Do niosomes have a place in the field of drug delivery?

KEYWORDS:

• Drug delivery system
• nanotechnology
• niosome
• non-ionic surfactant
• targeting release

1. Niosomes: a next attractive generation of drug delivery carriers

In the field of nanotechnology, niosomes are gaining increasing scientific interest as useful drug delivery systems for several therapeutic applications due to their unique versatility. Niosomes are vesicular nanocarriers made up of non-ionic surfactants, developed from scientists as the best alternative to liposomes. Niosomes and liposomes are both amphiphilic carriers with similar physicochemical properties, pharmaceutical applications and, also, equal in vivo behavior¹. Despite these comparable features, niosomes differ in chemical composition of the bilayer and this offers several advantages over liposomes. Liposomes are based on phospholipids, whereas niosomes are made of surfactants with improved physical, chemical, and biological stability. Furthermore, higher drug entrapment can be achieved by modulating the composition of niosomes bilayers and their industrial manufacture is less expensive because does not require special handling methods and storage conditions due to the higher stability. Most of the published papers focused on niosomes, highlighting their optimal skin permeation potential, sustained release characteristics, long shelf life and, high drug photo-protective activity as compared to liposomes [1].

Niosomes production was first reported in the 70s in cosmetic industry, but then potential applications of niosomes were expanded for the delivery of several pharmacological agents such as anticancer, antioxidants, anti-inflammatory, antiasthma, antimicrobial, antiviral, antibacterial molecules, and oligonucleotides. At the present state of the art, most of the publications in scientific literature and the first clinical trials about niosomes, highlight the great potential of these systems in dermal/transdermal applications but showed, also, the niosomal potentialities as oral formulations for blood glucose lowering or antihypertensive or analgesic drugs [2,3]. Enhanced skin permeation, direct vesicle fusion with the stratum corneum, formation of a drug reservoir into the skin, and sustained pattern of drug release seem to be the main characteristics that have attracted the interest of academia and industry [4].

Common non-ionic surfactants, used in the design of vesicular delivery systems, include alkyl ethers, alkyl glyceryl ethers, sorbitan fatty acid esters, and polyoxyethylene fatty acid esters. The choice of surfactant is a critical factor to be considered during the design of non-ionic vesicular systems. It is well known, indeed, how the surfactant molecular structure clearly affects the size, stability, entrapment efficiency, pharmacokinetics, pharmacodynamics, and targeting properties of vesicular systems. A large selection of surfactants displaying favorable properties for specific drug delivery applications is readily available.

This offers the possibility to select the more suitable surfactant in order to achieve tailor-made niosomes for the desired therapeutic response. Anyway, research is keeping to explore new materials in order to customize and optimize niosomes for different therapeutic purposes and for a potential translation in human clinical trials (Figure 1). One of the advantages of classical non-ionic surfactants is the easy chemical modification aimed to improve the selectivity toward specific organs and cells without affecting healthy tissues. In the last few years, the discovery of therapeutic targets involved in several diseases has greatly expanded and the use of these target molecules on niosomes surface allows an increased specificity and selectivity of the nanodevices. Different ligands, as small-molecules, proteins, cell-penetrating peptides, sugars, monoclonal antibodies, and their fragments, are usually involved in the design of niosomes with specific targeting properties to brain, tumor, colon, liver, lung, and eyes. Recent in vivo studies reported the ability of these engineered vesicles to selectively target tumor cells. Particularly, the design of potent candidates was attractive for targeting the glioblastoma cells of brain tumor via niosomal surface modification with peptide derived from the Israeli yellow scorpion’s venom due to its ability to penetrate the blood-brain-barrier [5]. Sugar surfactant systems, instead, are becoming popular in the design of niosomes for their natural ability to target brain or tumor tissues [6].

Figure 1. Main used applications of niosomes.

In recent years, particular attention has been paid on the design of more sophisticated stimuli-responsive surfactants able to take advantage of the physio-pathological differences occurring in several altered conditions such as cancer, inflammation, ischemia, and infections compared to healthy cells.

Much of the ongoing works focuses on the development of pH-sensitive surfactants able to undergo protonation once penetrated into acid compartments of pathological cells destabilizing their structure and improving intracellular release. Several studies proved the pH responsivity of niosomes based on Span® 20 and coated with pH insertion peptide or made of derivatives of Tween® 20 with different pH-sensitive moieties like glycine, N-methyl-glycine, N,N-dimethyl-glycine [7,8]. These showed a better cytotoxicity than conventional niosomes on cancer cells suggesting the role as useful tools for enhanced intracellular target delivery.

Based on their peculiar acid-base properties, these systems are also able to interact with DNA and other biologically relevant molecules like oligonucleotides and RNA with a consequent potential application as gene vectors for transfection.

Other stimuli, typically used to manipulate the surfactant properties, consist of temperature, light, glutathione, enzymes, and magnetic field.

Recent studies focused on the determination of the suitable niosomal compositions for gene therapies. Generally, cationic lipids are incorporated into niosomal formulations in order to create positively charged vesicles. Recently, Pengnam et al. [9] synthesized a new gemini surfactant plier-like with an ethylenediamine head group and the preliminary results showed that the niosomes based on Span® 20/cholesterol and their cationic gemini surfactant represent promising vehicles for nucleic acid delivery. Instead, Yang et al. [10] proposed the combination of gene delivery and cell labeling capacity into a single niosomal formulation based on Span® 80 and DOTAP to achieve a theranostic platform for stem cells-based therapy and regenerative medicine. The obtained results suggested optimal labeling ability and in vivo gene silencing of negative regulator of osteoblast differentiation of these devices after their implantation in mouse and, consequently, a promising utility in improving cellular regeneration.

Furthermore, a depth interest was focused on the develop of innovative surfactants from alternative renewable raw materials at competitive prices, to meet the required safety and environmental criteria. Among these, amino-acid-based surfactants have emerged as a novel and attractive class of surfactants derived from amino acids such as cysteine, lysine, and arginine, which showed promising results in several scientific works. These derivatives showed high biodegradability, low toxicity, and excellent antimicrobial activity against Gram-positive and Gram-negative microorganisms with huge potential applications in pharmaceutical, cosmetic, and nutrition fields [11].

A great innovation in niosomal formulation was also represented by the use of some amphiphilic drugs with surface active properties as main component of the bilayer. These synthetic compounds similar to a surfactant and known as ‘surfadrug’, playing the role of both carrier and drug, resulted able to form vesicular systems bypassing the use of other excipient and improving formulation biocompatibility [12].

2. Expert opinion

Niosomes are certainly a great and innovative promise for drug delivery and their near future could be very bright with several pharmacological therapies and other applications. Considering the abovementioned properties of niosome as drug carriers, they can represent a valid alternative to liposomes. The pioneer topic formulation was launched into the market by Lancome in 1987 and the benefits of these systems in cosmetic field are largely validated. However, the niosomal nanotechnology is still premature and a lot of work is still needed to guide their future applications in different clinical fields. Effectively, niosomes are young systems and few papers in the literature have focused on these carriers. Since their birth, as evidenced by Scopus database only 4896 scientific reports focus on niosomes in drug delivery against 95705 ones dealing with liposomes. In most of these works, the pharmaceutical researches have taken advantage of versatility and adaptability of easy modified and functionalized non-ionic surfactants, to obtain specific targeting tools or with intrinsic stimuli-responsive properties. The versatility of their constituents has led researchers to study their behavior as anti-cancer carriers or for applications in gene therapy. These reports and our experience in the pharmaceutical fields underline the importance of creativity and innovation to tailor-made the niosomes suitable for various therapeutic purposes. Furthermore, multi-functional niosomes have been proposed as a further evolution of traditional ‘magic bullet’ and the way to open new possibilities to achieve personalized therapies [13,14]. These strategies were also extensively explored for liposomes but the incorporation of non-ionic surfactant in the composition of lipid-based vesicular systems was largely reported in many studies as the main reason to improve their major limitations of phospholipids. Then, why do not replace fully phospholipids in vesicular bilayers after seeing their important drawbacks?

The niosome potentiality is already recognized in dermatological therapy; indeed, clinical trials for treatment of acne [15], psoriasis [16], leishmaniasis [17], wart [18], and oromucosal ulcers [19] are currently ongoing, but it would be desirable that the same interest is directed to different applications, such as diagnostics or therapeutics or also theranostics devices.

Therefore, it is essential to focus on the discovery of novel and innovative surfactants able to form niosomal formulations, adequate for preclinical studies and switch after to clinical studies.

The niosomes, despite their similarity to liposomes, have peculiar characteristics worth to be considered in order to increase availability pharmaceutical formulations more efficacy and less expensive. The real opportunities of these vesicular systems should be effectively considered and, in the near future, it will be important to spend more financial resources on their studies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

MIUR, the Italian Ministry for University, is acknowledged for financial support (EX-60%).

Additional information

Funding

This paper was not funded.