Nanoparticles Used in The Management of Psychotic Disorder Types, Novel Drug Delivery System and Advantages of SLN’s

Abstract

Nanoparticles are growing as an essential tool in the treatment of psychotic disorders because they offer new ways to identify indicators, deliver medication, and use imaging to diagnose patients. The purpose of this study is to determine whether the use of various nanoparticle types, including liposomes, dendrimers, and metallic nanoparticles, can enhance the accuracy and effectiveness of psychiatric treatments. We talk about their potential to reduce side effects, enhance drug targeting, and cross the blood-brain barrier. Furthermore, the application of nanoparticles in advanced imaging methods like MRIs and PET scans has shown increased sensitivity and resolution in identifying brain abnormalities linked to psychosis. In the last few years, the pharmaceutical industry has made extensive use of nanotechnology for the creation of new medications. The therapeutic efficacy of many diseases treated with conventional methods such as coated tablets, injectables, or capsules may not always be as high expected because of factors like drug stability, excipient stability, and bioavailability in aqueous media. This is the reason why the creation of nanoparticles, whether from synthetic sources like poly-?-caprolactone (PCL) or organic sources like chitosan, allows for the inclusion of a variety of liposoluble active compounds. The results have been excellent in the early treatment of behaviour disorders, for which medications are required but should be kept away from active sites at all times. Because of their great efficiency and low cytotoxicity, this review demonstrates how to create nanoparticles for the direct administration of mental medication, which might be viewed as a novel pharmacological instrument.

Keywords

Introduction

       
           
       
Fig 1: Drugs Class-Wise For Nanoparticles

TYPES OF NANOPARTICLES:

       
           
       
Fig 2: Different Types of Nanoparticles

DRUG DELIVERY:                 

       
           
       
Fig 3: The drug delivery system uses nanoparticles to cross and bypass the blood-brain barrier.

PSYCHIATRIC DISORDERS:

The best way to describe some mental disorders is as diseases, when an injury develops that causes a consistently recognised syndrome of observable events common to patient populations. The majority of the following mental disorders are treated with nanoparticles:

ALZHEIMER'S DISEASE (AD): The term "Alzheimer's disease" (AD) describes a specific beginning and progression of age-related cognitive and functional deterioration that eventually leads to death [16]. The clinical diagnostic criteria for Alzheimer's disease and dementia were updated in 1984 and then again in 2011 and 2018 to take into account the use of indicators and the improved capacity to identify the illness's early phases [17, 18, 19, 20, 30]. Alzheimer's disease was first qualitatively described in 1906, but it wasn't until the mid-1980s that the two defining pathologies of the illness—beta amyloid peptide, which is found in plaques, and hyperphosphorylated tau protein, which is found in tangles of neurones (NFTs)—were identified molecularly [21, 22, 23, 24, 25, 26]. In the US, AD is thought to be the most prevalent kind of neurodegenerative dementia, and its prevalence is disproportionately high in minority groups [16].

PARKINSON'S DISEASE (PD): Parkinson's disease has a major effect on everyone. All over the world, the disease affected about 6.1 million people in 2016 [27]. In terms of how many people are affected, it is a prevalent disorder. For those who provide care, Parkinson's disease has serious effects as well; the majority experience extreme stress [28]. The economic burden of Parkinson's disease is increasing for everyone [29]. Parkinson's disease may not be a singular entity, according to a number of observations. Firstly, parkinsonism is a clinical illness that appears identical and can have many different causes [30].

MAJOR DEPRESSIVE DISORDER: A prevalent mood disturbance condition known as major depressive disorder (MDD) is characterised by a generalised loss of interest in life that lasts for at least two weeks [31]. The long-term absorption of selective serotonin reuptake inhibitors may cause important toxicity, counteracting the therapeutic effects of these drugs, which are commonly used to treat major depressive disorder (MDD) [32]. Research is still being done to find novel antidepressant treatments for MDD.

SCHIZOPHRENIA: Three main classes of symptoms characterise schizophrenia, a chronic illness that has an important effect on cognition, social functioning, and work ability. Positive symptoms include delusions or hallucinations; negative symptoms include activity and social withdrawal; and cognitive symptoms include working memory problems. Given that the condition may be caused by genetic, developmental, or environmental causes, it is regarded as a complex disease. However, only 40% of schizophrenic patients effectively respond to traditional treatment [35] due to poor pharmaceutical efficacy and the fact that 20–30% of patients are predicted to be treatment resistant [33, 34].

PARTICLE SIZE:

In order for particles to be cleared by the oscillatory spleens of humans and rats, their size and deformation are crucial factors. Particles need to be sufficiently tiny or flexible to evade the splenic filtration process at the venous sinus walls' inter-endothelial cell slits (IES) [36, 37]. Circulated meshwork flow through the sinusoidal spleen is blocked by the IES. Both sets of cytoplasmic filaments are present in the endothelial cells of the sinus wall: a set of loosely grouped tonofilaments and a set of filaments that are tightly arranged into dense bands in the basal cytoplasm and contain actin and myosin. These filaments are likely able to change the stress in the endothelial cells and, consequently, the size of the IES [38]. Even when an erythrocyte is in transit, the slit size rarely extends above 200 to 500 nm in width [36]. Hence, bulk characteristics like size, spherical shape, and deformation affect how long blood cells and blood-borne particles remain at the IES. The red pulp of macrophages is thought to have eventually "pitted" erythrocytes with stiff inclusions (such as Heinz bodies and malarial plasmodia) from these cell slits [39].  An designed long circulatory particle's optimal size, thus, should not be greater than 200 nm. If the particle is larger, it needs to possess sufficient deformation to avoid IES filtering. In contrast, long-circulating, stiff particles larger than 200 nm may function as selenotropic agents and, if they are not rigid, be eliminated later [37, 40].

USE OF LIGANDS:

Long-circulating carriers can have their surface connected to ligands or homing devices that bind selectively to receptors or surface regions on the target sites. The B16 melanoma cell line exhibits higher expression of LDL receptors; folic acid is overexpressed in cells of cancers with epithelial origin; peptide receptors, such as somatostatin analogues, vasoactive intestinal peptides, gastrin-related peptides, cholecystokinin, and luteinizing hormone-releasing hormone, are also overexpressed in certain cancer cells. The specificity of the nanoparticles would be enhanced by attaching appropriate ligands for these specific receptors to them [41, 42]. According to the hypothesis put forward by Allen et al., the existence of particular ligands on the surface of nanoparticles may enhance their retention at the BBB and, as a result, raise the concentration of nanoparticles at the BBB's surface. They created coated nanoparticles from Brij 78 and emulsified wax with thiamine ligand (connected to DSPE via a PEG spacer) in an effort to confirm their hypothesis. However, a number of issues, including insufficient thiamine ligand coating and a preferential binding of the thiamine ligand to the blood thiamine transporters, contributed to the authors' inability to achieve extended nanoparticle concentration [43].

In comparison to bovine serum albumin, Thole et al. showed improved interaction with brain endothelial cells and increased intracellular accumulation of sterically stabilised colloidal particles related to cat ionized albumin [44]. Furthermore, an endocytic route triggered by caveolae transports the cat ionized albumin into the brain endothelia. Since they have a strong affinity for their targets, intact antibodies have been employed as extremely specific targeting agents. The antibodies serve as spies to transport nanoparticles into the blood-brain barrier [44].

In order to transport entrapped actives into the brain parenchyma without altering BBB permeability, brain-targeted pegylated immunonanoparticles and peptidomimetic antibodies that bind to the BBB transcytosis receptor are being investigated as well [45]. Similar reports have been made about the delivery of drugs to the brain by nanoparticulate drug carriers combined with the creative targeting principles of "differential protein adsorption (Path Finder Technology)" [46]. The pathfinder method targets intravenously delivered carriers by using blood proteins that adsorb on their surface. As previously mentioned, one such targeting moiety for particle delivery to the BBB endothelial is a type of protein E. The potential use of these technologies for enhancing SLN brain targeting can also be investigated.

NOVEL DRUG DELIVERY SYSTEM APPROACH:

The inability of drugs to reach the brain is mostly caused by two factors:

1) The drug's molecule does not penetrate the BBB well.

2) Medication backflow, or discharge, from the brain into the bloodstream. Several researchers have experimented with different colloidal delivery techniques in an attempt to address the first issue in particular. Solid lipid nanoparticles (SLNs), liposomes, microspheres, lipid microspheres, noisome, and nanoparticles are examples of these systems [47–52]. A few crucial elements for a successful delivery system include a high drug loading, the carrier's physical and chemical stability, and a low incidence of toxicity. Additionally, the carrier's fate in real life, the possibility of generating the drug delivery system at a larger scale, and the total cost are the other Factors [53–56] should be taken into account before determining if the system is appropriate. 
A wide variety of factors, including plasma protein binding, cerebral blood flow rate, influx and efflux rates at the blood-CSF barrier and the brain parenchyma, drug metabolism rate in the brain, drug-tissue interactions and binding in the brain, and flow rate, further regulate the cerebral distribution parameters of drugs. Therefore, it becomes crucial to take these factors into account and improve them while choosing an appropriate delivery mechanism for brain delivery.

By identifying candidate brain-specific transport systems that could be used to transfer drug items from the blood to the brain as a safe delivery method, various more recent techniques, such as proteins and genomics, could be used to guide the novel drug delivery system to its target sites [57]. These techniques also help uncover pathways involved in disease pathogenesis. 

However, there are a number of issues with using these polymeric nanoparticles, such as organic solvent-related contaminants that remain from the production process, large polymer particles, polymerisation initiation, toxic monomers, and toxic breakdown products [58, 59]. 

Some issues are the high cost of production techniques [60], the absence of large-scale production techniques [61], and the need for an appropriate sterilisation technique, like autoclaving. With nanoparticles' potential to cross the blood-brain barrier and their drawbacks, including toxicity and stability, SLNs represent an additional viable choice for medication administration into the brain. An appealing colloidal drug carrier system is made up of SLNs. Solid lipid nanoparticles in spherical form, distributed in water or an aqueous surfactant solution, make up SLNs. They typically consist of a monolayer of phospholipid coating covering a solid hydrophobic core. The hydrophobic end of the phospholipid chains may be lodged in the fat, and the solid core may contain the medicine dissolved or disseminated in the solid, high-melting fat matrix.

As a result, they may convey hydrophilic or lipophilic drugs or diagnostics [62–64]. To get above the medication 5-flouro-2, -deoxy uridine (FUdR)'s restricted access, Wang et al. reported synthesising 3', 5, -dioctanoyl-5-flouro-2, -deoxy uridine and incorporating it into solid lipid nanoparticles (DO-FUdR) [65]. In comparison to FUdR, the brain area under the concentration/time curve for DO-FUdR-SLN and DO-FUdR was 5.32 and 10.97 times larger, respectively. According to these findings, DO-FUdR-SLN exhibited good animal brain targeting efficiency (two times that of the free drug). The results of this study suggest that SLN is a promising drug targeting system for the treatment of illnesses of the central nervous system and that it can enhance the drug's capacity to cross the blood-brain barrier.

ADVANTAGES OF SLNs OVER POLYMERIC NANOPARTICLES (and other delivery systems like liposomes):

While avoiding their drawbacks, SLNs combine the benefits of liposomes, fat emulsions, and polymeric nanoparticles [66]. The following are some benefits of SLNs: 
1.] The RES (Reticulum Endothelial System) cells do not readily absorb the nanoparticles and SLNs, especially           those in the 120–200 nm range; therefore, they evade the liver and spleen's filtering process [67]. 
2.] The integrated medicine can have a controlled release for a few weeks [60, 68, 69]. Also, the range of drugs that can be targeted increases by coating or ligand-attaching SLNs [70, 71]. 
3.] It is possible to create SLN formulations that are stable for up to three years. In relation to the other colloidal carrier systems, this is quite important [72, 73]. 
4.] High payload for drugs.

5.] Outstanding repeatability using a cost-effective high-pressure homogenisation technique as the first step [61]. 
6.] The possibility of combining medications that are both hydrophilic and hydrophobic [62–64]. 
7.] The carrier lipids are harmless because they degrade naturally [74, 75, 76]. 
Avoid using organic solvents [71]. 
9.] Production and sterilisation on a large scale are possible [77, 60].

METHODS TO BELONG BRAIN RETENTION OF SLNs:

The size, hydrophobicity, motility, and other surface properties of SLNs have a significant impact on how distributed their bodies are. The delivery of hydrophilic medications like diminazens as well as other BCS class IV medications, including paclitaxel, vinblastine, camptothecin, etoposide, cyclosporine, etc., has been suggested for the SLNs [63, 75, 78, 79]. Due to their tiny size and lipophilic nature, these carriers can enter the blood compartment with ease; however, the reticuloendothelial system's (RES), or mixed phagocytic system's, cells must recognise these particles. MPS cells of the liver (Kupffer) and those of spleen macrophages are a major limitation for their use. Uptake of nanoparticles by RES could result in therapeutic failure due to insufficient pharmacological drug concentrations building up in the plasma and, hence, at the BBB. To overcome these limitations, various researchers have tried to increase the plasma half-life of SLNs by using the following methods:

DISCUSSION:

The primary study options in nanomedicine in psychiatry have been defined, and it has been discovered that the latter is presently being ignored in this field. To the best of our knowledge, this article is among the first to propose studying nanotechnology in relation to mental disorders. As demonstrated by their novel qualities, nanocarriers are significant to the blood-brain barrier, which has been linked to the development of some mental diseases, including schizophrenia [80]. In addition, we saw that these nanotechnologies could yield new information from the live imaging data of humans (psychiatry finds it particularly challenging to build animal models), fresh information on pharmacological effects and metabolism (from the early phases of research), understanding of possible pathophysiological pathways underlying mental diseases, etc. Research in the subject of psycho-immunology appears to be very promising, with the possibility to track the expression of viral particles that may serve as triggers for psychiatric disorders made possible by these new tools. The more complex qualitative modelling has the potential to completely transform our knowledge of mental illness. Regretfully, [81] highlighted that European financial investments in this field were far less than American ones. The health hazards connected to the use of these nanoparticles remain an important barrier. If nanotechnology makes it possible for medications to enter the brain more effectively, what stops those same compounds from exiting the brain as effectively? Particular respiratory or gastrointestinal disorders are favoured by particular nanoparticles, and some even cause excessive generation of free radicals and proinflammatory immunological responses [82]. In order to investigate the potential hazards associated with nanotechnology, the FDA also established work groups known as the "Nanotechnology Task Force" [83]. Thus, it is crucial to exercise caution and to impart knowledge about the applications and dangers of nanotechnology to medical students [84].

CONCLUSION:

Enhancing the efficacy, safety, and precision of medical treatments can be achieved through the potential use of nanoparticles in the treatment of psychiatric diseases. Through more effective blood-brain barrier crossing, targeting of certain neuronal circuits, and reduction of systemic side effects, nanoparticles can enhance drug delivery. Additionally, they facilitate the controlled and prolonged release of drugs, which is essential for the treatment of long-term illnesses such as anxiety disorders, schizophrenia, and depression. 
Furthermore, nanoparticles could transform personalised medicine in psychiatry by enabling the customisation of treatments to each patient's own neurobiological profile. This could result in treatments that are more successful overall and have fewer adverse effects. Materials are safe and biocompatible, and figuring out the ethical costs of using this advanced technology. Even though there are a lot of potential advantages, there are still issues and worries that must be overcome. These include knowing how long-term exposure to nanoparticles in the brain affects people, making sure these. In summary, whereas nanoparticles provide a novel approach to treating mental illnesses, further study, clinical testing, and moral considerations are needed to fully understand and properly apply the potential for treatment.

ABBREVIATION:

BBB – Blood Brain Barrier, SLN – Solid Lipid Nanoparticles, MRI – Magnetic Resonance Imaging,

PET – Polyethylene Terephthalate, PEG – Polyethylene Glycol, RES – Reticulum Endothelial System,

PCL – Poly-?-caprolactone.

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