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7 Conclusion: The Prospects for Harnessing Nature's Catalytic Principles
observed for enzymes. For example, the machine-like catalyst 6 turns over 5 H2
s−1 for at least 5 days of continuous operation with no observable deactivation.31
It is just as active at the end of the 5 days as it was at the beginning. Its turnover
number during that time exceeds 1,000,000 per catalyst molecule.38 Hill’s Copolyoxotungstate water oxidation catalyst also achieves an enzyme-like turnover
frequency of >5 s−1 at pH 8.58
Several of the new catalysts, furthermore, open new vistas in ﬁelds that are critically important to humankind but extraordinarily challenging. For example, solar
water splitting is achieved without need of an external energy input by 14+ /Naﬁon
in a dye-sensitized solar cell.51 The ability of 14+ /Naﬁon to selectively split seawater without generating toxic Cl2 gas must also rank as an important advance.55
Industry standard water oxidation catalysts like Pt and commercial electrolyzers
cannot achieve this feat.
These developments are cumulatively extremely promising and bode well for
the future. While it is still an open question as to whether the current understanding
of enzymes is complete, we have, at the very least, discovered a range of new and
powerful catalysts. These catalysts are a signiﬁcant advance on what was previously
possible; they set a new benchmark for synthetic catalysis in a variety of reactions.
This is precisely what would be expected if the current understanding of Nature’s
catalytic principles has at least some measure of validity and is trending toward a
The challenge now is to continue the quest and to harness the knowledge that we
have available in the development of still more powerful synthetic catalyst systems.
Whatever the pitfalls, bioinspired catalysis is clearly a ﬁeld with enormous potential
that is eminently worth pursuing.
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Biomimetic Amphiphiles and Vesicles
SABINE HIMMELEIN and BART JAN RAVOO
Organic Chemistry Institute and Graduate School of Chemistry, Westfalische
Corrensstrasse 40, 48149 Munster,
Without exaggeration, it could be stated that a bilayer of phospholipid molecules is
all that separates “internal” from “external” in living organisms. Biological membranes play a key role in the protection of the integrity, stability, and shape of a
cell as well as its interaction and communication with its environment. Moreover,
crucial processes such as recognition and adhesion of cells, membrane fusion, signal transduction, and enzyme catalysis occur at the membrane surface. In addition,
even the simplest of cells contain numerous subcompartments, each of which are
secluded by a separate bilayer membrane. Several key functions of cell membranes
are highlighted in Figure 8.1. It was shown by Bangham and Horne in 1964 that
phospholipid bilayer membranes can easily be formed in vitro1 and it was reported
by Kunitake and Okahata in 1977 that the formation of bilayers is not restricted
to biological phospholipids.2 Vesicles (Lat. vesicula = small bubble) have been an
important topic in both chemistry and the life sciences ever since. On the one hand,
vesicles are of interest as highly dynamic supramolecular structures that mimic the
remarkable properties of biological membranes. On the other hand, vesicles are of
interest as self-assembled responsive capsules that may be applied in drug delivery,
as nanoreactors and nanosensors, or in the design of soft materials.
This chapter focuses on the use of abiological amphiphiles to generate
biomimetic vesicles. The chapter opens with a general introduction to the use of
synthetic amphiphiles as building blocks for biomimetic vesicles. The major part
of the chapter is organized according to a number of sophisticated functions that
are typical of biological cell membranes. First, we discuss biomimetic vesicles
that display molecular-recognition-induced adhesion and fusion of membranes.
Second, we describe vesicles that are senstitive to stimuli-responsive shape
control. Third, we focus on vesicles that are capable of transmembrane signaling
Bioinspiration and Biomimicry in Chemistry: Reverse-Engineering Nature, First Edition.
Edited by Gerhard F. Swiegers.
© 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.
BIOMIMETIC AMPHIPHILES AND VESICLES
Figure 8.1 Schematic representation of key functions of a biological cell membrane.
and vesicles that can be used to compartmentalize chemical reactions. Finally, we
address the issue of formation of subcompartments within a vesicle. The chapter
closes with a brief outlook.
This chapter is intended to provide insights into the fascinating supramolecular
chemistry of biomimetic vesicles by highlighting a selected number of recent
publications. A comprehensive review of the literature is not provided. Langmuir–
Blodgett ﬁlms and supported bilayers—which are also versatile biomimetic
membranes—are not covered in this chapter.
8.2 SYNTHETIC AMPHIPHILES AS BUILDING BLOCKS
FOR BIOMIMETIC VESICLES
Vesicles are dynamic supramolecular structures that consist of a molecular layer
that encapsulates a small amount of solvent. Vesicles are predominantly formed in
aqueous solution. The term “liposome” is generally reserved for vesicles composed
of natural phospholipids, while the term “vesicle” includes vesicles composed of
synthetic amphiphiles, phospholipids, or any other components. “Polymersomes”
are vesicles composed of polymers.
Bilayer vesicles are closely related to liposomes and biological membranes.
Most molecules that form bilayer vesicles in water are amphiphilic: they have a
hydrophobic and a hydrophilic part. The hydrophilic part (“head group”) of the
molecule interacts favorably with the surrounding water, while the hydrophobic
part (“tail”) minimizes its exposure to water. Hence, the amphiphiles arrange in a
SYNTHETIC AMPHIPHILES AS BUILDING BLOCKS FOR BIOMIMETIC VESICLES
bilayer and the formation of vesicles is driven primarily by hydrophobic interaction.
Typically, the head group is polar and/or charged and contains phosphate, sulfate,
ammonium, amino acid, peptide, carbohydrate, or oligo(ethylene glycol) groups.
Typically, the “tail” is apolar and uncharged. The tail is usually composed of
long hydrocarbon chains, which may be saturated or unsaturated, linear, cyclic or
branched, aromatic or aliphatic, or ﬂuorinated. In accordance with the concept of
the packing parameter,3 the amphiphile must have an approximately cylindrical
shape, so that the molecules arrange into a bilayer, which may be slightly curved
so that it can close into a spherical vesicle. It should be noted that the packing
parameter cannot be deﬁned exclusively on geometric considerations: attractive and
repulsive interactions of head groups should also be taken into account.
With the advent of polymersomes and vesicles of other “nonconventional” (i.e.,
not phospholipid-like) amphiphiles, numerous examples of monolayer vesicles in
water have been reported. Typically, monolayer vesicles are prepared from small
molecules with a hydrophobic core and two hydrophilic head groups (bolaform
amphiphiles, see below) or from triblock copolymers with two hydrophilic terminal
blocks. The molecule must have a cylindrical or rectangular shape, so that it can
arrange into a monolayer.
Irrespective of their composition, it is useful to differentiate between small
unilamellar vesicles (SUVs, <100 nm), large unilamellar vesicles (LUVs,
100–1000 nm), giant unilamellar vesicles (GUVs, >1 μm), and multilamellar
vesicles (MLVs) (Figure 8.2). SUVs, LUVs, and GUVs have a unilamellar
membrane composed of a single molecular bilayer (or monolayer). SUVs and
LUVs are the most widely studied types of vesicles. GUVs are of particular
interest as biomimetic membranes since their size is comparable to living cells.4
MLVs have an onion-like structure and consist of many concentric bilayer (or
monolayer) membranes. It can easily be calculated that the smallest SUVs (ca.
50 nm) of small amphiphiles contain about ten thousand molecules, whereas
LUVs contain about a hundred thousand molecules, and GUVs and MLVs contain
many millions of molecules. The number of molecules in one vesicle can only be
Figure 8.2 Small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), giant
unilamellar vesicles (GUVs), and multilamellar vesicles (MLVs).
BIOMIMETIC AMPHIPHILES AND VESICLES
given as an approximate average, because it is difﬁcult to prepare vesicles of an
exactly deﬁned size (see Section 8.4).
The ﬁrst report on bilayer vesicles formed from synthetic amphiphiles dates
from 1977, when Kunitake and Okahata described the formation of vesicles from
di-n-dodecyl dimethyl ammonium bromide in aqueous solution.2 In the 1980s, it
was shown by many groups that a wide range of amphiphilic molecules can form
vesicles in water. In a sense, these amphiphiles are all very similar to phospholipids:
they generally have two hydrophobic tails and a hydrophilic head group, so that
the molecule has a cylindrical shape and packs efﬁciently into a bilayer sheet,
which curves and closes into a vesicle. On the other hand, the structural variety
of synthetic amphiphiles provides vesicles with a range of functions that clearly
surpass the properties of liposomes. Among others, synthetic vesicles can be made
light sensitive, vesicles can be made pH sensitive, and vesicles can be polymerized.
The pioneering work on synthetic vesicles is summarized in reviews by Kunitake,5
Ringsdorf et al.,6 and Engberts et al.7
Small amphiphiles must not necessarily have a phospholipid-like structure with
two tails and one head group. For example, bolaform (or bipolar) amphiphiles
are amphiphilic molecules that contain two head groups separated by an extended
hydrophobic chain. Bolaform amphiphiles form monolayer vesicles, in which
each amphiphile extends across the monolayer membrane, exposing both head
groups to water and sheltering the hydrophobic chain from water.8 However, these
types of vesicle-forming amphiphiles are in fact also inspired from Nature: many
extremophilic bacteria have membranes that contain a high percentage of bolaform
amphiphiles.9 Monolayer membranes of bolaform amphiphiles are much more
robust than bilayer membranes and contribute to the stability of extremophiles in
acidic, alkaline, and hot environments.
The innovative design of small amphiphiles continues to give rise to unconventional vesicles. Recently, there has been increasing interest in synthetic amphiphiles
equipped with a recognition unit.10 In many cases, such amphiphiles can form vesicles by themselves. Alternatively, they can be mixed with conventional amphiphiles
or phospholipids. In this way, it is possible to functionalize vesicles with complementary recognition motifs that can guide the selective adhesion and even fusion
of bilayer vesicles (see Section 8.3). Amphiphilic macrocyclic host molecules
have been investigated for many years. Vesicles composed of or containing synthetic host molecules are versatile model systems for receptors in biological membranes. Among others, it is known that amphiphilic crown ethers,11 cryptands,12
calixarenes,13 cyclodextrins,14 and cucurbiturils15 can form bilayer vesicles in aqueous solution. However, the host–guest chemistry of such host vesicles remained
largely unexplored for many years.
Ravoo and Darcy prepared bilayer vesicles composed entirely of amphiphilic
cyclodextrin host molecules.14 Such vesicles have a membrane that displays a high
density of embedded host molecules that bind hydrophobic guest molecules. The
characteristic size-selective inclusion behavior of the cyclodextrins is maintained,
even when the host molecules are embedded in a hydrophobic membrane. For
example, adamantane carboxylate binds preferentially to β-cyclodextrin vesicles
SYNTHETIC AMPHIPHILES AS BUILDING BLOCKS FOR BIOMIMETIC VESICLES
(Ka = 7000 M−1 ), weaker to γ -cyclodextrin vesicles (Ka = 3000 M−1 ), and very
poorly to α-cyclodextrin vesicles (Ka < 100 M− 1).16
Cucurbiturils are another class of host molecules that have been assembled
into bilayer vesicles in water. Kim and co-workers synthesized an amphiphilic
cucurbit[6 ]uril that forms vesicles and forms host–guest complexes at the vesicle surface.15 It is possible to decorate the surface of the host vesicles with guest
molecules. Exposure of cucurbituril vesicles to a ﬂuorescent spermidine derivative
leads to ﬂuorescent vesicles. Exposure of the cucurbituril vesicles to α-mannose
substituted spermidine leads to vesicles coated with α-mannose, which bind specifically to the lectin concanavalin A (ConA). ConA does not bind when the vesicles
are coated with a galactose spermidine conjugate. These experiments demonstrate
how synthetic host membranes can interact with proteins via multivalent interactions mediated by carbohydrates.
A major innovation in the area of vesicles was triggered by Eisenberg and
co-workers, who demonstrated in 1995 that very large amphiphilic molecules can
form vesicles.17 In a pioneering Science report, it was shown that poly(styrene)block -poly(acrylic acid) can form bilayer vesicles in water. These polymersomes
were prepared by slow addition of water to a DMF solution of the block copolymer,
followed by dialysis to remove the remaining DMF. The hydrophobic poly(styrene)
forms the interior of the bilayer membrane, while the hydrophilic poly(acrylic acid)
is exposed to water. It has been shown since that many block copolymers can form
vesicles. Important advantages of polymersomes include their high kinetic stability
and their very low membrane permeability (which increases with the length of the
Although block copolymers that merely contain a hydrophobic block connected
to a hydrophilic block can still be considered rather straightforward high molecular weight analogs of conventional small amphiphiles, the ﬁeld of polymersomes
has beneﬁted tremendously from the design of more complex block copolymer
architectures using new polymerization methods (such as atom transfer radical
polymerization, ATRP) and highly efﬁcient conjugation protocols (such as click
chemistry). For example, ABA block copolymers can form monolayer vesicles.
In fact, ABA block copolymers are the macromolecular equivalent of bolaform
amphiphiles. ABC block copolymers can form bilayer vesicles if A and B (but not
C), or B and C (but not A), are of similar polarity, but they can also form monolayer
vesicles if A and C (but not B) are of similar polarity. Figure 8.3 outlines the most
important block copolymer architectures for polymersomes. Block copolymers can
also contain biopolymer segments, such as polypeptides or polysaccharides conjugated to synthetic segments (“biohybrid copolymers”).18, 19 Biohybrid copolymers
are important biomimetic amphiphiles, since they combine the biological activity of
membrane-embedded biomacromolecules with the ability to self-organize in kinetically stable vesicles and microcapsules. The blossoming ﬁeld of polymersomes
has been the subject of several reviews.20, 21
The versatility of polymersomes was signiﬁcantly advanced by Nolte and
co-workers, who expanded the scope of block copolymers from large to giant
biohybrid amphiphiles.22 The key innovation in their work is the conjugation
BIOMIMETIC AMPHIPHILES AND VESICLES
Figure 8.3 Block copolymers for polymersomes. (Reproduced with permission. Copyright Royal Society of Chemistry: Ref. 21.)
of very large hydrophilic proteins to hydrophobic synthetic polymers. These
biohybrid block copolymers differ from other protein–polymer conjugates in
the sense that the protein to polymer ratio is predeﬁned and the position of the
conjugation site is precisely known. In a particularly elegant experiment, giant
biohybrid amphiphiles self-assembled by cofactor reconstitution of poly(styrene)
modiﬁed heme and apo-horseradish peroxidase (HRP) as well as apomyoglobin.
The biohybrid amphiphiles were obtained by adding a THF solution of the heme
cofactor-appended poly(styrene) to an aqueous solution of the apoenzyme. TEM
revealed the formation of LUVs with diameters of 80–400 nm. The activity of
the HRP and myoglobin enzymes is retained in the polymersomes.
Vesicle-forming amphiphiles must not be held together by covalent interactions
exclusively: it is easily conceivable that an amphiphile is formed by noncovalent
interaction of two (or more) components. Hence, although the individual components cannot form vesicles, vesicles self-assemble upon mixing of the components
in the appropriate molar ratio. A remarkable example of a ternary complex that
self-assembles into vesicles was reported by Kim and co-workers.23 It was shown
that vesicles are formed spontaneously in a mixture of cucurbit[6 ]uril, n-alkyl viologen, and dihydroxynaphthalene (Figure 8.4). Viologen and dihydroxynaphthalene
form a stable charge transfer complex in the cavity of the cucurbituril host. The
ternary complex is amphiphilic due to the presence of the long alkyl chain on the
viologen. If the alkyl substituent is n-dodecyl, SUVs are formed; if the alkyl substituent is n-hexadecyl, LUVs are formed. The vesicles can be imaged by scanning