and enhanced protection against chemical or enzymatic degradation. Moreover, nanoemulsions have better stability to flocculation, sedimentation, and creaming than conventional emulsions. Their small droplet dimensions and large droplet surface area positively influence drug transport and delivery, along with allowing targeting to specific sites. This chapter focuses on recent applications of nanoemulsions in the area of drug delivery.

A Tau-Targeted Multifunctional Nanocomposite for Combinational Therapy of Alzheimer’s Disease

Article

Jan 2018

Alzheimer’s disease (AD) remains to be an incurable disease and lacks efficient diagnostic methods. Most AD treatments have focused on amyloid-β (Aβ) targeted therapy, however, it is time to consider the alternative theranostics due to accumulated findings of weak correlation between Aβ deposition and cognition, as well as the failures of Phase III clinical trial on Aβ targeted therapy. Recent researches have shown that tau pathway is closely associated with clinical development of AD symptoms, which might be a potential therapeutic target. We herein construct a methylene blue (MB, a tau aggregation inhibitor) loaded nanocomposite (CeNC/IONC/MSN-T807), which not only possesses high binding affinity to hyperphosphorylated tau, but also inhibits multiple key pathways of tau-associated AD pathogenesis. We demonstrate that these nanocomposites can relieve the AD symptoms by mitigating mitochondrial oxidative stress, suppressing tau hyperphosphorylation and protecting neuronal death both in vitro and in vivo. The memory deﬁcits of AD rats are significantly rescued upon treatment with MB loaded CeNC/IONC/MSN-T807. Our results indicate that hyperphosphorylated tau-targeted multifunctional nanocomposites would be a promising therapeutic candidate for Alzheimer’s disease.

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems

Abstract and Figures

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