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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5888_Библиотеки_им_академика_М_И_Перельмана
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12 M.-C. Jones
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suggested that a more elongated shape could be advantageous for drug delivery
applications (Geng et al. 2007).
Most phospholipids and double-tailed surfactants will adopt a truncated cone
shape (1/2 ≤ CPP ≤ 1) and self-assemble into spherical bilayer vesicles (liposomes).
The addition of a hydrophilic co-surfactant (e.g. polysorbate 80 or sodium cholate)
can trigger a reversible transition from vesicle to spherical micelle (Haustein et al.
2015; Kunz et al. 2009; Mkam Tsengam et al. 2022). An intermediate morphology,
so-called bicelles, can also be generat ed which could be described as disk-shaped or
flattened bilayer vesicles. Bicelles have been suggested as cell membrane models
and have been investigated as nanomedicines in cancer and transdermal administration (Diller et al. 2009; Lin et al. 2016; Rubio et al. 2014).
Planar open lamellar assemblies are obtained when CPP ≈ 1, while highly
hydrophobic amphiphiles will only assemble in apolar solvents to form inverted or
reverse micelles (Table
2.1). Other, more complex morphologies have also been
observed from chiral LMWAs, including helices, microtubules and ribbons (Ghosh
2020). Any of the structures described can further aggregate as the concentra-
et al.
tion of the amphiphile is increased, leading to the formation of various mesophases ,
including cubic, bicontinuous cubic, hexagonal and lam ellar phases (Aveyard
2019).
This discussion of the relationship between LMWA properties and the shape of their
supramolecular structures highlights the versatility of these small molecules and how
simple modifications and careful design can allow control over the properties of the
self-association process.
2.3.1 Thermodynamics of Self-Association
The thermodynamic principles underpinning the self-assembly of LMWAs are more
easily described using spherical micelles as a model. Amphiphiles with the correct
geometry will self-assemble into micelles above a minimum concentration, the
critical micelle concentration (CMC). The micellisation process can be described
in simple thermodynamics terms using the Gibbs–Helmholtz equation (Eq. 2.2):
¼ ΔHm- T ΔS
ΔG
where ΔG
m
, ΔHm, ΔSm represent the change in the Gibbs free energy, enthalpy and
m
m
entropy, respectively, resulting from micellisation at a given temperature, T.
For most LMWAs, micellisation produces an unfavourable change in enthalpy
resulting from the steric or electrostatic repulsion between closely packed non-ionic
or ionic polar heads (Aveyard 2019). The negative impact of these changes is,
however, exceeded by the substantial gain in entropy associated with the release
of water molecules that no longer need to maintain a rigid structure around the
hydrophobic tail. Therefore, for surfactants, micelle formation is considered spontaneous and entropy-driven (Aveyard 2019).
For non-ionic surfactants, the Gibbs free energy is related to the CMC (Eq.
ð2:2Þ
2.3):
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ΔGm ¼ RT x lnCMC ð2:3Þ
where the CMC is expressed in M or as the molar fraction of surfactant. A similar
equation has been suggested for ionic surfactants that considers the degree of
ionisation and contribution of the counterion (Rosen and Kunjappu
2012).
In dilute solutions, micelles exist in a dynamic equilibrium with free monomers
(Patist et al. 2001). Above the CMC, extra surfactant molecules will partition
preferentially inside the micelle and thus, an increase in concentration will result
in an increase in the size and/or number of micelles up to a point (Aveyard 2019).
The aggregation number (N)defines the number of surfactant molecules forming the
micelles. For each morphology described previously (Table
2.1), it is also possible to
estimate the maximum aggregation number (i.e., the maximum number of amphiphilic monomers present in the aggregated structure, N
(Nagarajan 2002). For spherical micelles, once this number is reached, the micelles
l
c
) from the values of v0 and
max
shape may shift to worm-like micelles that can accommodate the excess monomers.
2.3.2 Characterisation of Self-Assembled Structures
For micelle-forming amphiphiles, a variety of methods can be used to determine the
CMC (Mabrouk et al.
change at the onset of micellisation can be used. Each method has its own limitations, and some require specialist equipment that may not be readily available.
Methods based on surface tension are simple and useful for a variety of LMWAs,
provided these are sufficiently surface-active, while changes in conductivity only
apply to ionic LMWAs (Aveyard
polarity-sensitive, often poorly soluble probes that can affect the micellisation
process and cause the CMC to be underestimated (Zhao et al. 2017). Despite this,
fluorescence is often the method of choice to study the micellisation process. In
addition to the CMC, light scattering-based techniques can provide informat ion on
micelle size, shape and aggregation number (Corti and Cantú
information on the kinetics (relaxation) of micellisation can be gained from smallangle neutron (SANS) or X-ray (SAXS) scattering experiments (Gradzielski 2003).
For liposomes and other bilayer assemblies, information on the properties of the
bilayer can be gained from NMR, differential scanning calorimetry and SANS/
SAXS experiments (Alahmadi et al. 2022; Mineev et al. 2016). For all structures,
isothermal titration calorimetry can be used to study the thermodynamics of the selfassembly process.
2022). In theory, any solution property experiencing a sharp
). Popular fluorescence-based methods use
2019
1990) while additional
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2.3.3 Factors Affecting the Critical Micelle Concentration
2.3.3.1 Surfactant Properties
The properties of the polar head and hydrophobic tail can affect the CMC, though the
impact of the latter is considered more important. In a homologous series of
surfactants, where the nature of the polar head is constant, the CMC is expected to
decrease with an increase in alkyl chain length (up to 16 carbons) for both ionic and
non-ionic surfactants. Adding aromatic rings or substituting hydrocarbons for fluorocarbons can both decrease the CMC by increasing hydrophobicity; while
branching or adding double-bonds or polar groups along the tail all increase the
CMC (Menger et al. 2005; Rosen and Kunjappu 2012).
The impact of alkyl chain length on the CMC can be summarised by Kleven’s
equation (Klevens 1953) (Eq. 2.4):
log CMCðÞ¼ A - Bm ð2:4Þ
where A is a constant for a particular polar head and B is a constant set at ~0.3 and 0.5
for single-tail ionic and non-ionic surfactants, respectively, and m is the number of
carbons in the hydrophobic tail.
The size, position and composition of the polar head can also influence
micellisation: ionic amphiphiles tend to have higher CMCs compared to equivalent
zwitterionic or non-ionic amphiphiles (Aveyard 2019). For polyoxyethylenated
surfactants, increasing the length of the polar chain can increase the CMC, though
not to the same extent as lengthening the hydrophobic tail.
2.3.3.2 Solution Properties and Temperature
For ionic LMWAs, the CMC will vary depending on pH (ionisabl e head groups),
ionic strength and radius of the hydrated counterion. In contrast, the impact of
temperature can b e harder to predict. The decreased hydration of the polar head at
higher temperature would predict a decrease in CMC for non-ionic surfactants.
However, temperature also disrupts the structure of water in the bulk, which can
weaken the entropy gain (Rosen and Kunjappu
2.4 Applications in Pharmaceutical Nanoscience
LMWAs are common excipients in drug formulation, and many have GRAS (generally recognised as safe) status. Many compounds within that class are added to
conventional dosage forms to improve the wetting of powders or stability of
dispersed systems (Sheskey et al. 2020). Their ability to form water-soluble micellar
2012).
2 Low-Molecular Weight Amphiphiles 15
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structures with a fluid hydrophobic core allows LMWAs to be used as solubilityenhancers, though their potency will depend on the chemistry of the amphiphile and
on the properties of their supramolecular structures. To some extent, this also applies
to phospholipid vesicles, though their capacity for poorly soluble drugs will be lower
compared to micelles and membrane properties also need to be considered. Phospholipids will not be covered in this section, but it shou
lipids, mainly lecithin,
particularly emulsified delivery systems and can be combined with other LMWAs
to generate mixed surfactant-lipid nanocarriers in water (Klang and Valenta
Mehmood and Ahmed 2020).
Drug-loaded micelles are easily prepared from various LMWAs. Historically, a
‘shake-flask’ method has been used to load drugs into micelles. In this method, the
drug in solid form is added to an aqueous micelle solution; unencapsulated drug can
then be removed by filtration or centrifugation. For solid LMWAs with a suitable
melting point, the surfactant can be heated and the drug, added to the molten
amphiphile, in a process referred to as ‘melt loading’. Alternatively, a solution of
the drug and LMWA can be prepared in a volatile, organic solvent which is then
exchanged for water (dialysis) or evaporated and re-hydrated (thin film hydration) to
produce a clear mic ellar solution. In both cases, the free drug can be removed by
filtration. However, one should carefully select the organic phase used for drug
loading to avoid issues with a potentially toxic residual solvent.
In addition to their use as solubilisers, LMWAs can also act as permeation
enhancers. Indeed, their amphiphilic character allows them to interact with cell
membranes and facilitate drug absorption. This propensity to disrupt membranes is
directly linked to their amphiphilic character and represents a double-edged sword as
it can also lead to adverse effects including haemolysis. Although the exact mechanism is poorly understood, it is generally accepted that surfactant concentration,
hydrophobicity, micelle size and charge all affect haemolytic potential (Agarwal
et al. 2021; Manaargadoo-Catin et al. 2016; Ohnishi and Sagitani 1993). Consequently, haemolytic activity testing should be a must to establish the full biocompatibility profiles of any new LMWAs and ensure their safe use in the clinic.
are commonly added to a variety of nanomedicines,
ld be noted that phospho-
2011;
2.4.1 Synthetic Surfactants
2.4.1.1 Non-ionic Surfactants
We have already discussed the classification of amphiphiles based on their molecular
geometry and how this affects self-assembly. The amphiphilicity of LMWA can also
be described in terms of their hydrophilic-lipophilic balance (HLB). The HLB scale
was first suggested to support the selection of surfactants for the formulation of
emulsions (Griffin 1949 ). The lower the HLB value, the more lipophilic the surfactant, making it more useful for the stabilisation of water-in-oil emulsions; these low
HLB surfactants are too insoluble to form micelles in water, but can form reverse
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Fig. 2.2 Structure of selected synthetic surfactants
micelles in apolar solvents (Naoe et al. 1998). Sorbitan fatty acid esters (Span
series) are well-known examples of low HLB surfactants (Fig. 2.2). In pharmaceutical nanoscience, sorbitan esters have been used in the formulation of niosomes
(Roque et al.
combination with hydrophilic surfactants.
Polysorbates (polyoxyethylene sorbitan fatty acid esters; Tween
2020; Yoshioka et al. 1994) and other emulsified nanosystems, often in
®
series) are
found at the higher end of the HLB scale. Polysorbates self-assemble into spherical
micelles in water. As expected, within an homologous series, the CMC of polysorbates decreases with the lengt h of the alkyl chain, but increases with the size of
the polar head; the presence of a double-bond tended to decrease the CMC compared
to the saturated equivalent (CMC 14 mg/L vs. 28 mg/L for polysorbate
80 (oleate) vs. polysorbate 60 (stearate )) (Dafer and May Essa 2013). The CMC
was also shown to decrease with increases in temperature as a result of the dehydration of the polyoxyethylene polar head (Dafer and May Essa
2013; Sheskey et al.
2020).
Most polysorbates are FDA-approved, with polysorbate 80 being a common
excipient in parenteral formulations, including those containing biologicals. Polysorbate 80 has been used as a micellar solubiliser for amiodarone (with benzyl
alcohol), doxercalciferol (Hectorol
®
in the US) and docetaxel (Taxotere® , with
ethanol). However, concerns over hypersensitivity and severe anaphylactoid advers e
reactions linked to polysorbates have prompted the development of new surfactantfree formulations (Schwartzberg and Navari
linked to the use of polyoxyethylenated castor oil in the formulation of paclitaxel
®
(Taxol
co-medication. Cremophor EL
) (Nan 2015) and informed recommendations for prophylactic
®
is part of the macrogol ether class of surfactants
(Fig. 2.2), which also includes the Brij
2018). Similar adverse events have been
®
series, often used in the formulation of
®
2 Low-Molecular Weight Amphiphiles 17
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niosomes (Bhardwaj et al. 2020) and macrogol 15 hydroxystearate (polyoxyl
15 hydroxysterate, Kolliphor
®
HS15). The latter has been used as a micellar
solubiliser and is also used in the formulation of other nanomedicines, notably
lipid nanocapsules (Huynh et al.
2009).
It should be noted that many of the non-ionic surfactants listed above have been
shown to inhibit the P-glycoprotein efflux transporter and modulate cytochrome
P450 and thus, could increase drug absorption and accumulation through mechanisms other than solubilisation (Gurjar et al.
2018; Sheskey et al. 2020).
2.4.1.2 Ionic Surfactants
The use of ionic surfactants in pharmaceutical nanoscience is somewhat limited,
although both cationic and anionic surfactants are found in a range of personal care
and cleaning products (Sheskey et al. 2020). Cationic surfactants generally have
either a quaternary ammonium or pyridinium and possess antibacterial properties;
many, for example benzalkonium chloride, are used as preservatives in drug formulations. Of the anionic surfactants, sodium dodecyl sulphate (SDS) is probably the
best known, partially due to controversy surrounding its use in consumer care
products (Fig.
2.2). Both cationic and anionic surfactants have been used in combi-
nation with non-ionic amphiphiles in the formulation of nanomedicines, including
mixed-surfactant micelles and niosomes (Chaikul et al.
Shen et al.
2019). Some have also suggested the synthesis of catanionic surfactants
2019; Gerber et al. 2005;
(combination of a cationic and anionic surfactant) by combining cetrimonium
bromide and SDS. Although these surfactants can self-assemble, stability may be
an issue and their usefulness for drug delivery needs to be con firmed (Mahiuddin
et al.
2009).
2.4.2 Bile Salts
Bile acids (BAs) or bile salts are natural LMWAs. At physiological pH, BAs exist in
their ionised anionic form with a cationic counterion (often Na
terms BAs and bile salts can be used interchangeably. Bile salts are broadly
classified as primary or secondary, depending on whether they are directly
synthesised from cholesterol in the liver or result from secondary metabolism by
gut bacteria (di Gregorio et al. 2021). Bile salts are further classified based on the
number, position, orientation of their hydroxyl group(s) and nature of the conjugated
amino acid (Fig. 2.3).
Although in many ways, bile salts behave as other LWMAs, their peculiar
chemistry gives rise to some interesting differences. Contrary to surfactants and
phospholipids, the hydrophobic and hydrophilic regions of bile salts are less spatially segregated as the hydroxyl functions are held close to the steroid backbone
(Pavlović et al. 2018). Moreover, the rigidity of the backbone forces bile salts to
+
) consequently, the
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Fig. 2.3 Chemical structure of bile salts and self-assembly into micelles. (a) Structure formula of
bile acids; (b) 3D-structure of conjugated bile salts. The dashed line represents the curvature of the
structure which is also shown in (c) cartoon representation of a bile salt monomer with the
hydrophobic region on the convex side (grey) and hydrophilic moieties on the concave face
(white). The conjugated amino acid is drawn as a circle. Two or more bile salts monomers can
associate at concentrations close to the CMC to form primary micelles. (Adapted from Madenci and
Egelhaaf (2010))
adopt a slightly curved shape which is hydrophobic on the convex side and hydrophilic on the concave face (Fig.
2.3). This particular arrangement also means that bile
salts are not as surface-active as other surfactants (Pavlović et al. 2018).
Despite these differences, bile salts do self-assemble in aqueous environments to
form micelles (di Gregorio et al. 2019). However, the transition from monomers to
micelles is not as sharp as for other surfactants. In fact, the micellisation of bile salts
has been described as a ‘stepwise aggregation process’ (Carey and Small
1972)
which happens over a range of ‘non-critical multimer concentrations’ (Roda et al.
1983). Consequently, self-assembly cannot be defined by a single value and tradi-
tional techniques may not be as useful when study ing bile salt micelles. One of the
earliest models described the formation of primary and secondary micelles where, at
concentrations close to the ‘CMC’, hydrophobic interaction drives the initial formation of primary micelles which can accommodate up to 10 monomers. This loose
assembly is then consolidated through the formation of hydrogen bonds between
hydroxyl functions on adjacent monomers (Fig. 2.3) (Madenci and Egelhaaf 2010;
Natalini et al. 2014; Small 1968).
Fundamental differences exist between bile salt micelles and those obtained from
conventional surfactants. For example, bile salt micelles are generally smaller than
surfactant micelles (lower aggregation number 2–20 vs. 50–100) and have a more
rigid core. They also tend to be more polydisperse and have faster dynamics, making
them harder to study (Madenci and Egelhaaf
2010; Natalini et al. 2014; Pavlović
et al. 2018). The increased rigidit y of the ster oid backbone (vs. linear chain) results
in a loosely packed micelle core which could allow some water penetration, making
the core less hydrophobic and the CMC higher than for other surfactants. This also
2 Low-Molecular Weight Amphiphiles 19
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has the potential to affect solubilisation properties and their efficacy as drug delivery
systems (Madenci and Egelhaaf 2010; Wiedmann and Kamel 2002 ).
The association of bile salts mostly varies as expected with hydrophobicity.
However, the orientation, not just number, of OH groups matter as cooperative
hydrogen bonding also contributes to micellisation. UDCA has one hydroxyl group
in an unfavourable β-position and associates at higher concentrations than DCA,
despite both being dihydroxyl bile salts (Fig.
2.3). Conjugation also affects
micellisation: unconjugated bile salts assemble at higher concentrations than glycine
and taurine conjugates. Like other amphiphiles, the micellisation process can be
affect by external factors, including ionic strength and pH and, to a much lesser
extent, temperature. As expected, increasing ionic strength decreases the CMC, so
does a decrease in pH but only so far as pH affects the degree of ionisation of the BS
(Madenci and Egelhaaf 2010).
2.4.2.1 Pharmaceutical Applications
®
Bile salts have been used as therapeutics agents (e.g. UDCA in Ursofalk
) and can
be used as ligands for active targeting of nanomedicines (Deng et al. 2022; Kim et al.
2018; Kou et al. 2018). Many studies have also suggested that UDCA could act as a
chemo-preventive and chemotherapeutic agent in colon cancer (Huang et al. 2016;
Zhang et al. 2021).
Fungizone
®
, a DCA micelle formulation of Amphotericin B, is probably the bestknown example of the use of bile salts in nanomedicine. However, this formulation
has been linked to severe toxicity, likely caused by poor retention of the drug within
the core, though this also could result from inherent DCA toxicity (Brajtburg and
Bolard
1996). Interestingly, adding lecithin to Fungizone
®
could help increase
specificity and decrease toxicity (Brajtburg et al. 1990, 1994). Hydrophobic BAs
have been associated with liver injury and, confusingly, colon cancer progression
which should be borne in mind when designing nanom edicines and trying to balance
loading efficiency and toxicity (Attili et al. 1986; Farhana et al. 2016). New
developments using bile salts include bilosomes (Mondal et al. 2022), which could
be an alternative to liposomes and niosomes for the oral administration of poorly
soluble drugs or vaccines (Shukla et al. 2016).
2.4.3 Self-Assembling Peptides
Amphiphilic peptides represent an exciting development in LMWA research. The
ability to harness peptides’ natural tendency to organise into complex structures
stabilised by weak forces makes them ideally suited. Amino acids (natural or
synthetic) can be used as building blocks to produce a diverse array of biodegradable, biocompatible amphiphiles with tunable properties. Amphiphiles can be made
solely from amino acids or obtained through conjugation of a peptide with an alkyl
20 M.-C. Jones
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chain generating surfactant-like peptides (SLPs) or peptide amphiphiles (PAs),
respectively. Furthermore, the purposeful selection of a bioactive peptide epitope
can confer therapeutic activity or allow active targeting. The latter strategy has been
exploited to improve accumulation in the brain (Mazza et al.
2013) or atherosclerosis
plaques (So et al. 2018), target the tumour microenvironment (Ji et al. 2015) or boost
the immune response (Rudra et al.
important to desig
n the amphiphilic peptide carefully to ensure that the active
2010). However, if used for this purpose, it will be
epitope maintains the correct secondary structure, is accessible and can bind to its
target.
The self-assembly of amphiphilic peptides will be driven mostly by the hydrophobic effect and hydrogen-bonding and can be assessed using similar methods as
for common surfactants. Additionally, techniques such as circular dichroism,
neutron/X-ray scattering are commonplace, reflecting the importance of the secondary structure of the peptide. In many cases, the self-assembly process can be made
stimuli-responsive which offers further opportunities in drug delivery (Zeng et al.
2021).
The exact morphology of the self-assembled nanostructures will mostly depend
on composition, concentration and molecular geometry. In most cases, the presence
of amino acids with strong β-sheet-forming abilities will force the self-assembled
structure to adopt a cylindrical (e.g. nanofibers and nanotubes), rather than spherical
shape (Paramonov et al.
2006). Sis and Webber (2019) have reviewed the use of self-
assembling peptides for drug delivery, showcasing their versatility and efficacy as
carriers for both small and macromolecular therapeutics. Stimuli-responsive and
actively targeted systems can be obtained easily through careful design of the
peptide sequence. The same review also highlights potential pitfalls that need to
be addressed before self-assembling peptides can fulfil their promise in pharmaceutical nanoscience (Sis and Webber 2019). Of particular concern is the risk of
immunogenicity which has been linked to properties that also make self-assembling materials desirable for pharmaceutical applications. This re-enforces the
importance of careful design when developing new amphiphilic materials.
2.4.3.1 Surfactant-Like Peptides
Surfactant-like peptides (S LPs) as the name suggests share the head-and-tail structure of conventional surfactants (Fig.
C- or N-terminal and self-assembly can be controlled by varying the length of the
hydrophobic tail and/or size or location of the polar head. Often, a single amino acid
will be repeated in the tail (e.g. Leu
or two amino acid(s) with the same charge (Li et al.
length of the hydrophobic tail is limited to 6–8 amino acids which allows them to
mimic the molecular dimensions of phospholipids, but also avoid issues with
polydispersity and immunotoxicity (Qiu et al.
been shown to produce a diverse array of morphologies, which can be fined-tuned by
2.4). The polar head can be located at either the
), while the polar head is typically made of one
6
2020). For many SLPs, the
2018). Self-assembly of SLPs has
2 Low-Molecular Weight Amphiphiles 21
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Fig. 2.4 Structure of a surfactant-like peptide (SLP). SLP are head-and-tail molecules obtained by
combining short sequences of hydrophilic (left) and hydrophobic (right) amino acids to provide the
right balance of amphiphilicity. A selection of natural amino acids for both the polar head and
hydrophobic tail is shown
adjusting the pH (for cationic SLPs) or adding organic cations (Castelletto et al.
2020; Hamley et al. 2016).
Cationic SLPs, particularly with arginine-rich polar heads have been investigated
for their cell-penetrating and antimicrobial activity (Castelletto et al. 2018). Geminiand bola-SLPs have also been evaluated and compared to more conventional headand-tail equivalents. Peng et al. (2021) compared linear A6K SLP to its gemini
equivalent (APK); the latter was characterised by a cationic polar head consisting of
two lysine molecules, each attached to an hexa-alanine tail via a proline linker
2.5). In addition to having a lower CMC, APK demonstrated a higher encap-
(Fig.
sulation efficiency compared to A6K when pyrene was used as a model . In vitro,
paclitaxel-loaded APK showed similar activity to Taxol
alternative to the current formulation (Fig.
2.5). Interestingly, although at high
®
and may be a safer
concentrations both SLPs formed nanofibers, in more dilute solutions, APK could
also form nanosheets (Peng et al.
2021). Research into bola-SLPs would sugges t that
such nanosheet morphology would not be effective for drug delivery. Indeed, bolashaped cationic Arg
-Phe4 exhibited lower cellular uptake compared to their linear
4
equivalent. It was hypothesis that this resulted from a difference in morphology with
the linear and bola-SLPs assembling into spherical/cylindrical structures and flat
nanotapes, respectively (Mello et al. 2020).
2.4.3.2 Peptide Amphiphiles
Conjugation of an alkyl chain to a polar peptide head is a simple method to generate
peptide amphiphiles (PA), though PA must be desig ned carefully to optimise the
self-assembly process. Pioneering work by Stupp et al. helped establish a framework
for the design of peptide amphiphiles, highlighting the intricate relationship between
chemical structure and PA self-assembly (Sato et al.
and others showed how amino acid selection can be adapted to obtain various, and
sometimes unexpected, shapes. Simple modifications, for example, introducing a
2018; Stupp 2020). This work
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