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42 M. G. Fabiano et al.
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3.5.3 Bilayer Characterization
Niosomes may be classified morphologically, according to the number of membrane
bilayers (lamellae) as unilamellar and multilamellar vesicles. Unilamellar vesicles
are characterized by the presence of one surfactant bilayer while multilamellar
vesicles by several concentric surfactant bilayers in an onion-skin arrangement.
The number of lamellae is determined by using AFM (Di Marzio et al.
et al. 2019; Gadapa et al. 2022) microscopy techniques, NMR spectroscopy (Kreuter
1994), and small angle X-ray scattering (Carafa et al. 2006; Liu and Guo 2007a, b;
Rinaldi et al. 2019b, 2020). The latter method together with the in situ energydispersive X-ray diffraction (EDXD) have been also used to characterize the bilayer
thickness (Caracciolo et al.
Welsh et al. 2001) using SEM images to estimate the thickness of proniosomes at
various concentrations of surfactants.
Another feature of the niosomes is the fluidity of their membranes, which allows
membrane deformation without disrupting bilayer integrity (vesicle stability) and
drug release ability.
These parameters may be measured by means of fluorescence probes (e.g. DPH
and pyrene) as a function of temperature and/or time (Girigoswami et al. 2006; Lentz
1993; Liu and Guo 2007b; Macdonald et al. 1988; Manosroi et al. 2003; Sarkar et al.
2002; Zhai et al. 2004; Ghode and Ghode 2021; Rinaldi et al. 2019a, b).
Manosroi et al. determined the microviscosity of niosomal membranes by fluorescence polarization in order to study packing structure of the vesicular membrane
(Manosroi et al.
2003, 2008a).
2008; Pozzi et al. 2010, Ghode and Ghode 2021; Blazek-
2011;Ge
3.5.4 Vesicle Stability
Vesicle stability is a complex issue and involves chemical stability, physical stability, and biological stability, which are all inter-related. The evaluation of these
parameters is fundamental when determining the potential in vitro/in vivo applications in nanomedicine. Biological stability, however, depends on the presence of
agents that interact with the vesicular structure after patient administration, and it
therefore also depends on the administration route. Generally, stability is determined
by means of size and zeta potential variations (DLS or microscopy techniques) or by
the evaluation of the release rate of different probes as a function of time and/or
temperature and in the absence or in presence of biological fluids.
TURBISCAN
and size variation in liquid dispersions with high sensitive and reliable analysis of
transparent to opaque samples even at high concentrations. It is capable of checking
destabilization phenomenon kinetics (short- or long-term stability) (Imperlini et al.
2021).
®
uses Static Multiple Light Scattering to detect particle migration
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3.5.5 Entrapment Efficiency
The entrapment efficiency may be defined as the amount of active substances
delivered by niosomes. The entrapment efficiency (EE) of vesicular systems may
be expressed as:
Amount entrapped
EE ¼
Total amount
x 100 ð3:4Þ
The entrapment efficiency may be determin
2002; Muzzalupo et al. 2005) or in the case of genetic material (e.g. a luciferase
et al.
ed by spectrophotometry (Manconi
plasmid) by gel electrophoresis followed by UV densitometry (Manosroi et al.
2008b). In addition, the entrapment efficiency may be evaluated fluorometrically
using a hydrophilic fluorescent marker (e.g. calcein) (Santucci et al. 1996; Manosroi
et al. 2003) and one of following equations:
Mole
and I
where I
total
are fluorescence intensity before (I
in
of cobalt chloride (CoCl
EE ¼
EE ¼
), I
is fluorescence intensity after addition CoCl2, organic
2
tx
probe entrapped
Mole
surfactant
I
- Itxx r x 100
in
- x
I
total Itx
x 100 ð3:5Þ
x 100 ð3:6Þ
r
) and after (Iin) the addition
total
solvent, such as n-propanol or detergent, such as Triton X-100, r is the volume
correction factor (~1.04). Equation
3.5 does not require vesicle purification.
3.5.6 In Vitro Release
The release of drugs from niosomal suspensions may be affected by various parameters such as
niosomes. These parameters may be monitored using fluorescent probes.
Girigoswami et al. (2006) used Fluorescence Resonance Ene rgy Transfer (FRET)
to monitor release of enca psulated substances in niosomes, monitoring the entry/exit
dynamics of donor/acceptor dyes.
Another m
tubes placed in buffer solution with constant shaking at 25
various time intervals, the buffer is analysed for the drug content by an appropriate
assay method.
The release kinetics in vitro may be studied by a simple equation (Sinclair and
Peppas
1984):
hydration volume, drug concentration, and location within the
ethod u
sed to evaluate in vitro release rates includes the use of dialysis
˚
C, 32˚C, or 37˚C. At
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M
t
n
M
1
¼ Kt
ð3:7Þ
where M
is the amount of drug released at time t, M1 is the loaded drug amount, K is
t
the kinetic constant, and n is the exponent related to the release mechanism (Carafa
et al.
2004).
3.5.7 pH Sensitivity Assessment
Stimuli-sensitive nioso mes, which release their cargo in response to external stimuli,
constitute interesting alternatives for therapies directed towards solid tumours and
other spatially well-defined targets. The gradual decrease in pH experienced by
niosomes that are internalized via endocytosis constitutes a potentially very useful
intrinsic stimulus and several pH-sensitive niosome formulations based on this
strategy have been developed and evaluated biologically (Bergstrand et al.
Carafa et al. 2006; Di Marzio et al. 2008, 2011; Masotti et al. 2010).
Steady-state fluorescence spectroscopy has also been used to characterize the pH
sensitivity of the niosomes. The fluorescent probes chosen for such experiments
were 8-Hydroxypyrene-1,3,6-t risulfonic acid (HPTS) and Nile Red. HPTS is a
hydrophilic molecule used as a pH-sensitive fluorescence probe for measurements
of the aqueous interior of artificial vesicular systems. The fluorescence intensity
(at 510 nm) of HPTS is strongly dependent upon the degree of ionization of the
8-hydroxyl group (pK ¼ 7.2) and hence upon the environmental pH. The hydrophobic probe Nile Red has a low solubility and fluorescence in water and hence its
fluorescence emission properties are strongly medium dependent. This probe, when
integrated into the vesicle bilayers, is monitored for its shift in emission maximum
that occurs during the transition from lamellar to micellar phase (Di Marzio et al.
2011).
To study the effect of pH on physical stability, niosomes must be diluted with
buffers at pH 7.4 or at pH 5.5. The effect of pH on colloidal stability may be
evaluated by dynamic light scattering and by turbidity measurements.
The effect of pH on vesicle bilayers may also be evaluated by small angle X-ray
scattering (SAXS). This technique can measu re bilayer thickness changes at different pH values (Marianecci et al. 2016). The maintenance of pH sensitivity in serum
must also be defined by monitoring fluorescent probe release at different pH values
and in the presence of serum (Carafa et al.
2006; Di Marzio et al. 2008).
An assay, performed at different pH values, for vesicle–vesicle fusion, is based on
the non-radioactive resonance energy transfer (NRET) between two fluorescent
lipids N-(7-nitro-2,1,3-benzoxadiazol-4-yl) phosphatidylethanolamine (N-NBD-PE,
energy donor) and N-(lissamine rhodamine B sulfonyl) phosphatidylethanolamine
(N-Rh-PE, energy acceptor). This technique provides a means by which lipid mixing
during vesicle fusion may be followed, since fusion of the vesicles will result in
intermixing of the membrane lipids and energy transfer between the probes (Francis
et al.
2001).
2003;
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3.6 Niosome Applications
Niosomal drug delivery is potentially applicable to many pharmacological agents.
There are a growing number of publications on potential niosome applications in
therapy. Some examples of these numerous studies are reported below.
3.6.1 Oral Delivery
The oral route is the most widely accepted means of drug administration. To
overcome the gastrointestinal barriers, various types of colloidal systems such as
niosomes have been investigated to improve the poor and variable oral bioavailability of some drugs. With respect to hydrophobic drugs, evidence exists that the
in vitro gastrointestinal stability of paclitaxel is well preserved with Span
40 niosomes (Bayindir and Yuksel 2010); moreover, Span 20, Span 40, and Span
60 vesicles significantly improved the oral bioavailability of griseofulvin in albino
rats after a single oral dose (Jadon et al.
40, Span 60, and cholesterol were proposed as a potential oral delivery system for
ganciclovir. In vivo studies in rats revealed a fivefold increase in the bioavailability
of the drug after oral administration of an optimized formulation when compared to a
standard tablet dosage form (Akhter et al.
Also, Tween 20 niosomes have been proposed as delivery systems for oral
administration of drugs. The in vitro stability results demonstrated that the pH
environments and enzymes (pepsin and/or pancreatin) of the gastrointestinal fluids
did not influence surfactant vesicle stability. The in vitro mucoadhesive experiments
showed that the capacity of nanovesicles to adsorb mucin was higher at neutral pH
than at acidic pH (Di Marzio et al.
A proniosome formulation (Span 60: cholesterol: dicetyl phosphate, 1:1: 0.1) was
studied as a means of improving the extent of celecoxib absorption, compared to a
conventional marketed celecoxib capsule in human volunteers (Nasr 2010).
Furthermore, due to great progress in biotechnology, the pharmaceutical
industry can produce a large number of potential therapeutic proteins and peptides
in high quantities. The main features of many therapeutic molecules are hydrophilicity, susceptibility to degradation by gastrointestinal enzymes, and the acidic pH of
the stomach. Those features are responsible for the low oral bioavailability experienced with these products. An investigation was initiated to determine if niosomes
might stabilize these molecules in the gastrointestinal tract and improve their
permeation through the intestinal mucosa. In an in vitro study conducted by Yoshida
et al. (
1992) on a vasopressin derivative entrapped in niosomes, it was shown that the
entrapment of the drug in niosomes significantly increased the stability of the
peptide, in an intestinal loop model.
2013).
2009). Niosomes prepared from Span
2012).
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Recently, new Glutatione-loaded niosomes were prepared by E. M. Aboubakr
et al. not only to enhance the bioavailability, but also the hepatic tissue uptake and
hepatoprotective activity of glutathione (Aboubakr et al. 2021).
3.6.2 Intravenous Delivery
Niosomes can be delivered by the intravascular route. The benefit of administering
the drug via the i.v. route is that drugs get entry directly into the systemic circulation,
niosomes enhance the stability of the drug, and niosomes prolong its duration in the
blood. Furthermore, the drug can also be delivered to a targeted site with some
modifications. Haroun et al., for example, prepared PEGylated niosomes of Brucine
to increase the therapeutic efficacy of the drug (Haroun et al.
2022).
3.6.3 Ocular Delivery
Topical ocular drug delivery is one of the commonly used and preferred routes for
treating conditions that a ffect the anterior segment of the eye (cornea, conjunctiva,
sclera, iris, and lens). However, there are many anatomical and physiological barriers
and a strategy to cross these barriers is required.
Mucoadhesive niosomal ophthalmic formulations of acetazolamide (Aggarwal
2007) and timolol (Aggarwal and Kaur 2005; Kaur et al. 2010) have been
et al.
studied and compared to marketed formulations, in order to reduce intraocular
pressure. Furthermore, Span 60-based giant oval niosomes were reported to be
capable of enhancing the corneal permeation of naltrexone hydrochloride, while
also being practically non-irritant (Abdelkader et al.
lations, prepared using various surfactants (Tween 60, Tween 80 or Brij 35), showed
a controlled in vitro release of gentamicin (Abdelbary and El-gendy 2008).
Recently Y. Xue et al. have studied Latanoprost-loaded Niosome-laden contact
lenses to increase the drug loading and provided extended release up to 96 h without
altering the opto-physical properties of the contact lens (Xue et al. 2022).
2011). Finally niosomal formu-
3.6.4 Dermal and Transdermal Delivery
The slow penetration of drugs through the skin is the major draw back of the
transdermal route of delivery. In the last decade, several studies have been performed
to evaluate the effect of niosomes on the dermal and transdermal delivery of different
active substances. The transdermal field has seen some promising data emerge.
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Some examples of applications include the transdermal or dermal delivery of
gallidermin (Manosroi et al. 2010), terbinafine (Sathali and Rajalakshmi 2010),
curcumin (Gupta and Dixit 2011), vinpocetine (El-Laithy et al. 2011), elagic acid
(Junyaprasert et al.
2012), ammonium glycyrrhizinate (Marianecci et al. 2012). The
potential clinical benefit associated with the use of niosomes is widely recognized in
dermatological therapy. Indeed, clinical trials for the treatment of acne (Mohammadi
2017)
and Mohebbi
zadeh
(Faraj
et
, psoriasis (Lakshmi and Bhaskaran
al.
2018a, b),
warts (Farajzadeh et al.
ulcers (Arafa and Ayoub 2018 ) are ongoing.
A clinical trial to evaluate the efficacy of Papilocare
lesions caused by HPV has been proposed. Papilocare
ingredients: hyaluronic acid niosomes, β-glucan (magnolol, honokiol, and
carboxymethyl betaglucan) niosomes, BioEcolia
®
(Alpha-oligoglycan), Coriolus
2011),
2018a, b), and oromucosal
®
gel in the repair of cervical
®
consists of the following
leishman
iasis
versicolor, Azadirachta indica (Neem) extract, Centella asiatica, and Aloe vera
(Combalia
2019).
Additionally, pH-sensitive niosomes composed of Tween 20 or Span 60 mixed
with cholesterol and cholesteryl hemisuccinate (CHEMS) have been used for the
topical delivery of ibuprofen. When niosomes with Span 60 and CHEMS were
prepared, there was a statistically significant increase in the in vitro skin permeation
of the drug (Carafa et al.
elastic niosomes (Di Marzio et al.
2009). To enhance the trans dermal adsorption of drugs,
2012; Manosroi et al. 2008c, 2009, 2011) and
niosome-loaded hydrogel systems (Antunes et al. 2011; Lakshmi et al. 2007;
Marianecci et al. 2011) have also been used.
Topical immunization is novel and as such needle-free strategies involving
vaccine delivery through topical application of the antigen and adjuvants directly,
or via a suitable carrier system, to intact skin, have been studied, with niosomes
exploited for topical immunization (Maheshwari et al.
2011; Mahor et al. 2007).
3.6.5 Pulmonary Delivery
In inflammatory diseases, infections or cancer of the respiratory tract, the therapeutic
value of pulmonary administration may exceed that of oral or parenteral administration since the area affected is directly reached by the drug. In diseases characterized by bronchial mucus hypersecretion, lipophilic substances, such as
corticosteroids, are remarkably impeded from reaching their receptors, which are
localized within the cytoplasm of bronchial epithelial cells. Niosomes have been
used to circumvent this problem (Marianecci et al. 2010; Terzano et al. 2005).
Recently, Span and Tween niosomes were studied for the pulmonary delivery of
anti-tuberculosis drugs (Jatav et al. 2011; Mehta et al. 2011; Moazeni et al. 2010;
El-Ridy et al. 2011).
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Niosomes prepared by mixing span 60 and cholesterol in a 1:1 molar ratio,
entrapping salbutamol sulphate, have been proposed to be packaged into metered
dose inhalers (MDI), offering a novel approach to respiratory delivery (Arafa et al.
2018).
3.6.6 Nose-to-Brain Delivery
The use of the nose-to-brain delivery route is an important and non-invasive method
of drug delivery to bypass the blood–brain barrier (BBB). In fact, there is an
intranasal direct anatomical connection between the nasal cavity and the central
nervous system (CNS) and it is possible because of the direct transport of the drug to
the brain by the olfactory and trigeminal nerve pathways (Giunchedi et al.
Drug adminis tration via the nasal route also bypasses hepatic first pass metabolism, results in quicker onset of action, necessitates lower doses, and, over all,
produces fewer side effects.
Niosomes has been used to deliver bromocriptine by this route (Sita et al. 2020),
olanzapine (Khallaf et al. 2020), and valproic acid (Chaudhari and Chatur 2013).
Finally, chitosan glutamate-coated niosomes loaded with pentamidine were prepared
to enhance the mucoadhesive properties of the niosomes (Rinaldi et al. 2018) and for
the treatment of Parkinson’s disease in mice (Rinal di et al. 2019a, b).
2020).
3.6.7 Anti-neoplastic Therapy
One of the advantages of the drug loading in a niosome is the selective delivery of
cytotoxic agents to the tumour site; this has been associated with a decrease in toxic
effects. Drug-loaded nanovesicles have been shown to improve the therapeutic outcome
of traditional chemotherapeutics by altering drug pharmacokinetics and biodistribution.
For example, the intravenous administration of hydroxycamptothecin (HCPT),
entrapped in niosomes, to S-180 tumour-bearing mice resulted in total regression of
tumours, higher plasma drug levels, and slower drug elimination when compared to the
drug in solution (Shi et al. 2006).
Niosomes have also been used in melanoma therapies (Cosco et al. 2009; Gude
et al. 2002; Paolino et al. 2008).
New nanohybrid systems composed of non-ionic surfactants inserted within
liposomes, which were then loaded with paclitaxel (PTX), were prepared to overcome multidrug resistance in PTX-resistant human lung cancer cell lines. Three
non-ionic surfactants: Solutol
inserted into liposomes. The apoptotic assay and the cell cycle analysis showed
that the nanohybrid systems could induce more apoptotic cells in drug-resistant cells
when compared with liposomes (Ji et al. 2012).
Rectal dexmedetomidine-loaded niosomes have been proposed for postoperative
analgesia in paediatric cancer patients (Hala and Sahar
®
HS 15, Pluronic F68, and Cr emophor EL were
2022).
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3.6.8 Drug Targeting
3.6.8.1 The Reticulo-Endothelial System (RES)
After intravenous administration, the lipid and surfactant vesicles are surrounded by
blood components including many types of circulating serum factors known as
opsonins which mark them for clearance by RES macrophages.
Niosomes may be used to target drugs in the treatment of diseases in which the
infecting organism reside in the organs of RES; diseases such as leishmaniasis. The
study of antimony distribution in mice, performed by Hunter et al. (
high liver levels of the drug after intravenous administration of the carrier forms of
the drug, without damage to the heart and kidney.
More recently, Span 60/Tween 61 niosomes conjugated with a purified monoclonal antibody against the CD44 receptor were proposed for immuno-targeting
(Hood et al. 2007) and ‘hybrid’ Tween 20 niosomes were reported to show intrinsic
selectivity towards macrophages (Agrati et al. 2011).
3.6.8.2 Organs Other Than RES
Glucose and transferrin conjugation to nioso mes enhance vesicle distribution to the
brain (Dufes et al. 2004) and solid tumours (Hong et al. 2009).
To obtain a potential brain targeted delivery system for the anticancer agent
doxorubicin, a niosomal formulation was functionalized by N-palmitoyl glucosamine. The intravenous administration to rats of these NPG-niosomal formulations
reduced drug accumulation in the heart, prolonged drug residence time in the blood
and enhanced the concentration in the brain, when compared to the commercial
formulation (Bragagni et al. 2012).
To deliver the drug only to the glioblastoma cells and avoid the normal brain
tissue damage, for example, De et al. modified the niosome surface with a targetspecific peptide: chlorotoxin, that has a high affinity for brain specifically gliomas
(De et al. 2018).
1988), showed
3.6.9 Immunological Applications
Niosomes have been used to study the nature of the immune response to antigens.
Brewer and Alexander (1992) have reported niosomes as potent adjuvants as they
were shown to demonstrate immunological selectivity and low toxicity.
Span niosomes have also been studied as DNA vaccine carriers, after conjugation
with o-palmitoyl mannan (Jain et al.
2005; Vyas et al. 2005).
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3.6.10 Gene Delivery
Gene therapy has been studied intensively as a possible treatment for a variety of
inherited or acquired disorders. The success of gene therapy is highly dependent on
the delivery vector, used for the gene. Although niosomes have been applied in
pharmaceutics since the 1980s, only a few reports have focused on their application
as vectors for gene delivery. To be used as vectors, the niosomes need to incorporate
charged moieties into the bilayer. Cationic niosomes (also called Nioplexes) are
made up of several elements including a non-ionic surfactant, cholesterol or squalene, and a cationic lipid (Grijalvo et al.
been used as carriers for plasmid (Manosroi et al. 2008b) and oligonucleotide
delivery (Huang et al. 2008, 2011). Recently, S. Grijalvo et al. also used hydrogels
to encapsulate cationic nioplexes to deliver nucleic acids (Grijalvo et al.
N. Attia et al. have prepared cationic niosomes for bone regeneration (Attia et al.
2018), and M. Mashal et al. proposed nioplexes for gene delivery to central nervous
system cells (Mashal et al. 2018). This kind of system has been used also for gene
delivery to retina (Al Qtaish et al. 2020).
Recently, nanodiamonds have shown to be a promising material for gene delivery
also thanks to their possibility of combination with other non-viral system like
niosomes. The ‘nanodiasomes’ may be used as a potential non-viral gene delivery
nanoplatform for therapeutic applications in the treatment of central nervous system
diseases, for example (Al Qtaish et al. 2022).
2019). For example, cationic niosomes have
2017),
3.6.11 Diagnostic Agents
Nanocarrier-mediated delivery has emerged as a means of enhancing the delivery of
imaging agents to tumours, thereby increasing the potential for diagnosis at an earlier
stage. It has been shown that the combination of PEG and glucose conjugates to the
surface of niosomes significantly improved tumour targeting of an encapsulated
paramagnetic magnetic resonance imaging in a human carcinoma xenograft model
(Luciani et al.
2004).
3.6.12 Theranostic Agents
The combination of diagnostic and therapeutic agents encapsulated into niosomes
has been reported. It allows the loading of various molecules such as imaging and
therapeutic agents and also allows the release at a specific target site, leading to
reduced side effects and reduced toxicity (Demir et al. 2018).
Yang et al. have developed a theranostic platform composed of indocyanine
green in a vesicle comprising Span 80 and a cationic lipid to deliver small RNAs
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to human mesenchymal stem cells and promote differentiation and specifically label
the transfected cells for in vivo tracking purposes (Yang et al. 2018).
3.6.13 Essential Oils Delivery
Essential Oils (EO) extracted from aromatic plants have demonstrated therapeutic
properties, together with low toxicity and fewer environmental effects. The risks of
using synthetic chemicals has increased public awareness and demand for safer and
eco-friendly products and natural plant extracts are now considered good alternatives. However, some EO compounds are highly volatile and the use of a niosomebased EO product could be a useful way to extend an EO product’s shelf life and
preserve its activity (García-Díaz et al.
Trinh et al. have incorporated the Trachyspermum copticum essential oil into
niosomes to test their potential application for cancer therapy (Trinh et al. 2019).
Niosome-based EOs also have been evaluated for their efficacy in the treatment of
pathologies such as Alzheimer’s disease (Ansari and Eslami
exploiting their antioxidant and anti-inflammatory activities (Leelarungrayub et al.
2017). These EO-based niosomes have also been evaluated for their mosquito
larvicidal properties (Aswin Jeno et al. 2018).
2019).
2020); in effect,
3.6.14 Multifunctional Niosomes
In recent years, the concept of an active agent-controlled release system, from which
encapsulated compounds are delivered at the right time and place and in the desired
concentration, has become one of the challenges in developing new active compound delivery devices for different applications both in the pharmaceutical and
food industries. For this reason, diff erent strategies have been proposed and different
systems incorporated in niosomes, such as adding β-cyclodextrin to the niosomes to
improve the hydroph obic compound encapsulation (Machado et al. 2018), magnetizing and PEGylating the niosomes to target specific tissues and to increase the
bioavailability of niosomes (Davarpanah et al. 2018) or formulating a hybrid
niosomal thermosensitive in situ forming gel (Gugleva et al.
2022).
3.7 Final Considerations
Niosomes have been extensively studied as an alternative to liposomes. Niosomes
have some advantages over liposomes, such as their relatively higher chemical
stability, improved purity, and relatively lower cost in comparison with liposomes.
The niosome bilayer is different from the liposome bilayer in that niosomes are
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