Nano Carrier Drug Delivery Systems for the Treatment of Neuropsychiatric Disorders: Advantages and Limitations

Neuropsychiatric diseases are one of the main causes of disability, affecting millions of people. Various drugs are used for its treatment, although no effective therapy has been found yet. The blood brain barrier (BBB) significantly complicates drugs delivery to the target cells in the brain tissues. One of the problem-solving methods is the usage of nanocontainer systems. In this review we summarized the data about nanoparticles drug delivery systems and their application for the treatment of neuropsychiatric disorders. Firstly, we described and characterized types of nanocarriers: inorganic nanoparticles, polymeric and lipid nanocarriers, their advantages and disadvantages. We discussed ways to interact with nerve tissue and methods of BBB penetration. We provided a summary of nanotechnology-based pharmacotherapy of schizophrenia, bipolar disorder, depression, anxiety disorder and Alzheimer’s disease, where development of nanocontainer drugs derives the most active. We described various experimental drugs for the treatment of Alzheimer’s disease that include vector nanocontainers targeted on β-amyloid or tau-protein. Integrally, nanoparticles can substantially improve the drug delivery as its implication can increase BBB permeability, the pharmacodynamics and bioavailability of applied drugs. Thus, nanotechnology is anticipated to overcome the limitations of existing pharmacotherapy of psychiatric disorders and to effectively combine various treatment modalities in that direction.


Introduction
According to statistics, one in four people in the world afflicts with various mental or neurological illnesses at some point of their lives. Around 450 million people currently suffer from such conditions, placing mental disorders among the leading causes of ill and disability worldwide [1].
There is a great clinical need for development a new-generation of psychoactive drugs, because the global burden of mental illness continues to increase. Despite the wide range of existing drugs One of the promising methods to overcome BBB is the loading of drugs into nanocontainers that are characterized by relatively small size and ability to cross the BBB. Using this method of drug delivery significantly increases substances bioavailability and reduces the side effects.
The mechanisms of NPs transportation through BBB can be classified into tree main types [17]: • Transient opening of BBB is induced by a stimulus derived from bioactive components on the surface of nanoparticles, or by a stimulus derived from the "nanoeffects" or "nanotoxicity" of nanoparticles. This opening promotes the diffusion of drug conjugates into brain tissue; • The adsorption of nanocarrier conjugates on the surface of capillary endothelium cells facilitates the release of the drug from carriers on the cell surface. This process increases the concentration gradient of the drug and promotes the diffusion of substances into the brain; • Transcytosis, endocytosis and exocytosis of nanocarriers by capillary endothelial cells of the brain provides direct penetration of the substances into brain tissue. Figure 1 describes the main pathways of nanoparticles entering the brain: mechanisms for BBB penetration and transport across the cell membrane.
Basically, there are three main mechanisms of NPs cellular uptake [18]. The first one is pinocytosis, which is divided into macro-and micropinocytosis, depending on the nanocarrier size and the type of targeted cell. Another method of nanotherapeutics uptake is clathrin-mediated endocytosis or receptor-mediated endocytosis [18]. This process is based on the formation of clathrin-coated endocytic vesicles. The third way to load NPs into cells is caveolae-dependent endocytosis with calveolar vesicles generation. This type of endocytosis is commonly found in endothelial and muscle cells [18].
In the brain different types of neural cells, including neurons, astrocytes, oligodendrocytes and microglia can represent a target for drug delivery. Targeting ability of nanotherapeutic agents depends on NPs functionality and sometimes requires the presence of specific molecules. Neuron-specific delivery is rather difficult because neurons have a non-phagocytic nature in comparison to glial cells. In some studies, neuron-specific targeting was achieved by the properties of connecting ability of loaded substances. To enhance the neuronal targeting, active strategies such as utilizing ligands with dopamine [19], and rabies virus glycoprotein peptide (RVG and RDP peptide) [20] have being used. Receptor-mediated endocytosis strategies are commonly used to induce neuron uptake of NPs. For example, nanocarriers coated with apolipoprotein E can be uptaken by neurons through the agency of the lipoprotein-binding receptors on neurons surface [21].
Astrocytes are also very promising targets for nanomedicine. Commonly NPs can be transported into astrocytes via phagocytosis. Their targeting can affect the neurotransmitters release (e.g., glutamate, γ-aminobutyric acid, glycine and histamine), which is crucial for the maintenance of neuronal excitability [22].
Oligodendrocytes are specialized neural cells, where their role is to myelinate the axons in CNS. Properties of their surface can simplify drug delivery via nanopreparations. In particular, NG-2 chondroitin sulphate proteoglycans are expressed on oligodendrocyte precursor cells, which represent useful targets for specific NPs like poly(lactic-co-glycolic acid (PLGA). Such nanocarriers loaded with leukemia inhibitory factor can increase myelin repair [23].
Targeting of microglia or macrophages is also a promising direction for nanomedicine. It is known, that clathrin-mediated endocytosis serves as the major pathway for microglia to uptake NPs. NPs with a larger surface area demonstrate higher uptake efficiency, because clathrin-mediated endocytosis is carried out by the binding of clathrin receptor with the surface of nanocarriers. This property was manifested by the experiments demonstrated that gold NPs with "urchin-mimicking" geometry were absorbed more effectively by microglial cells compared to spherical and rod-like gold NPs [24]. In addition to clathrin-mediated endocytosis, mannose receptors and macrophage scavenger receptors have also been implicated in playing a role in nanocarriers uptake in non-activated microglia [25,26]. There are two main ways to affect microglia or macrophages with nanotherapy. The first one allows controlling microglia/macrophages population by inhibition of infiltrating monocytes/macrophages. For these reason cytotoxic drugs, such as clodronate, glucocorticoids, doxorubicin and methotrexate are usually applied. For example, it was demonstrated that locally delivered methylprednisolone encapsulated into PLGA nanoparticles dramatically reduced the number of macrophages/reactive microglia [27]. The second way to modulate glial cells functions is the use of control release of cytokines via NPs.
Therefore, various research groups are developing nanocontainer systems for drug delivery. There are several types of using nanoparticles with different advantages and disadvantages. In the following we will consider the types of nanoparticles and their way of penetration through BBB, which is necessary for the treatment of neuropsychiatric disorders.
Molecules 2020, 25, x FOR PEER REVIEW 4 of 67 The mechanisms of NPs transportation through BBB can be classified into tree main types [17]:  Transient opening of BBB is induced by a stimulus derived from bioactive components on the surface of nanoparticles, or by a stimulus derived from the "nanoeffects" or "nanotoxicity" of nanoparticles. This opening promotes the diffusion of drug conjugates into brain tissue;  The adsorption of nanocarrier conjugates on the surface of capillary endothelium cells facilitates the release of the drug from carriers on the cell surface. This process increases the concentration gradient of the drug and promotes the diffusion of substances into the brain;  Transcytosis, endocytosis and exocytosis of nanocarriers by capillary endothelial cells of the brain provides direct penetration of the substances into brain tissue. Figure 1 describes the main pathways of nanoparticles entering the brain: mechanisms for BBB penetration and transport across the cell membrane.  BBB-blood-brain barrier; NPs-nanoparticles.

Categories of Nanocarriers
Currently the spectrum of nanoparticles used for targeted drug delivery is quite wide. Such nanocontainers can be divided into three main groups: polymeric nanoparticles (NPs), lipid-based NPs and inorganic NPs ( Table 2). The surface groups can be conjugated with targeting ligands.
The surface functionalization with targeting ligands.

•
The surface groups can be conjugated with targeting ligands.
The efficiency delivering across the intact BBB still needs further investigation. [17] Dendrimers The monodisperse symmetric molecules that comprise a series of branching units around an inner core, which have a spheroidal shape and radially crowded layers.

•
The core is loosely packed in comparison to the periphery and is suitable for the entrapment of drugs.

•
The presence of numerous surface groups allows for high drug payload and multifunctionality.

•
The surface groups can be conjugated with targeting ligands.

Polymeric Nanoparticles
This class includes polymer-based nanoparticles and micelles and dendrimers (Table 2). Nanoparticles based on polylactide acid (PLA) and poly (lactic-co-glycolic acid) (PLGA) developed over several decades have proved to be a promising alternative system for delivering drugs to the brain, primarily due to their high biocompatibility and low toxicity. They have uncomplicated synthesis methods (emulsification, evaporation, solvent replacement method (deposition), solvent diffusion method, etc.) and are metabolized into lactic and glycolic acids using a simple mechanism. So, they are biodegradable, with optimal sizes ranging from 100 to 200 nm. PLGA/PLA nanoparticles are U.S. Food and Drug Administration (FDA) certified and can be used in implants, biodegradable scaffolds and human medicines.
The therapeutic molecules encapsulated in polymer nanoparticles can form the following thermodynamically stable structures, depending on the loading method. Either they are nanospheres where the drug is loaded across the entire polymer matrix or only on its surface, or they are nanocapsules where the active substance is surrounded by a polymer shell.
The surface of such particles is easily modifiable, both with ligands for target delivery and molecules that promote adsorption on target cells. Thus, using the example of the anticonvulsant Clonazepam contained in the PLGA matrix, it was possible to achieve effective delivery of the drug through BBB by conjugating the poloxamer-188 to the surface of the NP [35]. Conclusion in PLGA nanocarriers curcumin solved the problem of its insolubility in water, and conjugation with Tet-1 made it possible to increase nanoparticles capture in the treatment of Alzheimer's disease (AD) [36].
Polymer nanoparticles penetrate the BBB through endocytosis. They can also avoid the phagocytosis of the reticular endothelial system, thereby increasing the concentration of drugs in the brain [37]. In vitro studies have shown that the use of polymer nanoparticles increases the delivery of drugs to the brain. For example, improved delivery of curcumin (in the treatment of AD) is more effective in reducing oxidative stress, inflammation and plaque load.

Dendrimers
Dendrimers are monodisperse symmetrical macromolecules consisting of a series of branched blocks around the inner nucleus. The spherical structure of dendrimers consists of the core, layers of branched, repeating blocks coming out of the core and functional end groups on the outer layer [17].
In the treatment of brain diseases, polyamidoamine dendrimers are most commonly used among dendrimers. For example, there is a study on the use of encapsulated carbamazepine (an antiepileptic drug) for the treatment of AD [38].

Micelles
Micelles consist of amphiphilic block copolymers. They aggregate in aqueous solutions to form stable spheroidal nanostructures that have a hydrophobic core and hydrophilic surface.
The micelles are promising agents for delivering drugs to the brain. This is made possible by the dissolution of poorly soluble substances in the hydrophobic nucleus area and the ability to conjugate with certain target ligands [17].

Liposomes
Liposomes are the family of nanostructures, the main characteristic of which is a spherical shape and lipid bilayer. Optimal sizes range from 100 to 200 nm. The first FDA approved nanodrug in 1995 was Doxil represented a preparation based on liposomes [39]. Over the next 2 decades all types of liposome forms, methods of construction and modifications have been developed [40]. For example, liposomal nanoparticles produced by microfluidics were constructed. These nanocarriers allow increasing the percentage of drug loading and obtaining a balanced size of nanocontainer [41]. Generally, liposomes are characterized by the high biocompatibility, biodegradability, improved bioavailability and stability of therapeutic agents [42]. Moreover, they are able to modify the surfaces for active targeting [43]. Nanoparticles structure allows the incorporation of auxiliary lipids such as dioleylphosphatidylethanolamine (DOPE) or cholesterol. DOPE is able to conjugate with other lipids when exposed to low pH, which promotes increased efficiency of loading into cytosol and favor endosomes construction [44]. Cholesterol provides structural stability. The linkers are sensitive to different biological stimuli and contribute to the release of the drug under certain conditions. For example, modifications of gold nanoshells liposomes mediating by chitosan can provide liver protection [45]. Opsonization and capture by macrophages of the organs of the mononuclear phagocytic system obstructs the delivery of drugs via unmodified liposomes. Modification with polyethylene glycol (PEG) increases nanoparticles circulation time and reduces cell capture [17].
The using of liposomal constructions for BBB crossing has been investigated for decades [43]. Liposomes are modified for targeting transcytosis through CNS endothelium via the liposomal surface functionalization with biologically active ligands, such as peptides, antibodies or small molecules. G-Technology ® (FDA approved technology) is another method for transformation of the liposomal surface. It represents a strategy for using glutathione-PEGylated liposomes, which are able to bind with glutathione transporter [46].
Thus, liposomes are promising candidates for BBB penetration and targeting delivery of therapeutic agents.

Solid Lipid Nanoparticles
Unlike liposomes, this type of nanoparticles does not possess a lipid layer, but is characterized by the presence of a solid lipid core matrix that can encapsulate lipophilic molecules. Solid lipid nanoparticles (SLNs) are nanoscale suspensions of biologically compatible lipids such as triglycerides, fatty acids or waxes stabilized by bioactive substances possessing a hydrophile-lipophile balance [17].
Such nanoparticles are also subjected to surface modification, which significantly increases the efficiency of drug transporting through BBB [47]. As containers for drug delivery, they demonstrate a high level of biocompatibility, biodegradability and the ability to transform the surface with target bioactive molecules. However, their hydrophobicity promotes easier clearance by the reticuloendothelial system (RES), which alleviates nanoparticles effectiveness.

Nanoemulsion
Nanoemulsions are heterogeneous dispersions of the composition "oil in water" (O/W) or "water in oil" (W/O), stabilized by surfactants. The diameter of the internal phase in such nanosystems is reduced to a nanometric scale. Due to their properties, nanoemulsions demonstrate the ability to carrier both hydrophobic (O/W) or hydrophilic (W/O) drugs. The surface of these nanoparticles can also be modified with bioactive ligands. Delivery of drugs via nanoemulsions is carried out through receptor-mediated endocytosis of cells.
Compared to other nanocarriers, the preponderance of nanoemulsions for BBB penetration is the ability to use safe oils. In addition, the application of this type of nanoparticles possesses a number of useful biological properties due to the presence of essential omega-3 and omega-6 fatty acids in the oils [17].

Inorganic NPs
Inorganic nanoparticles represent solid nanosize objects consisting of inorganic materials such as silicon dioxide, carbon nanotubes, metal or metal oxide. This type of nanoparticles is widely used for visualization research, including neuroimaging.
To facilitate penetration through BBB, they are covered with several polymers such as polysaccharides, polyacrylamide, poly(vinyl alcohol), poly(N-vinyl-2-pyrrolidone), PEG and PEG-containing copolymers. The most commonly used covering polymer is PEG. These surface modifications enhance nanoparticles stability, improve water solubility and allow modifying of the particle surface with vector molecules [48]. In addition, such PEGylation of nanocontainers averts the capture of particles by the RES and prevents non-specific interactions with opsonin proteins [49].
Besides PEG covering inorganic nanoparticles are also modified with lactoferrin (Lf). It is interesting that this conjunction demonstrated better efficiency during BBB penetration than PEG because of Lf-receptor-mediated transcytosis of cerebral endothelial cells [50].
In addition to chemical modification, the physical properties of inorganic nanoparticles can also be changed for an increase of penetration through BBB. For example, Fe 3 O 4 nanoparticles demonstrate the ability to be magnetized in the presence of a magnetic field. It has been shown that superparamagnetic iron oxide nanoparticles (SPIONs) contained magnetite (Fe 3 O 4 ) and maghemite (c-Fe 2 O 3 ) can cross human brain microvascular endothelial cells via an external magnet pressure. Therefore, this mechanism demonstrates the ability of BBB penetration and targeted drug delivery to the brain to be carried out by the magnetic force-mediated dragging of SPIONs through the BBB. Such property of iron oxide nanoparticles as magnetism can be applied for diagnostics and simultaneous therapy of neurodegenerative diseases [51]. Along with iron nanocarriers gold nanoparticles can also penetrate through BBB and can be administered for therapy of neuropsychiatric diseases [52].
Nevertheless, despite the advantages of these types of nanoparticles, they exhibit potential toxicity due to their nondegradability. For this reason, their application requires further research.

Drug Delivery for Depression
Depression is a widespread disorder, affecting almost 350 million people worldwide [53]. Depressive symptoms influence quality of life of patients and aggravate the course of comorbid diseases. Depression pathogenesis affects various neurobiological processes including HPA axis activity, monoamine systems functioning, neurogenesis, neuroinflammation, etc. [54]. Traditional medications for the treatment of depression are antidepressants with different mechanisms of action affecting monoamine neurotransmission in the brain.
Antidepressants are divided into several classes according to its mechanisms [55].
• Tricyclic antidepressants (TCAs) block the reuptake of monoamine neurotransmitters (primarily serotonin and norepinephrine) presynaptically.  Norepinephrine-dopamine reuptake inhibitors block the action of norepinephrine and dopamine transporters thereby inducing reuptake suppression.

•
Norepinephrine reuptake inhibitors block norepinephrine and epinephrine reuptake via norepinephrine transporter inhibition. • Serotonin antagonists and reuptake inhibitors (SARIs) act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine and/or dopamine. Most of them also act as α1-adrenergic receptor antagonists. The majority of the currently marketed SARIs belong to the phenylpiperazine class of substances. • NMDA receptor antagonists deactivate NMDA glutamate receptors. This class of antidepressants characterizes as rapid-action drugs and includes such substances as ketamine and esketamine.
In spite of the variety of therapy methods, depression treatment is still a serious concern among psychiatrists. A major study by the National Institute of Mental Health found that less than 50% of people are completely recovered from symptoms of depression even after taking two different antidepressants. Moreover, many of those who respond to treatment soon become depressed again, even though they continue to take their medication [55].
Effectiveness of antidepressant therapy depends on the concentration of the drug in the brain. Conventional oral and parenteral therapies are limited because it requires the drug to cross the BBB.
Antidepressants in dosage forms that manageably release the drug directly into the brain reduce their systemic effects, side effects, drug interactions and ultimately bypass pharmacoresistant problems.
At present, quite a few research groups are busy studying the pharmacokinetics, pharmacodynamics and efficacy of antidepressant nanodrugs. Their research are at various stages: from nanoproducts design to preclinical and clinical stages of testing. So far, none of the antidepressants with targeted delivery to the brain have passed the FDA.
Literature analysis suggests that the intranasal administration of nanotherapy (where the drug is encapsulated in nanoparticles) is the most advantageous way to deliver a whole set of antidepressants of different classes to the brain [56,57]. Moreover, this is consistent with the assumption that a faster start of action accompanied by prolonged circulation of active molecules increases efficiency. Polymer nanoparticles are the most frequently investigated among the various nanosystems (Table 3). N-Acetyl Pro-Gly-Pro (to binding to neutrophil CXCR2 receptor), The enhanced concentration of drug in the basolateral amygdala. Antidepressant effect in vitro and in vivo. [60] BDNF Polyion complex formulation of BDNF (nano-BDNF) Significant reduction in cerebral tissue loss. Improved memory/cognition, reduced post-stroke depressive phenotypes, and maintained myelin basic protein and brain BDNF levels. [61]

HU-211 and curcumin
Solid lipid dual-drug NPs Polyoxyethylene (40) stearate, stearic acid, and lecithin. 58 Protection of PC12 cells from corticosterone-induced apoptosis. Antidepressant-like effect and enhanced fall latency in rotarod test, improved level of dopamine in the mice blood. NPs can deliver more curcumin to the brain and thus produce a significant increase in neurotransmitters level in brain tissue, especially in the hippocampus and striatum. [ Improved antidepressant-like activity in comparison with the venlafaxine (i.n. and oral form). The greater brain/blood ratios for VNPs (i.n.) [76] Zn( 2+ )

PLGA NPs conjugated with glycopeptides
Antibodies against NCAM1 and CD44, PLGA conjugated with tetramethylrhodamine and glycopeptides.

190-210
NPs were able to cross the BBB and to deliver Zn(2+) ions at non-toxic concentrations. Easily modified for preferential targeting of specific cell populations. [77]

Anxiety Disorders
Peptide antisauvagine-30 (ASV-30) Iron oxide NPs Systemically administered NPs were observed in the brain. Association with neurons and reduced amphetamine withdrawal-induced anxiety in rats without affecting locomotion were demonstrated.
[78] Improved anxiolytic activity in mice. The plasma nitrite level decreased in GA, GANP and cGANP (most pronounced for cGANP) treated group as compared to saline treated control group while no change in plasma corticosterone levels was observed after any treatment. [82]

Schizophrenia and Bipolar Disorders
In vitro and ex vivo drug permeation, exhibited mucoadhesion and sustained drug release. The formulation containing HP-β-CD complex of paliperidone demonstrated higher level of drug permeation through sheep nasal mucosa without injury of nasal mucosa architecture. [99]  Significantly higher brain/blood ratio and 2 folds higher nasal bioavailability in the brain in comparison to pure drug solution (i.n.). [112] BBB-Blood-brain barrier; NPs-nanoparticles; PS-particle size; ZP-zeta potential; EE-drug entrapment efficiency; LC-loading capacity; PDI-polydispersity index; i.m.

TCAs
Doxepin is one of the tricyclic antidepressants used for depression treatment. During the last few years doxepin was also investigated as a nanoform. In particular, doxepin in the form of thermoreversible biogel or chitosan and glycerophosphate or polyethylenenglycol demonstrated lower local toxicity and significant effectiveness in the forced swim test [113].

MAOIs
Antidepressants from MAOIs class have been also investigated for targeting drug delivery. For example, a selective inhibitor of MAO type B-Selegiline was loaded into nanoparticles for depression treatment. It was demonstrated that thiolated chitosan nanoparticles developed by Singh et al. (2016) enhanced the nasal delivery of selegiline and produced antidepressant-like effect in rats [69].

SSRIs
SSRIs have also being studied as potential nanopreparations. Paroxetine as nanoemulsion form [114] and fluoxetine as ion sensitive in situ nasal gel [115], showed significant responses in locomotor activity level and immobility in injected rats compared to control groups.
Citalopram is also one of the SSRIs. It belongs to the few drugs that can be used safely in childhood psychiatric disorders treatment. Along with other SSRIs Citalopram was loaded in interpenetrating polyelectrolytes nanocomplexes (composed of chitosan: pectin in a 3:1 ratio) constructed by Kamel and colleagues [116]. During experiment researchers demonstrated extended drug release pattern, higher serotonin brain level up to 24 h, more rapid onset of action and more extended behavioral effects in rats with depressive-like behavior treated with these complexes compared to pure citalopram.
Sertraline is another SSRI drug characterized by poor water-solubility and low oral bioavailability. Sertraline-loaded solid lipid nanoparticles improved the drug releasing. In particular, the maximum plasma concentration after nanoparticles injection was 10-fold higher compared to pure drug. Moreover, Sertraline-loaded SLN were found to be stable at 4 • C for 6 months of the study period [117].

SNRIs
One of the promising antidepressants for targeting delivery is venflaksin hydrochloride (SNRI). There are several ways to deliver it into the brain, for example by Lutrol F127 [118], nanoparticle-based NLC gel [56], alginate-chitosan nanoparticles (AGNPs) [119]. It was shown that nanoparticles loaded with venlafaxine hydrochloride produced a more pronounced effect after intranasal administration in vivo in comparison to oral administration of equivalent dose [118,119]. Desvenlafaxine is another preparation that belongs to that class of drugs. It represents an active metabolite of venlafaxine also investigated in PLGA-chitosan nanoparticles [120].
Duloxetine (SNRI) is another antidepressant that demonstrated better response in NLC [47]. The scintigraphy images are consistent with the biodistribution and pharmacokinetic studies, having revealed a high uptake of duloxetine into the rat brain [47].

SARIs
Serotonin antagonists and reuptake inhibitors are drugs characterized by antidepressant, anxiolytics and hypnotics effects. This class of substances includes trazodone and nefazodone. These drugs were also loaded into nanoform. In particular, Casolaro et al. (2015) constructed hydrogels bearing l-phenylalanine (Phe-Nip3) or l-valine (Ava2) residues, with citalopram and trazodone. Hydrogel form showed improved release of these drugs compared to pure substances [121].

Other Drugs
Agomelatine is atypical antidepressant that both stimulates melatonin receptors (MT1 and MT2) and blocks 5-HT2C-receptors. This drug is characterized by low side-effects because it does not counteract with other serotonin receptors, does not affect reuptake of monoamines and does not interact with adrenergic, cholinergic, dopamine, histamine and GABA receptors. Nevertheless, agomelatine has a low biological half-life coupled with extensive hepatic first-pass metabolism [59]. In that context the loading of preparation into nanoform could improve its therapeutic effect. Thus, it was demonstrated that intranasal administration of Agomelatine-loaded poly-lactic-co-glycolic acid nanoparticles shown significant antidepressant-like effect in rats [58]. Another type of nanoparticles was developed by Shinde et al. (2020) and represented polymeric nanoparticles with Agomelatine for transdermal use. These nanocarriers demonstrated good permeability across rat skin [59].
Another type of irregular antidepressant is flavonoid Baicalein. Chen and colleagues constructed solid lipid NPs loaded with Baicalein [60]. These NPs were modified with N-Acetyl Pro-Gly-Pro (PGP) peptide, which is characterized by high specific binding affinity to neutrophils through the CXCR2 receptor. When associated with neutrophils, these particles can penetrate through the BBB and reach targets in the brain.
Along with research of classical antidepressants in nanoforms, it is quite interesting to study various peptides and neurotrophins as antidepressant treatment. In this regard, challenging data concern the proven neuroprotective and antidepressant properties of the brain-derived neurotrophic factor (BDNF). In vitro experiments showed that BDNF delivery using the adenoviral vector produce neuroprotective effects. AAV-Syn-BDNF-EGFP virus vector maintains brain cell viability and preserves the neural network functional structure in the late posthypoxic period [122].
It was found that intranasal administration of BDNF-HA2TAT/AAV to normal mice produce an antidepressant effect in the forced swimming test, but only with chronic treatment. No statistical difference was found in the forced swim test after acute intranasal injection of the AAV to the mice. After the BDNF-HA2TAT/AAV administration to the animals with the chronic mild stress model of depression the successful therapeutic effect was demonstrated in the tail suspension test and forced swim test, but not in open field test [123]. Moreover, the female mice were more sensitive to the drug administration. One of the possible explanations is that the prevalence of depression in females is much higher than that in males [124].
Therefore, different nanocontainer forms of drugs have been developed for the treatment of depression. Such systems contain not only the most popular antidepressants, such as SNRI and SSRI, but also various original forms including vector systems for target delivery in the brain. Application of nanocarriers could help to reduce side effects and to improve drugs bioavailability.

Drug Delivery for Anxiety Disorders
Anxiety disorders are the largest group of mental disorders in most Western societies. Essential features of anxiety disorders are excessive and persistent fear, avoidance of perceived threats and panic attacks in certain instances. Although the pathophysiology of anxiety disorders is not fully understood, targeting systems for their treatment are of interest. Drugs for treating anxiety disorders include medications that affect serotonergic, adrenergic, glutamatergic, endocannabinoid systems and various neuropeptides [125]. First of all, tranquilizers with anxiolytic, myorelaxing, sedative and anticonvulsant activity are used for the treatment of anxiety disorders. Many anxiolytic drugs are derived from benzodiazepine and affect benzodiazepine receptors (second generation anxiolytics). However, there is also a spectrum of tranquilizers aimed at other therapeutic targets. Examples include such drugs as buspirone, meprobamate, benactin, etc. Significant progress has been made in the development of formulations and psychosocial treatment strategies for anxiety disorders. However, symptoms persist in many patients despite improvements in therapy. Randomized controlled trials of anxiety disorders pharmacotherapy report a response rate of 40-70% and a remission rate of 20-47%. Anxiety disorders are considered as resistant to treatment when there are residual symptoms or when symptoms do not improve at all after some form of therapeutic intervention. The optimal use of available medication and the development of new pharmacological strategies and agents promise to improve this situation [126].
Polymer nanocarriers are used to develop delivery forms for therapeutic drugs against anxiety disorders. Nanoparticles created from biodegradable polymers such as PLGA are widely studied as drug delivery systems because of their two important properties, such as biocompatibility and controlled drug release. For example, replicable spherical diazepam PLGA nanoparticles have been developed and characterized by Bohrey and colleagues [81]. Chitosan is another natural carbohydrate polymer with ideal for nanoparticles polymer carrier properties such as biocompatibility, biodegradability, non-toxicity and low cost. It exhibits bioadhesive properties and the ability to significantly increase permeability for hydrophilic compounds. Chitosan with thiol groups provides much higher adhesion properties.
Buspirone is a drug belonging to the group of tranquilizers using for anxiety disorders treatment. It is a complete agonist of 5-HT1A presynaptic serotonin receptors, which leads to a decrease of serotonin release and the resulting reduction of anxiety symptoms. Buspirone also acts as a partial agonist of the post-synaptic serotonin receptors, which contribute to the release of serotonin in synapses, resulting in increased serotonin concentration and reduced depression. Additionally, buspirone inhibits the dopamine receptors D2 [127]. Bari et al. (2015) loaded buspirone hydrochloride into polymeric thiolated chitosan nanoparticles for intranasal administration. Ex vivo study carried out via the porcine mucin binding efficiency test demonstrated excellent bioadhesion. Moreover, the drug concentration in the brain after the intranasal injection was significantly higher than after pure Buspirone hydrochloride administration [79]. Along with chitosan nanoparticles construction two types of nanovesicular in situ gels (based on carbopol 974P and poloxamer 407) were developed for delivery of buspirone hydrochloride. The carbopol composition showed higher permeability compared to the poloxamer. It was demonstrated that buspirone hydrochloride has low bioavailability of about 4% after oral administration due to first pass metabolism. Nevertheless, the bioavailability of buspirone hydrochloride increased by 3.26 times when used in the composition of the nanovesicular gel of carbopol compared to the nasal solution of a pure drug [80].
Gallic acid has significant anxiolytic activity, which may be due to its antioxidant properties and reduced nitrite levels in plasma. Chitosan nanoparticles coated with Tween 80 ligand were used to deliver gallic acid to the brain. Behavioral studies have shown that GA nanoparticles significantly improve anxiolytic activity in mice. Nitrite levels decrease in plasma was most pronounced in the group that received the nanoparticle with loaded with drugs. This may have been due to the reduction in plasma nitrite levels by gallic acid. This effect was improved by the increase of GA brain absorption through the nanoparticles application [82].
Inorganic nanoparticles are also used to create delivery systems for anxiety disorders. Many peptides and their analogues cannot effectively cross the BBB. For that reason, Vinzant and colleagues conjugated peptide antisauvagine-30 (ASV-30) with iron oxide nanoparticles [78]. It was shown that ASV-30 peptide affects corticotrophin releasing factor type 2 receptors when directly injected into the brain and thus reduces anxious behavior in animals. Imaging studies demonstrated that iron oxide + ASV-30 particles were present in the brain and were associated with neurons, including those that express CRF2 receptors after intraperitoneal injection. Brain distribution studies were affirmed nanoparticles anxiolytic activity in rats [78].
Currently, the range of application of anxiolytic drugs and their assortment are quite wide. These drugs include preparations of benzodiazepine-line and non-benzodiazepine anxiolytics. Nevertheless, not many nanocontainer forms have been developed for the standard medicines using for anxiety disorders treatment. The loading of other types of drugs in nanocarriers besides the usual forms of anxiolytics could help to improve the treatment of anxiety disorders and to prevent aggravation into depression or severe generalized form.

Drug Delivery for Schizophrenia and Bipolar Disorders
Schizophrenia is a complex endogenous mental disorder characterized by cognitive and emotional symptoms that significantly reduce the quality of life of patients [128]. The main drugs used to treat the pathology are antipsychotic drugs that reduce the increased dopaminergic transmission in the brain of patients. Atypical antipsychotics of a new generation, characterized by a narrower range of side effects compared to the first generation, are also used to treat bipolar disorder, along with lithium and antiepileptic drugs [129].
The first drug for the treatment of schizophrenia, chlorpromazine, was first used in 1952, but already in the 60s researchers tried to develop long-acting substances consisting of an antipsychotic agent and fat-soluble solution [130].
Despite the fact that new antipsychotic drugs have appeared on the market, providing greater efficiency with significantly reduced side effects, delivery systems of antipsychotic drugs are still in the stage of conventional drug forms, such as tablets, capsules and solutions, and need to be dosed 2-4 times a day. There is no doubt that new drug delivery systems, such as stable and controlled release systems, will be useful for antipsychotics. They should reduce the frequency of dosing, increase bioavailability of the drug and improve adherence of the therapy course [131]. The drug delivery system produces less pronounced side effects than the original drugs, because they provide lower inpatient concentrations of therapeutic drugs and more stable release characteristics than oral drugs. Thus, such combined drugs increase exposure to oral medications, further reducing morbidity and mortality [132]. As nanocarriers bypass the gastrointestinal tract, such a type of therapy reduces the amount of medication needed and can minimize some peripheral side effects, including hepatotoxicity and hyperprolactinemia [130].
Nanocontainer systems based on PLA were developed in 1989 for chlorpromazine-the first antipsychotic agent [131].
Since then atypical neuroleptics have appeared and become widespread in medical practice. A lot of publications about nanocontainers involve drugs with olanzapine-a second-generation or atypical antipsychotic, which selectively binds to central dopamine D2 and serotonin (5-HT(2c)) receptors. It has poor bioavailability due to hepatic first-pass metabolism and low permeability into the brain due to efflux by P-glycoproteins [133]. Due to its low oral bioavailability, researchers have created various container preparations [134]. Joseph et al. 2017 conducted research on glyceryl monostearate nanoparticles with olanzapine [133]. A longer release of the drug within 48 hours was shown, compared with 8 hours of the antipsychotic action of pure olanzapine solution. Pervaiz and colleagues described the release of olanzapine loaded in PNA (poly(N-isopropylacrylamide-co-acrylic acid)) microgels for 72 h [135]. In vitro bioaccessibility research of Jawahar and colleagues indicated 5 1 2 -fold increase in oral bioavailability for nano structured lipid carriers with olanzapine [134]. Cyclodextrins containers were also used for this neuroleptic [136]. An in vitro study on kinetics of clozapine solid lipid nanoparticles showed an increase in lymphatic bioavailability of the drug and its steady release up to 48 h [137]. The study done by Shafaat and coworkers demonstrated that clozapine nanoemulsions resulted in 4.4-fold increase in bioavailability and better drug loading capacity of hydrophobic drug molecules compared with marketed drug formulation [138]. There are also studies on the intranasal introduction of nanoparticles with olanzapine [94]. Nanoparticles containing olanzapine (PLGA) have been shown to be more effectively delivered to the brain by intranasal administration of poly(lactic-co-glycolic acid) nanoparticles [97]. Olanzapine-SLNs showed a 23-fold increase in the relative bioavailability of olanzapine in the brain after nasal administration [92]. The innovative therapeutic approach represents a new form of pharmaceuticals-transdermal drug delivery systems-"patches" containing lipid nanocontainers with this neuroleptic [139]. In addition to improving bioavailability, a study [140] with biodegradable polymeric lipid-core nanocapsules and a decrease in extrapyramidal side effects were shown for polymeric nanoparticles polycaprolactone [141]. Animal model studies have demonstrated improved therapeutic efficacy compared to pure olanzapine [141].
Lurasidone (another atypical antipsychotic) was loaded into SLNs. Its improved therapeutic effect in MK-801 induced schizophrenia model in rats after oral administration was shown [89].
Aripiprazole, a second-generation (or atypical antipsychotic), is poorly soluble and undergoes extensive hepatic metabolism and P-glycoprotein efflux, which lead to reduced in vivo efficacy and increased dose-related side effects. Solid lipid nanoparticles with aripiprazole enhance bioaccessibility of this neuroleptic [83]. In another study, intranasal administration of poly-caprolactone nanoparticles showed a 2-fold increase in aripiprazole distribution in rat brain when compared to aripiprazole nanoparticles administered intravenously [84]. An interesting study was devoted to buccoadhesive chitosan films with aripiprazole. Ex vivo nanocrystal loaded buccal films FAPZ 14 have the potential to provide a faster availability of aripiprazole. The aim of the present study was to design a mucoadhesive dosage form for buccal delivery of aripiprazole, which could provide a rapid drug delivery to the systemic circulation [142].
The same mucoadhesive drug delivery systems were created for riperidone, another atypical neuroleptic used to treat schizophrenia and bipolar disorder. A mucoadhesive buccal tablet formulation of risperidone allowed 90% release of the drug over 8 h, thereby providing direct systemic delivery of risperidone [143]. Risperidone-loaded solid lipid nanoparticles drug release and transport studies illustrated the advantages of oral delivery over poorly water-soluble drugs such as risperidone [144,145]. Pharmacokinetic studies of NLCs of iloperidone 2-fold increase in the % drug targeting efficiency relative to iloperidone pure drug suspension [146]. The pharmacokinetic study revealed almost 8.30-fold increase in oral bioavailability of iloperidone NLCs as compared to the plain drug solution. The nanoemulsions of riperidone also showed improved bioavailability and brain uptake [147]. Intranasal administration of risperidone-loaded mucoadhesive nanoemulsion demonstrated higher efficacy, enhanced brain targeting and higher drug transport to the brain in Swiss albino rats, when compared with intranasal risperidone solution and risperidone nanoemulsion intravenously [105]. In another study, riperidone was enclosed in biodegradable proteinoids. These systems were synthesized by thermal step-growth polymerization from the amino acids l-glutamic acid, l-phenylalanine and l-histidine and poly (l-lactic acid). Behavioral studies on mice found enhanced antipsychotic activity compared to free risperidone.
Quetiapine fumarate, a second generation atypical antipsychotic drug has a plasma half-life of 6h, hence requires frequent administration to maintain effective therapeutic concentration. The increase in bioavailability of mucoadhesive microemulsion Quetiapine during intranasal injection is shown [111].
Azenapine appeared on market in 2009. It was a new atypical antipsychotic for the treatment of schizophrenia and bipolar disorder. However, it had the same disadvantage-low bioavailability when used orally (less than 2%). Most of this drug is metabolized in the liver. The antipsychotic activity of azenapine is thought to be due to antagonistic activity on D2 dopamine and 5-HT2A serotonin receptors. To improve its bioavailability some of the researchers developed sublingual film, intranasal and injectable formulations of azenapine [86]. Shreya  Lithium medications-psychotropic drugs from the group of normotimists-are historically the first drugs of this group, discovered in 1949. However, they remain essential in the treatment of affective disorders, primarily manic and hypomaniacal phases of bipolar disorder [148]. They are also used to prevent its exacerbation and to treat severe and resistant depression. Their important property is to get rid of suicidal thoughts, so they can prevent suicide.
Lithium ions have a variety of effects on the nervous system, particularly as an antagonist of sodium ions in nerve and muscle cells. In this way, they weaken the nerve impulse (this also explains one of the frequent side effects of lithium preparations: muscle weakness). Lithium also affects the metabolism and transport of monoamines (noradrenaline and serotonin) and increases the sensitivity of some areas of the brain to dopamine. According to some data, the main role in the mechanism of action of lithium is its ability to block the activity of enzymes involved in the synthesis of inositol, which plays a role in regulating the sensitivity of neurons.
The treatment with lithium bipolar disorders is based on its property to selectively inhibit kinase 3 glycogen synthase activity [149]. In addition, it was found that in mania, there is an irregular increase in the activity of proteinkinase C, and a recent study has shown that lithium inhibits its activity. Thus, lithium, like other PkC inhibitors, exhibits antimaniac properties.
Formulations with lithium are the standard drugs for the treatment of bipolar disorders [148]. In one work, the researchers concluded lithium carbonate in chitosan nanoparticles to improve bioavailability. It is postulated that the encapsulation of lithium carbonate within chitosan nanoparticles enables the drug to overcome the intracellular degradative blocks such as endosomes and lysosomes. The ion chelation route was used for encapsulating lithium carbonate [88].
Neuroleptics therapy frequently used for schizophrenia and bipolar disorder treatment requires constant use of drugs and thereby induces various side effects. The loading of drugs into nanocontainers for the controlled release is modern and relevant approach. In addition to targeted delivery and increased bioavailability, it reduces the doses and side effects of antipsychotics, often accompanied its application.

Drug Delivery for Alzheimer's Disease
Currently, the most intensive development of drugs based on nanocontainer systems is being carried out to treat AD. The progress of modern medicine has significantly increased average life expectancy. At the same time, the risks of neurodegenerative diseases rise with age. For example, the percent of people suffering from the most frequent neurodegenerative pathology, AD, in the ages from 65 to 74 is 3% and in the ages from 75 to 84 is already 17%. AD is a progressive disorder characterized by memory, cognition and behavioral impairment (dementia), which eventually leads to mood fluctuation and fatal delirium [150].
The action of the existing drug groups is directed on the pathogenesis blocks presumed as the hypotheses of AD pathogenesis.
Hypotheses of AD development can be divided into several main causes [32,151].
• Accumulation of β-amyloid (Aβ(1 → 40) and Aβ(1 → 42)), which is resulted from pathologic proteolysis of amyloid precursor protein (APP). The aggregates of this protein are toxic and induce neurodegeneration, cytotoxicity and inevitably leading to dementia manifestations. • Tau accumulation. It is known that a normal mature neuron produces three microtubule-associated protein (MAP) taus; MAP1A, MAP1B and MAP2. These proteins are responsible for the promotion of the assembly and stability of microtubules. The biological activity of tau is regulated by its phosphorylation level. For example, in the brain of AD patients, tau hyperphosphorylates abnormally, which impairs its binding to microtubules; leading to the accumulation of neurofibrillary tangles and dementia development. Several anti-tau therapies including lithium, valproate and nicotinamide have been already investigated for the prevention of Tau protein hyperphosphorylation.

•
Progressive decline of acetylcholine concentration. This is the earliest hypothesis of AD progression. It was demonstrated that AD is accompanied by substantial presynaptic cholinergic deficit, which expresses as a reduced choline uptake and acetylcholine release in the brain. That leads to memory and cognition impairment. Drugs that eliminate these symptoms include acetylcholinesterase inhibitors (AChEs) such as tacrine, donepezil, rivastigmine and galantamine. • NMDA excitotoxicity. Some experimental and neuropathological evidence suggests that glutamatergic system is also involved in the neurodegenerative progression. NMDA receptor is essential for the control of synaptic plasticity and memory function. It is activated by glutamate and glycine, allowing Ca2+ and Na+ influx. It was demonstrated that the hyperexcitability of NMDA receptors induces Ca2+ overload, eventually leading to apoptosis and producing cognitive impairments. The drug that affects this pathogenesis block is memantine (NMDA inhibitor). • Abnormality of mitochondria energy metabolism. It is suggested that genetic mutations alter the regulation of the electron transport chain complex enzymes, which are capable of generating ROS. That leads to cell apoptosis and neurodegeneration. Figure 2 describes the main pathological pathway of Alzheimer's disease and therapy methods, targeted to these mechanisms. Currently, nanoparticles with various therapeutic mechanism associated with AD pathogenesis have been developed (Table 4). Currently, nanoparticles with various therapeutic mechanism associated with AD pathogenesis have been developed (Table 4).  Increase of the permeability of the conjugate into the brain was shown.
[165]   The NPs facilitated the distribution of drug in the brain. [184] Tacrine In situ gels -Plu F127, Plu F68, CS, PEG 8000 - The enhanced nasal residence time, improved bioavailability, increased brain uptake of the drug and decreased exposure of metabolites were shown. [185] Tacrine Albumin NPs carrying beta cyclodextrin and two beta cyclodextrin derivatives -Beta cyclodextrinderivatives, hydroxypropyl beta cyclodextrin, sulphobutylether beta cyclodextrin.

177-266
From −10 to   NPs demonstrated better brain targeting efficiency and represented a promising approach for i.n. delivery of rivastigmine for the treatment and prevention of AD. [195] Others p38 MAPK inhibitor PH797804 NPs reduced the oxidative stress, and beta-amyloid plaque deposition in the hippocampus more effectively than the pure drug. The memory was significantly restored in cognitive deficit rats treated with NPs. [197]      The NPs improved the acquisition and retention of spatial learning and memory in Aβ treated rats. Expression of BDNF, cAMP, CREB and stromal interaction molecules, e.g., STIM1 and STIM2 was increased. [227] AD-Alzheimer's disease; Aβ-amyloid-β peptide; BBB-Blood-brain barrier; NC-nanocarrier; NPs-nanoparticles; PS-particle size; ZP-zeta potential; EE-drug entrapment efficiency; LC-loading capacity; PDI-polydispersity index; i.m.

Nanoparticles with High Affinity to Aβ1-42 Peptide
This type of nanocarriers represents a completely new approach to treating AD. Such a method includes application of multifunctional nanoparticles modified by antitransferrin antibodies in combination with MAbs-IgG domains and transferrin ligands for delivery of the iAβ5 peptide, inhibiting the aggregates associated with AD [228]. Another strategy involves monoclonal antibodies (MAbs) targeting Aβ fibril formation [164]. For example, Kuo with coauthors investigated various modifications of gold nanoparticle systems loaded with the neuron growth factor in combination with transferrin, lactoferrin, p-aminophenyl-alpha-d-mannopyranoside and apolipoprotein E and added peptide sequence [218][219][220]. This sequence interacts with the transferrin receptor present in the microvascular endothelial cells of the blood-brain barrier, thus causing an increase in the permeability of the conjugate in brain, as shown by experiments in vitro and in vivo. It is highly relevant for the therapeutic applications of gold nanoparticles for molecular surgery in the treatment of neurodegenerative diseases such as AD. By irradiation with weak microwaves, Ab aggregates bound to the conjugate peptide sequence with a gold nanoparticle were destroyed by local dissipation of the absorbed energy in vitro [165]. Along with gold nanoparticles PLGA nanoparticles with surface functionalized by antitransferrin receptor monoclonal antibody (OX26) and anti-Aβ (DE2B4) have also been developed for the delivery of encapsulated iAβ5 into the brain. This system efficacy and toxicity were evaluated with porcine brain capillary endothelial cells (PBCECs) used as a BBB model [158].
Another form of nanocarriers [162] presents the construction of Aβ-targeted stealth liposomal nanoparticles using the Aβ-targeted lipid conjugate DSPE-PEG with Methoxy-XO4, which interconnect with amyloid. It was demonstrated that these nanoparticles selectively bind to amyloid plaques in the brain tissue of APP/PSEN1 transgenic mice. Ex vivo analyses of brain samples showed that injected nanoparticles efficiently bind both parenchymal plaques and cerebral amyloid angiopathy associated amyloid throughout the brain [162]. Along with other nanocarriers PEG coated and anti-Ab antibody-conjugated antioxidant (cerium oxide) nanoparticles were developed, and their effects on neuronal survival and BDNF signaling pathway were examined. For this nanoparticles protective effect against oxidative stress and Ab-mediated neurodegeneration were reported. In particular, these nanoforms specifically targets the Ab aggregates, produce an antioxidant effect and thereby perform neuroprotection [168].
β-sheet breaker peptides compose a class of compounds that are highly potent in Aβ1−42-or α-synuclein-inflicted cell toxicity neutralization. β-sheet breaker peptides are highly effective for Aβ amyloidogenesis inhibition as they are homologous to regions of the β-sheet hydrophobic carboxyl segments [229]. These peptides represent oligopeptides structurally analogous to specific epitopes of Aβ. Such substances have been also loaded in nanocarriers for Aβ-targeted delivery. It was demonstrated that the use of gold nanoparticles loaded with LPFFD peptide induces Aβ-aggregate inhibition, Aβ fibrils dissociation and Aβ-mediated peroxidase reduction [166]. TGN TGNYKALHPHNG and QSH D-enantiomeric peptide QSHYRHISPAQV were also conjugated to the surface of the nanoparticles for blood-brain barrier transport and Aβ42 targeting. Nanoparticles implication enhanced bioavailability of drug in the brain and produced neuroprotective effects in the mouse model of AD in vivo [159]. In another work [230] researchers developed a dual-functional nanoparticle drug delivery system loaded with β-sheet breaker peptide H102 (HKQLPFFEED). This peptide was encapsulated into liposomes to reduce the degradation level and was administrated nasally to increase brain penetration. It was demonstrated that the nanosystem application recovered spatial memory impairment in AD model rats both in a low dose and in a high dose [230].
Liposomes are frequently used for drug delivery during targeted AD therapy. For example, liposome nanoparticles are loaded with Aβ1-42 ligands with high affinity, phosphatidic acid and cardiolipin phospholipids [160]. Another research demonstrates the induction of amyloid degradation via administration of apolipoprotein E3-reconstituted high-density lipoprotein nanoparticles bond with Aβ oligomers [163]. Therapeutic effect was also reported for bifunctional liposomes, loaded with phosphatidic acid and peptide derived from apolipoprotein-E receptor-binding domain. In particular, peptide implication allowed penetrating through BBB and phosphatidic acid use caused Aβ aggregates degradation in APP/PS1 transgenic mice [161]. Thus, liposome administration reduced amyloid concentration and improved cognitive function in transgenic mice [161].
Nanoparticles using Congo Red/Rutin/MNP are another method of AD treatment. It was shown that the intranasal administration of Congo Red/Rutina-MNP contributed to the dissipation of amyloid plaques in MRI, increased drug delivery and reduced the production of active oxygen forms and Aβ-induced cytotoxicity in vitro. The intravenous administration of such nanosystems also increased the detection of amyloid aggregates, prevented memory deficit and neurological disorders in transgenic APPswe/PS1dE9 mice in vivo [231].
Multifunctional nanoparticles are being also used for diagnostic and therapy of other pathologies associated with Aβ accumulation. One of them is cerebral amyloid angiopathy described as a condition resulted from Aβ protein lodgment within the walls of cerebral vascular cells. The peptide accumulation leads to vascular inflammation and periodic hemorrhagic strokes. Therapeutic nano-transportable vehicles containing a polymeric core of chitosan-conjugated magnetivist (magnetic resonance imaging (MRI) contrast agent) have been developed for the treatment and early diagnosis cerebral amyloid angiopathy [157]. Cyclophosphamine, an agent that suppresses inflammation of brain vessels, was also loaded into the THB nanonucleus, and a Putreskin-modified F(ab')2 fragment of an antiamyloid antibody, IgG4.1 (pF(ab')24.1), was bound to the surface of the nanonucleus to target the cerebrovascular amyloid. Similar systems have already been tested in vitro with human endothelial cells (hCMEC/D3) and in vivo in laboratory mice [157]. It has been shown that other anti-inflammatory and antiamyloidogenic agents capable of reducing the inflammation of cerebrovascular vessels can also be loaded into such nanotransport systems [212].

Drugs Directed on the Inhibition of Tau Aggregation
Tau represents an intracellular protein, playing a crucial role in the microtubules stabilization. It was demonstrated that tau protein could respond to various factors via aggregates formation. The accumulation of these aggregates induces neurofibrillary tangles conglomeration in neurons and neurodegeneration. As the peptide contains two hexapeptide motifs in the repeat region, after pathological impact tau can randomly coil into the β-sheet structure and perform aggregation.
By now serious research has been done in the field of protein aggregation prevention in neurodegenerative diseases. In spite of investigation of various drugs from different classes like peptide inhibitors, natural substances, etc., little success was achieved. Some research has been performed in the area of nanoparticles, which offers a challenge in AD treatment improvement.
For example, a tau aggregation suppressor phenothiazine was loaded in polymer-based (PLGA-PEG) hydrophobic-glutathione coated nanoparticles [170]. Moreover, for some types of nanocarriers aggregation inhibitory activity were demonstrated of its own accord. The cadmium sulfide and iron oxide (Fe 3 O 4 ) nanoparticles inhibit tau fibrillization in vitro. Despite its antiaggregation activity and excellent delivery properties, the in vivo experiments are hampered by interfering molecular species [171].
Red blood cell membrane-coated PLGA particles with T807 can also be used as a resource for tau aggregation inhibition. As T807 demonstrates high permeability for neurons and pronounced p-tau-specific tracing activity, it can be considered as a therapeutic agent of targeted delivery for AD treatment. One more virtue of that type of nanocarriers is red blood cell membranes, characterized by low immunogenicity and long half-life in the circulation, which allow performing effective drug delivery. Synergetic action of T807 with triphenylphosphine (TPP) produces an inhibitory effect on key components of AD pathogenesis associated with tau-phosphorylation and prevents neurodegeneration. Thus, the systemic administration red blood cell PLGA nanoparticles loaded with curcumin recover cognitive impairments in the mouse model of AD [232].

Acetylcholinesterase Inhibitors (AChE)
This class of drugs is characterized by many side effects due to their action on the peripheral tissues, high doses of administration and hepatic metabolism. These side effects are aggravated by the low pharmacokinetic (half-life) profiles of the drugs [150]. The loading of such preparation into nanocontainers would help to eliminate these side effects and to improve their bioavailability to the brain via an intranasal form.
One of the drugs used to treat AD is rivastigmine, which inhibits both the AChE and butyrylcholinesterase enzymes in brain and boosts the cholinergic function. It improves cognition and memory by increasing the ACh concentration in the brain. Nevertheless, the half-life period of rivastigmine in blood circulation is only 1.5 h, which complicates its therapeutic action. Loading drugs in nanocontainers increases its half-life and decreases the necessary dosage, thereby reducing side effects. For example, it has been already demonstrated for AChE inhibitors represented as naturally derived polyphenols, such as epigallocatechin-3-gallate and catechin placed into the sodium-taurocholate liposomal carrier [192], cholesterol/soy-lecithinated liposomal NP formulation [190], PLGA, PEG and gold NPs [233]. Yang and colleagues have also performed analysis of rivastigmine-liposome and CPP27 modified rivastigmine-loaded liposome for intranasal administration and showed the improvement of drug activity [191]. In particular, it was demonstrated that CPP modification increases the drug diffusion across the BBB by enhanced transcytosis and cell membrane permeability. It was acknowledged by the pharmacokinetic study indicated a significant increase of drug concentration in the various regions of the brain like cortex, hippocampus, and olfactory regional. Additionally, that modification has not exerted any toxic effects in the nasal cavity and in the brain. Improved drug properties were also demonstrated for rivastigmine via various nanoparticles. For example, rivastigmine-loaded mucoadhesive NP developed by Fazil [193][194][195]. In was also shown that gelling cationic nanostructured lipid carriers enhance brain distribution and pharmacodynamics [188]. Moreover, liposomes with RHN increased half-life, decreased the toxicity and improved memory and neurological deficits in Male albino rat with the model of AD [189].
Another AChE inhibitor using for AD treatment is galantamine. Some studies reported that galantamine could also reduce Aβ aggregation and neurotoxicity. Nevertheless, the application of galantamine is limited by its side effects such as nausea, vomiting, dizziness, drowsiness, loss of appetite, etc. That makes it inconvenient for the long-term oral treatment. In addition, galantamine is not able to cross the BBB efficiently [33]. For this reason, NP can improve response and bioavailability of galantamine. For example, Hanafy and colleagues constructed chitosan nanoparticle and cationic nanoparticles for intranasal drug administration [175]. Li et al. developed liposomal system, as a drug carrier for efficient delivery of galantamine through intranasal administration [173]. Other research groups created PLGA [174] and solid lipid NP [172] with galantamine, which have not only increased its bioavailability but also improved cognitive function and memory in Wistar rats.
Donepezil is another frequently used drug for AD treatment, represented as a centrally acting reversible AChE inhibitor. It is characterized by high pharmacokinetic properties with 100% bioavailable and a biological half-life of 70 h. However, the long-term administration leads to severe side effects, especially when taken in a high dose (>10 mg/day) [234]. The development of chitosan nanosuspension for intranasal administration [178] and the chitosan intranasal form of donepezil [235] promoted the usage of lower drug dose. Along with these nanoparticles LGA-b-PEG by Baysal et al. and liposomes by Al Asmari et al. were constructed for this drug [177,180].
Tacrine is AChE inhibitor acting as a histamine N-methyltransferase inhibitor. This drug produces various side effects including not only nausea, vomiting, dizziness, drowsiness, hallucination, confusion, insomnia and anxiety, but also hepatotoxicity, convulsion, urinary tract infection, bradycardia, depression, hypotension, etc. For the problem solution Qian and colleagues have developed in situ gelling systems for intranasal administration of tacrine [185]. That drug form enhanced the substance retention time in the nasal cavity and improved the nasomucosal absorbance. Wilson et al. have constructed a tacrine loaded chitosan nanoparticle coated with polysorbate 80 and demonstrated the improvement of its biodistribution [197]. Luppi et al. has also developed albumin nanoparticles carrying cyclodextrins for nasal delivery and drug properties advance [186].
Huperzine is another preparation used for AD treatment. For improvement of it bioavailability some research groups also constructed NP. For example, Yang et al. created nanostructured lipid carriers [181]. The treatment with huperzine lipid NP performed by Patel et al. demonstrated behavioral and memory improvement in the mouse model of AD [182].

Memantine, the NMDA Receptors Antagonist
Memantine hydrochloride (MEM) is the only anti-AD drug used in the US and Europe for the moderate-to-severe form of AD. The labeled formulation for memantine hydrochloride is Namenda, which is prescribed in tablet or capsule form. MEM prevents the aggregation of Aβ1-40 and enhances memory in rodents. Despite the best results in improving cognitive impairments in patients, the clinical applicability of MEM is limited. MEM should be administered daily, which leads to poor compliance with the drug regimen [205]. The development of nanocarriers with memantine can help to solve these problems. Toxicologically safe lipid nanoparticles with lipoyl-memantine have been elaborated and can be used to deliver memantine to the brain [206]. Gothwal et al. (2019) developed memantine-loaded polyamidoamine dendrimers. He used lactoferrin as a targeting ligand. The profile of memantine release from nanoparticles was slow and persisted for up to 48 h. The brain absorption of NPs was significantly higher than that of pure memantine. The in vivo research in an AlCl3-induced AD mice model demonstrated a considerable improving in behavioral tests [205].

Other Drugs for AD Treatment
Many literature data suggest that various growth factors may have therapeutic potential in the AD treatment. In particular, growth factors such as basic fibroblast growth factor, neurotrophins (nerve growth factors; glial-derived neurotrophic factor and BDNF and insulin-like growth factor (IGF-1/IGF-2)) and bone morphogenetic proteins are promising molecules [236]. In such a way PEG-PLGA nanoparticles loaded with basic fibroblast growth factor have been shown to improve cognitive function in the Morris test in rats exposed to intraventricular administration of β-amyloid 25-35 and ionic acid [221].
Metal chelators are another potential drugs to treat AD because they block the effects of metal ions stimulating the formation of Aβ aggregates and active oxygen forms. However, their use is limited due to non-specific interactions with metal ions and the inability to pass through BBB. Such problems have been solved by using controlled release systems of gold nanoparticles with mesoporous silica based on H 2 O 2 . Loading metal chelator CQ in these nanocontainers allowed targeted CQ release in the brain areas where the level of H 2 O 2 is increased, for example, in Aβ-plaques [201].
Several recent studies have demonstrated that some antidiabetic drugs also have a therapeutic potential in AD patients. For example, Hsieh and colleagues has shown the inhibitory effect of gold nanoparticles on the fibrillogenesis of insulin fibrils [167]. Gold nanoparticles, coincubated with insulin, retarded the structural transformation of insulin fibrils into amyloid-like fibrils for about a week [167]. The neuroprotective effect was also demonstrated for nanoparticles with peptide NAPVSIPQ as a model drug and lactoferrin as a targeting ligand, which improved cognitive function in mice. As lactoferrin is a natural iron binding protein, whose receptor is highly expressed in both respiratory epithelial cells and neurons, its administration facilitates the nose-to-brain drug delivery of neuroprotection peptides like NAPVSIPQ [200].

Others Methods of AD Treatment
Currently, siRNA gene therapy is a promising method of treating of many brain disorders. Potentially it can also be used for the treatment of AD. An example of such a therapy method is the inhibition of the Beta-Secretase 1 (BACE1), which leads to suppression of disease development.
Nanoparticles of the solid lipid with and without chitosan were used for directed delivery of BACE1 siRNA to the brain. These nanoparticles contained a RVG-9R peptide derived from the rabies virus glycoprotein, which enhanced the transcellular delivery of nanosystems to the brain during their intranasal injection. It was demonstrated that the investigated siRNA permeates the monolayer of the cell culture Caco-2 to a greater extent when released from nanocarriers, primarily from chitosan-coated solid lipid nanoparticles, than from bare siRNA [153].
The same research strategies were developed by other researchers. Wang and colleagues designed siRNA nanocarriers based on PEGylated poly(2-(N,N-dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) modified with both the CGN peptide for BBB penetration and the Tet1 peptide for neuron-specific binding [154]. These nanocomplexes have been shown to successfully enter the cytoplasm of neurons, effectively suppressing the expression of BACE1 mRNA (by about 50%) and preventing synaptic damage caused by Aβ25-35. These results were also confirmed by studies of transgenic APP/PS1 mice, where the administration of nanoparticles stimulated neurogenesis in the hippocampus, inhibited the formation of amyloid plaques and tau-protein by repression of BACE1 mRNA. The administration of the nanocomplexes restored the cognitive function of the AD transgenic mice to the level of wild-type control without significant adverse effects on myelination [154].
Downregulation of the key enzyme in amyloid-β formation by delivering non-coding RNA plasmid is another potential way of AD treatment. It was shown that simultaneous delivery of the therapeutic peptide into the brain leads to the suppression of neurofibrillary tangles formation. In particular, a multifunctional nanocarrier contained the peptide to achieve the therapeutic gene, based on the PEGylated dendrigraphte of polylysines, has been developed for the treatment of AD [155]. Directional nanoparticle delivery has been investigated in transgenic AD mice [155].
Treatment of AD is extremely difficult because no precise mechanisms have been discovered for its development and pathogenesis. Despite that fact, a large number of different drug forms and therapy methods are being investigated. Among others, many nanocontainer systems have been constructed for different groups of drugs, inducing targeted delivery to pathological brain centers. Various clinical data provide an opportunity to hope that these strategies will bring their results.

Conclusions
The development of nanocontainer systems for the treatment of various diseases is a modern, promising and actively evolving field of science. Among other things, nanoparticles also contain agents for the treatment of neuropsychiatric diseases. All mental illnesses require long-term therapy, and patients need constant medication for months or even years. For this reason, it is important that the drug is delivered using nanocontainer systems that facilitate a longer release of the medicine. Various nanocontainers are opening up prospects for new forms of medication, such as subcutaneous transdermal drug delivery systems-"patches". Non-compliance with therapy in patients is a very common and serious problem, which can be solved by prescribing injections of long-acting drugs or implants. Many neuroleptics have low bioavailability when used orally due to liver metabolism and low brain permeability, and drug delivery systems can improve these indicators. Prolonged therapy inevitably leads to side effects. Studies of some combined medications for the treatment of neuropsychiatric diseases have shown a reduction in side effects compared to pure drugs. Thus, the use of nanocontainer systems for the delivery of antidepressants, antipsychotics and drugs for the treatment of neurodegenerative diseases can contribute to more effective therapy and improve patients' quality of life.

Conflicts of Interest:
The authors declare no conflict of interest.