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2 I. F. Uchegbu
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Fig. 1.1 Pharmaceutical nanotechnology and its application to medicine. (Prepared using
Biorender)
self-assemblies/nanoprecipitates present as nanoparticles of 10–800 nm in diameter.
Some nanosystems, such as the polymer drug conjugates (Duncan 2003), present as
molecular entities
in solution but on administration behave like a nanoparticle.
Inorganic silica and gold nanoparticles are also being increasingly studied. However,
both classical self-assembly and controlled and stabilised nanoprecipitation are the
phenomenon that underpin most nanomedicines. As such, polar lipids assemble into
micelles and liposomes, amphiphilic polymers self-assemble into polymeric
e a
micelles, polymeric vesicles and dens
particles
and
hydroph
obic
polymers form nanoprecipitates in the presence of a polar
morphous nanoprecipitates and both drug
amphiphile. The science underpinning these pharmaceutical nanoparticles is now
broadly understood, but how do these nanosystem s assist us in drug development. In
other words, how is pharmaceutical nanoscience relevant to the treatment of disease?
1.2 Pharmaceutical Innovation
Pharmaceutical nanoscience has led to real pharmaceutical innovation. This innovation is exemplified by the development of nanotechnologies that are capable of
fundamentally changing the way in which drugs work, with a reduction in side
effects and an improvement in therapeutic indices docum ented for some of the early
1 Introduction 3
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Fig. 1.2 Drug delivery across the challenging biological barrier: the blood brain barrier
exponents such as Doxil (a reduction in cardiac toxicities (Gabizon et al. 2003)),
Ambisome (a reduction in renal toxicities (Lee et al.
1994, Walsh et al. 1998)) and
Abraxane (a reduction in the hypersensitivity reactions seen with Taxol) (Pellegrino
et al. 2017). These nanotechnologies have made drugs safer by directing them
mostly to the site of pathology.
While safety is a key benefit of the first crop of nanomedicines, other advantages
focusing on pure efficacy are also being pursued. In preclinical settings, there are a
number of proof of concept studies that indicate that more nanomedici nes may one
day be approved to solve specific drug delivery problems. The evidence in no way
points to a certainty, however. One such preclinical proof of concept dataset was
advanced by our group. We found that despite the formidable barrier posed by the
blood brain barrier (Fig. 1.2), there is eviden ce that some nanomaterials are able to
deliver drug molecules across this brain barrier following intravenous injection. As
such, peptide analgesic nanofibres, which enable peptide delivery to the brain on
intravenous administration (Mazza et al. 2013), have been reported. However, using
nanoparticles via the intravenous route for neurology therapeutic purposes has not
yet progressed to a solid clinical outcome, even in early-stage clinical trials.
Delivery to the brain using nanotechnology and the nose to brain route is a
promising alternative strategy and this method of delivery is what underpins
Envelta
™
, an enkephalin-based painkiller currently in development (Godfrey et al.
2017). The nose to brain route is becoming more interesting to those developing
neurology assets, as even genes may be delivered via this route (Fatani et al. 2023).
Nanotechnologies have also been effective at increasing the overall systemic
exposure, e.g. by promoting drug absorption via the oral route for example (Siew
2012). So while scientists and drug development specialists seek to achieve real
et al.
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Fig. 1.3 (a) Nanomedicines are used to target drug molecules to largely inaccessible parts of the
anatomy such as the brain (1), exclusively to a tumour site (2), the bladder (3). (b) Nanomedicines
are used to target drug molecules to the retina using eye drops. (Prepared using Biorender)
drug targeting to the brain, the bladder, tumours and other areas of pathology such as
the retina (Fig.
1.3); the majority of proof of concept studies are still at the preclinical
stage and the standout successful application currently lies with the Covid-19
mRNA vaccines (Thomas et al.
2021).
In the 1970s, it was realised that conjugating a hydrophilic polymer to a protein
drug resulted in an enlargement in its hydrodynamic diameter, a degree of improved
metabolic stability and a resistance to both glomerular filtration and liver clearance
(Veronese 2009). By the 1990s, liposomes, which until then had been an academic
curiosity, demonstrated that the encapsulation of a hydrophilic drug within the
liposome’s hydrophilic core could achieve a change in the drug’s biodistribution,
causing it to accumulate in tumour areas, extravasate the vasculature and avoid heart
tissue, the site of a particular drug’s toxicity (Gabizon et al. 2003). The net result was
the launch of Doxil (liposomal doxorubicin). Finally in 2001, it was discovered that
the hydrophobic drug paclitaxel could be stabilised in aqueous media by binding
non-covalently to albumin (Paal et al. 2001). Further studies revealed that the
albumin coating on nanocrystalline paclitaxel could direct drug to secret ed amino
acids rich in cysteine (SPARC) residues (Cortes and Saura 2010). SPARC residues
are associated with malignant tissue. In essence, these data underpinned the launch
of Abraxane. However, today, there is considerable debate about the use of
nanomedicines to passively targe t drugs to tumours in humans as there has been
1 Introduction 5
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poor translation in humans of this nanomedicine tumour accumulation seen in
preclinical studies.
There are still efforts to use the functionality of the nanoscale to develop drugs to
treat other diseases. One example is the creation of a glucose-responsive insulin
delivery systems for the treatment of Type II diabetes (Volpatti et al.
2020) and the
creation of eye drops to treat retinal diseases (Badr et al. 2022).
Apart from the use of nanomedicines to create efficacious therapeutics, there are a
few new nanoscale diagnostic modalities that have been launched and much work in
this area is aimed at discerning the molecular markers of disease using nanoparticle
contrast agents and non-invasive imaging modalities.
It is interesting to note the current move away from merely investigating the
impact of particle size on biodistribution and biological properties to a concerted and
international effort to investigate the impact of shape on biological properties.
Mitragotri (Mitragotri 2009) and DeSimone (Gratton et al. 2008) have shown that
the shape of a particle alters the way in which a particle interacts with cells, with
rod-like particles being favourably internalised by HeLa cells (Gratton et al.
2008)
and rod-like particles not being internalised by macrophages (Mitragotri 2009; Doshi
and Mitragotri 2010). Furthermore our own work has shown that peptide nanofibres
are excellent systems for the delivery of peptides to the brain via the intravenous
route (Mazza et al. 2013). With data from these early studies now firmly presented,
there are now ample opportunities for scientists to study how nanoparticle shape
(Lalatsa et al.
2012) quantitatively alters drug biodistribution, pharmacological
activity and toxicokinetics; i.e. leading to the new discipline of nanogeometry.
In essence, the last 50 years has seen nanoscience grow up to yield nanotechnology and eventu ally nanomedicines. This volume serves as an informative introduction to this pharmaceutical innovation.
References
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topical ocular delivery of rapamycin to posterior eye tissues and the suppression of retinal
inflammatory disease. Int J Pharm. 2022;621:121755.
Cortes J, Saura C. Nanoparticle albumin-bound (nab (TM))-paclitaxel: improving efficacy and
tolerability by targeted drug delivery in metastatic breast cancer. EJC Suppl. 2010;8(1):1–10.
Doshi N, Mitragotri S. Macrophages recognize size and shape of their targets. PLoS One. 2010;5
(4):e10051.
Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov. 2003;2:347–60.
Fatani AS, Petkova A, Schatzlein AG, Uchegbu IF. Dose-dependent delivery of genes to the
cerebral cortex via the nasal route. Int J Pharm. 2023;644:123343.
Gabizon AA. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of
chemotherapy. Cancer Investig. 2001;19(4):424–36.
Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal doxorubicin –
review of animal and human studies. Clin Pharmacokinet. 2003;42(5):419–36.
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Godfrey L, Iannitelli A, Garrett NL, Moger J, Imbert I, King T, Porreca F, Soundararajan R,
Lalatsa A, Schatzlein AG, Uchegbu IF. Nanoparticulate peptide delivery exclusively to the brain
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Mitragotri S. In drug delivery, shape does matter. Pharm Res. 2009;26(1):232–4.
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Pellegrino B, Boggiani D, Tommasi C, Palli D, Musolino A. Nab-paclitaxel after docetaxel
hypersensitivity reaction: case report and literature review. Acta Biomed. 2017;88(3):329–33.
Siew A, Le H, Thiovolet M, Gellert P, Schatzlein A, Uchegbu I. Enhanced oral absorption of
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nanoparticles. Mol Pharm. 2012;9(1):14–28.
Thakor AS, Jokerst JV, Ghanouni P, Campbell JL, Mittra E, Gambhir SS. Clinically approved
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Part I
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Nanomaterials Fabrication,
Characterisation, and Use
Chapter 2
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Low-Molecular Weight Amphiphiles
Marie-Christine Jones
2.1 Introduction
A compound is said to be amphiphilic when it bears both solvent-loving (lyophilic)
and solvent-hating (lyophobic) moieties. In pharmaceutical nanoscience, amphiphilic molecules are defined in relation to their affinity for water and thus, are said
to present both hydrophilic and hydrophobic elements. In this chapter, we will focus
on low-molecular weight amphiphiles (LMWAs), that is amphiphiles with a molecular weight below 1500 Da. Though somewhat arbitrary, this limit is helpful when
trying to differentiate LMWAs from polymeric amphiphiles and focus the scope of
this chapter.
2.2 Molecular Architecture and Surface Activity
LMWAs can be represented schematically as head-and-tail structures (Fig. 2.1). The
‘head’ is hydrophilic, can be charged or neutral (non-ionic or zwitterionic) and is
covalently bound to the hydrophobic ‘tail’ which often consists of one or two long
alkyl chain(s). Double-headed, amphiphilic structures have also been described
where the polar heads are covalently bound through a linker (gemini-amphiphiles)
or located at both ends of a long hydrophobic chain (bola-amphiphiles) (Bombelli
et al. 2009; Lee et al. 2021).
The basic head-and-tail description of amphiphiles suggests well-defined hydrophilic and hydrophobic regions, which is true for some, but not all LMWAs. Still,
M.-C. Jones (*)
School of Pharmacy, College of Medicine and Health, University of Birmingham, Birmingham,
UK
© The Editor(s) (if applicable) and The Author(s), under exclusive license to
Springer Nature Switzerland AG 2024
I. F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience,
https://doi.org/10.1007/978-3-031-59478-6_2
9
10 M.-C. Jones
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Fig. 2.1 Schematic representation of ( a) single-tail, (b) double-tail, (c) gemini and (d) bola
LMWAs
this description is useful to explain the basic behaviour of many amphiphiles at
surfaces and interfaces and why many are referred to as surfactants. In water, at low
concentrations, amphiphilic monomers will naturally orient themselves to maximise
the interaction between the polar head and water, and between the hydrophobic tail
and air or an apolar solvent (Florence 2011; Wang et al. 2012). This ability to reduce
surface or interfacial tension explains why LMWAs are used as wetting agents,
emulsifiers, or stabilisers in pharmaceutical and biologic drug formulations, but also
why many are haemolytic (Ghosh et al.
Sheskey et al. 2020). Surface-activity
2020; Manaargadoo-Catin et al. 2016;
will depend on many factors; structures with
a long, linear hydrophobic tail and a single neutral or zwitterionic polar head
positioned at the end of the tail tend to be better surfactants (Florence
2011).
2.3 Self-Assembly of Low-Molecular Weight Amphiphiles
In dilute aqueous solution s, LMWAs can associate to form various supramolecular
structures that allow the hydrophobic tail(s) to be shielded from water. Consequently, most assemblies wi ll be characterised by hydrophobic domains sheltered
behind a shell formed by the polar heads. Some structures (e.g. micelles) form
spontaneously, while others (e.g. liposomes) require a small input of energy to
disperse the amphiphile in water (Ghosh et al. 2020).
The self-assembled structures formed by LMWAs are stabilised by weak
non-covalent forces, often combining hydrophobic van der Waals interactions and
hydrogen bonding (Florence 2011; Lombardo et al. 2015). For ionisable and aromatic LMWAs, electrostatic and π-π interactions can also contribute to the formation
of stable assemblies (Zhao et al. 2017). The relative contribution of each of these
forces will depend on the molecular chemistry of the amphiphile.
Small spherical micelles (5–10 nm) are the most common, and often the most
stable, supramolecular arrangement for LMWAs. However, the molecular geometry
of the amphiphile may impose some restrictions on packing, resulting in
non-spherical assemblies that can accommodate both the tails and heads more
2 Low-Molecular Weight Amphiphiles 11
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Table 2.1 Impact of amphiphile geometry on aggregate morphology
a
Maximum aggregation number
comfortably (Table 2.1). The morphology adopted by LMWAs in water will depend
on the relative size of the hydrophilic and hydrophobic moieties and can be predicted
using Israelachvili’s critical packing parameter (CPP, Eq. 2.1):
v
CPP ¼
where v
length) of the hydrophobic tail and a
of v
and branching; a
and lc are the volume and critical length (ca. 80–90% of full extended
0
0
will vary depending on the number of tails, the presence of unsaturated bonds
0
will depend on the degree of hydration of the polar head and, for
0
a0l
0
c
ð2:1Þ
is the area of the hydrophilic head. The value
charged amphiphiles, on the degree ionisation (Israelachvili 1985; Israelachvili et al.
1976).
For spherical micelles to form, the radius of the micelle core cannot exceed the
value of l
; this condition is only met when CPP ≤ 1/3, which applies to most single-
c
tailed surfactants with a relatively large polar head. For LMWAs with a slightly
smaller polar head relative to the tail and thus, larger CPP (1/3 ≤ CPP ≤ 1/2),
self-assembly will result in cylindrical, rod-shaped, or worm-like micelles. These
elongated micelles have hemi-spherical ends and can be obtained through the
dehydration of a non-ionic polar head (heating or cosolvent addition) or increasing
the amphiphile concentration (Ghosh et al. 2020). In comparison, for ionic LMWAs,
sphere-to-rod transitions can be induced by changing the ionic strength or pH of the
aqueous phase (Chaudhuri et al.
2012; Sterpone et al. 2009; Velinova et al. 2011).
The formation of worm-like micelles causes the viscosity of the solution to increase,
a property that is exploited in the formulation of hydrogels. Both spherical and
cylindrical micelles have been used for drug delivery. Interestingly, it has been
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