Niosomes provide a novel drug delivery technology that may accommodate both hydrophilic and hydrophobic pharmaceuticals, as they trap hydrophilic drugs inside the core cavity and hydrophobic drugs within the non-polar region situated inside the bilayer [1]. The non-ionic surfactant that creates the vesicle encasing the medicine is the moniker given to niosomes because of its ampiphillic nature. Niosomes are extremely small particles [2]. The first niosome formulations were developed and patented by L'Oreal in 1975. when surfactants and the charge-inducing substances from the thermodynamically stable vesicles are correctly combined. Because niosomes reduce the disadvantages of liposomes, their primary application is as a liposome replacement [3]. Because they lack the chemical instability of liposomes, niosomes are superior to liposomes. Liposomes' chemical instability is caused by their oxidative degradation susceptibility and the variable purity of phospholipids. Niosomal system development aims to achieve several key objectives, including low production costs, low toxicity, chemical stability, biodegradability, biocompatibility, and ease of handling and storage [4,5]. Niosomes can be applied topically, sublingually, orally, and parenterally. A wide range of drugs, including synthetic and natural treatments, hormones, antigens, and other bioactive materials, are delivered via niosomes [6,7,8]. This page summarizes the key features of niosomes, describes how they are made, and discusses how they are currently used to encapsulate and distribute bioactive compounds.

In order to distinguish between their various varieties, niosomes can be categorized into three classes based on the size of their vesicles: There are three varieties of

1. Unicellar vesicles are accessible:

1. Small (SUV, size = 0.025-0.05?m);
2. Large  (LUV, size = >0.10?m); and

2. Multilamellar (MLV, size = >0.05?m).[9]

Advantage of niosomes

1. Vesicle features can be altered by adjusting the vesicle composition, size lamellarity, surface charge, tapping volume, and concentration.
2. The drug can be released gradually and under supervision.
3. Surfactants do not require special handling or storage conditions, such as inert environments or low temperatures.
4. They can be used as a depot formulation, which allows for controlled release of the medication.
5. They increase the oral bioavailability of the poorly soluble medications.
6. They maintain a stable structure even as an emulsion.
7. Surfactants are biocompatible, biodegradable, non-immunogenic, and non-toxic.
8. They are reasonably priced for large-scale production.
9. They have the ability to protect the drug from enzyme metabolism.
10. They improve the medication's stability.[10-11]

Disadvantage of niosomes

The aqueous niosome solutions have a short shelf life because of drug encapsulation hydrolysis, fusion, aggregation, and leakage.

1. The preparation of multilamellar vesicles via the extrusion and sonication procedures requires a significant amount of time and specialized processing equipment. [12]

Role in Targeting drug delivery     

The primary goal of pharmaceutical therapy is to reach a steady state blood or tissue level that is both therapeutically effective and nontoxic over an extended period of time. Attaining the goal required developing a suitable dosing schedule. By delivering the medication at the site of action and supplying it at a rate dictated by the body's demands over the course of therapy, innovative drug delivery systems aim to achieve these two objectives. Targeted drug delivery is perceived to imply the selective and effective localization of the pharmacologically active moiety at the pre-identified (preselected) targeted in therapeutic contexts by limiting the drug's access to normal cellular linings that are not the target and thereby minimizing its toxic effect and optimizing its therapeutic index. Targeted drug delivery is the process by which a drug conjugate or carrier complex selectively delivers a drug to pre-identified target cells in a certain manner. The optical pharmacological action might be pursued by releasing functional molecules from their carrier at the site of action, where they would continue to function. The targeting methods fall into one of three categories: chemical, covalent bonding, or physical. To produce a derivative that was only active at the designated area, chemical methods involved modifying the original component. A range of physical procedures were used to utilise the carriers, which included liposomes, niosomes, resealed erythrocytes, platelets, magnetic microspheres, nanoparticles, and monoclonal antibodies. The benefits of the niosomal drug delivery system over conventional drug administration systems have drawn a lot of attention lately. It is also referred to as the particle colloidal carrier system [13–17].

       
           
       
    Figure 1 :  Structure of Niosome

Components of Niosomes :

The two main substances that are used to prepare niosomes are nonionic surfactants and cholesterol. Cholesterol is used to give the niosomes their unyielding character and proper form. Surfactants have a significant role in the formation of niosomes. For the most part, the non-ionic surfactants that follow are used to organize niosomes in the spans (span 60,40,20,85,80), tweens (tween 20,40,60,80), and brijs (30,35,52,58,72,76).

Cholestrol :

Being an amphiphilic molecule, cholesterol aligns its aliphatic chain with the hydrocarbon chain of the surfactant and its OH group with the aqueous phase. In order to give non-ionic surfactants stiffness, cholesterol, a waxy steroid metabolite, is typically added. It is also known that cholesterol stops the gel to liquid phase transition, thereby preventing leaks.[18]

Non-ionic surfactants :

Niosomes are synthetic non-ionic surfactant vesicles that can be unilamellar or multilamellar. A non-ionic surfactant has a hydrophobic tail and a hydrophilic head group. The size of the niosome grows as the HLB value increases and the alkyl chain increases. HLB values 14–17 are therefore inappropriate for niosome formulation. 8 is the maximum entrapment efficiency for HLB values. These are non-ionic surfactants:

Ether-linked surfactants:

These surfactants have hydrophilic and hydrophobic moieties joined by ether. They are polyoxyethylene alkyl ethers, with the general formula (CnEOm), where m = 3–7 represents the number of oxyethylene units and n = 12–18 represents the number of carbon atoms.

Di-alkyl chain surfactant:

The ability of this surfactant to transport sodium stibogluconate in experimental marine visceral leishmaniasis has been investigated. It was utilized as a key component of the niosomal formulation of stibogluconate.

C16H33CH-O[-CH2-CH-O]7-H

| |

CH2 CH2OH

|

C12H25-O (mol. Wt. 972)

Ester linked:

These surfactants are also known as ester linked surfactants because they feature an ester bond between hydrophilic and hydrophobic groups.

The application of this surfactant in the creation of niosomes carrying stibogluconate and in the transport of sodium stibogluconate to the experimental marine visceral leishmaniasis were also investigated.

C15H31CO[O-CH2-CH-CH2]2-OH

|

OH (mol. Wt. 393)

Sorbitan esters:

The ester-linked surfactants are called sorbitol esters. Commercial sorbitan esters are made by combining oleic acid with the partial esters of sorbital and its mono- and di-anhydrides.

CH2

|

H-C-OH

|

RCOO- C-H

|

H-C-OH

|

H-C-OOC-R

|

CH2OOC-R

Where, R is H or an alkyl chain.

These have been employed to ensnare a variety of medications, such as doxorubicin. Fatty acid and amino acid compounds: In certain niosome manufacturing processes, long chain fatty acids and amino acid moieties have been utilized to create "Ufasome" vesicles. [18, 19]

Charge inducers :

Positive and negative charge inducers are the two different categories of charged inducers. By introducing a charge to the surface of the produced vesicles, it improves their stability. It functions by offering larger zeta potential values and inhibiting the fusion of vesicles caused by repulsive forces of the same charge. Dicetyl phosphate, dihexadecyl phosphate, lipoamine acid, and sterylamine are the often used negative charge inducers whereas cetylpyridinium chloride and sterylamine are the regularly utilized positive charge inducers [18].

Anticancer activity of niosome :

Worldwide, cancer is the primary cause of mortality and a low quality of life. The effectiveness of various cancer treatments is questionable, despite the fact that numerous methods have been developed to lower mortality, lessen chronic pain, and enhance quality of life. Early cancer cell diagnosis and the administration of highly precise medications to limit toxicity are two of the most crucial elements to ensuring optimal cancer treatment. Since traditional cancer treatment and diagnostics are so harmful and inefficient, researchers are turning to alternative approaches, such as nanotechnology, to improve cancer detection and lessen the disease's severity. Immunotherapeutic drugs based on nanotechnology have been utilized for a long time to treat various cancers by preventing cancer cell invasion and maintaining the presence of healthy cells at the site [20]. Clinical usage of the medication is complicated by its poor solubility, which results in low bioavailability and quick degradation. Agarwal et al. overcame this by employing a niosomic system that included cholesterol and the neon surfactant SPAN 60 to increase the drug's solubility in the aqueous phase. Smooth, homogenous, spherical, highly cytocompatible niosomes with an average size of 479 nm were produced with ease. Nanomorocin is readily distributed in an aqueous environment, in contrast to free morocin. In four distinct cancer cell lines, a very high entrapment efficacy (97%) controlled and sustained release of morocin was seen, leading to increased therapeutic efficacy. The findings imply that the morose niosome system is a potentially useful tactic to boost antitumor activity against a variety of cancer types and could be a key component of future targeted chemotherapeutic approaches [21]. Kong et al. reported on a different investigation in which operated niosomes were used as a transdermal medication delivery system for the treatment of tumors. These scientists have created a novel drug nanoparticle with the potential to target tumors that is based on hyaluronic acid and niosomes that enhances drug transport through the skin. Their findings showed that the endocytosis of nanocarriers in tumor cells was greatly enhanced by the addition of hyaluronic acid. Hyaluronic acid niosomes are thought to be safe, efficient skin penetration carriers as well as a useful and prospective treatment option for malignancies through dermal administration [22]. The physiological and biological properties of niosomes loaded with the nucleophilic Ru (III)-complex HoThyRu as an anticancer agent and the nucleolin-targeting AS1411 aptamer that enables the selective recognition of cancer cells were examined in another study by Bayindir et al. The morphology, average size, Zeta potential, electrophoretic mobility, and stability were examined using a variety of biophysical methods. The outcomes demonstrated a considerable increase in HeLa cells' antiproliferative activity. Ru (III)-containing niosomes' bioactivity was effectively increased by AS1411 in each of the examined cell lines [23, 24, 25].

Application of niosomal formulation in cancer therapy :

Molecular dynamic simulation:

 A molecular dynamic simulation (MDS) tool is necessary for the design of an in silico drug delivery formulation because it predicts formulation features before synthesis and offers information about potential self-assembled structures. This reduces the need for in vitro and in vivo experiments [26 , 27]. MDSs are suitable for investigating atomic-level interactions between molecules; they are in charge of figuring out drug diffusivity, solubility, carrier-drug miscibility, drug build-up in organs, cell distribution, clearance, kidney filtration, and the drug release kinetics that impact niosomes [28]. Poor bioavailability resulting from inefficient cell membrane penetration is a major factor contributing to medication failure in clinical studies [29]. When used extensively, MDS is a reliable technique that has been used for the examination of interactions and orientations between drug molecules and bilayer forms [31].

   It also estimates the drug-loaded nanocarrier per-meation to a cell membrane [30]. The first critical stage in a drug's absorption from bilayer structures to the target is its solubility [32]. The production of niosomes requires the application of several processes in the solvent media. However, the solvent may have an impact on the production, purity, and reaction kinetics of processes like crystallization and extraction [33]. Therefore, solubility plays a crucial role in the pharmaceutical sector when choosing the right solvent. These days, molecular surface area evaluations, hydrophilicity/hydrophobicity calculations, electronic, and topological assessments are necessary for the computational prediction of solubility [34]. By adjusting the pH and salt content in a range of organs, drug nanocarrier solubility changes can be fully understood using MDS. Multiple applied carrier molecules are responsible for boosting the drug's stability when it comes to moderately soluble or insoluble medicines [35, 36]. A computer approach is devised [37, 38] to determine the miscibility of medicines and carrier molecules. Drug loading and releasing assessment is one of the MDS components [39, 40]. The simulations demonstrated that the drug load variations lead to a considerable alteration in the naparroker structure. Regarding medication release, other critical factors include the drug's size, internal structure, and position within the nanocarriers [41, 42]. The location of medication components within nanocarriers and the manner in which they release can be greatly influenced by free energy calculations. Frequently, nanocarriers are engineered and modelled to release the medication assessment in reaction to pH variations [43, 44]. One of the essential physicochemical variables for describing the association and dissociation rates of a binding or non-binding ligand to its target using MDS techniques is kinetics [45]. The majority of proteins feature small-molecule binding pockets that are not easily identified, so while NMR and X-ray crystallographic structures frequently show ligand-binding pockets, experimental models can occasionally conceal other potentially druggable locations [46]. To be apparent, these allosteric [47] and cryptic [48] binding sites must undergo a conformational change.One important property of pharmaceuticals is their ability to crystallize in several forms or polymorphs. MDS can study the crystallization of complex drug crystals and the possibility of new polymorphs of the crystal structure. Each polymorph of the medicine may differ from others in physiochemical features, such as density, solubility, bioavailability, mechanical strength, dissolution rate, and alike, that can affect fabrication and the therapeutic performance [49–51].  Complete reports on every MDS niosome study conducted to date are available. Sanghwa et al. [52] provided the first report of a niosomal bilayer. The MD simulation of span 80 and cholesterol was studied on several physical properties, including number of hydrogen bonds, area per lipid, thickness, and diffusion coefficient, at a duration of 60 nanoseconds. After that, in 2016, Aksornnarong et al. [53] used the Span 60 with and without 50 mmol% cholesterol to create a niosome in 60 ns for each step, according to Gromaces 4.5.4 software. Niosome characteristics were computed from the dynamic simulation at temperature, including area per lipid, molecular orientation, membrane thickness, lateral and transversal diffusion, and the number and kinetics of hydrogen bonds with or without cholesterol. The dynamic simulation showed that the niosome favored gel-phase formation with a higher order structure when it was free of cholesterol, but it showed more fluidity and a less ordered structure when it was present. Yoochan et al. [54] used the Gromacs software tool (version 4.5.2) to model the interaction between the Span 60/cholesterol niosome with flavones. Low concentrations allowed flavone to pass through the bilayer, but high concentrations caused it to accumulate at the core of the niosome and thicken the membrane. Following that, in 2018, I [55] represented the dynamical characteristics and structure of a niosome generated by Span 60 and cholesterol molecules at different concentrations of cholesterol (ranging from 0 to 70 mol%) using molecular dynamics simulations. They investigated whether cholesterol affects the niosome's structure and properties, such as thickness, area per molecule, and compressibility. Lastly, in 2019, Barani et al. [56] used the Gromacs software (version 4.5.4) for MD simulation to show the dynamic properties of Span 60 / Teen 60 / cholesterol and Span 60 / Teen 60 / ergosterol. Additionally, they proposed loading DNA with protamine-compressed niosomes and Fe3O4 nanoparticles containing ergosterol rather than cholesterol. Predicting formulations with benefits like high trapping efficiency and low cytotoxicity, decreased drug consumption frequency, and magnetic characteristics for targeted distribution are the goals of building drug delivery systems.

ADME properties:

Absorption, distribution, metabolism, and excretion (ADME) is necessary to achieve any therapeutic goal with a new drug delivery system from the early stages to the final clinical evaluations [57, 58]. On the other hand, pharmacokinetic knowledge of ADME is an essential component of the drug delivery system study. In order to verify the absorption, calculations are made for Caco-2 permeability, human intestinal absorption, F bioavailability (20% and 30%), Pgp inhibitor, and Pgp sub-strate. For distribution prediction, plasma protein binding, the blood–brain barrier, and volume distribution are evaluated. Membrane enzymes known as CYPs are primarily found in the intestinal and hepatocyte endoplasmic reticulum and mitochondria. CYPs, including CYPs 3A4, 2D6, 2C19, 2C9, and 1A2, are responsible for almost 80% of of clinically used drugs [59]. To assess exertion, clearance and T1/2 (half-life) are examined. Furthermore, human hepatotoxicity and hERG blockers are primarily used to assess toxicity [60, 61]. Biomolecules are absorbed differently depending on their hydrophobicity (log P), solubility (log S), polarity, ionization, molecular weight, and size. Chemical constructions also affect metabolism and excretion, thus it's important to determine the chemical groups that are most exposed to metabolism. For example, lipophilic compounds have a fast metabolism, but hydrophilic ones are quickly removed. To examine chemical characteristics, a variety of software tools are available, including SWISS ADME (http://www.swissadme.ch/) and ADMETLAB (http://admet.scbdd.com/calcpre/index/) [62–65].

Molecular docking:

Molecular coupling is another type of virtual screening that simulates biological systems and forecasts the interaction of two or more molecular structures (drug and protein or enzyme) with varying binding affinities and root mean square deviations [66]. Out of the sixty distinct molecular docking algorithms, MOE-Dock [67], AutoDock Vina [68] and GOLD [69] have the highest scores; also, GOLD [69] and LeDock [70] recognize the proper active sites, and both Glide (XP) [71] and GOLD identify postures with a 90.0?ficiency [72]. A representation of niosome molecular coupling is given. Combining in silico techniques such as artificial intelligence, molecular dynamics, molecular coupling, and binding free energy [73] can improve performance prediction. To summarize, in silico design and simulations play a major role in drug delivery studies since they enable the creation of a fully detailed design that includes all of the molecular features of the medication and carrier for the patient. This breakthrough allows for considerably faster, less expensive, and more efficient design of nanocarriers with optimal characteristics [74, 75].

Anti - cancer drug loading into niosome :

CONCLUSION :