Bolaamphiphilic molecules: Assembly and applications

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Bolaamphiphilic molecules: Assembly and applications Nurxat Nuraje a,∗,1 , Hanying Bai b,∗,1 , Kai Su c,∗,1 a b c

Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Orthopeadic Surgery Department, Columbia University Medical Center, 650 W168th Street, New York, NY 10032, USA BASF Corporation, 500 White Plains Road, Tarrytown, NY 10591, USA

a r t i c l e

i n f o

Article history: Received 16 May 2012 Received in revised form 7 September 2012 Accepted 10 September 2012 Available online xxx Keywords: Lipid nanotubes Nanostructures Self-assembly Bolaamphiphile Bola Hydrophilic Amphiphilic Template Drug nanocarriers Nanofibers

a b s t r a c t This review describes the state-of-the-art scientific developments of bolaamphiphilic molecules composed of two hydrophilic headgroups connected by a hydrophobic chain in the middle of the molecule. In contrast to previous review articles, this review focuses on the discussion of the bolaamphiphilic molecules from assembly to applications in various fields. The main principles of the assembly structures of bolaamphiphilic molecules are discussed, both at interfaces, including air/water and liquid/solid, and in solutions. Since different interactions exist among hydrophilic or polar head groups of the molecules, and the complexity of different hydrophobic, van der Waals, ␲–␲ interactions, etc., between the chains, the assembly structures of the bolaamphiphilic molecules in the solution are more complicated and are therefore discussed in more detail. Finally, current applications for several important structures and assembly mechanisms of the molecules are introduced. © 2012 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Assembly at air/water and liquid/solid interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Assembly in the solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Assembly of unsymmetrical bolaamphiphilic molecules in solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Assembly of symmetrical bolaamphiphilic molecules in solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications of bolaamphiphilic molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Bolaamphiphilic molecule templates for synthesis of nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Electronics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Gene delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding authors. E-mail addresses: [email protected] (N. Nuraje), [email protected] (H. Bai), [email protected] (K. Su). 1 All three authors contributed equally to this work. 0079-6700/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.progpolymsci.2012.09.003

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3.6. Catalytic reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspectives and outlooks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Bolaamphiphilic molecules contain two functional head groups. The two hydrophilic head groups connect via a hydrophobic molecule chain, as shown in Fig. 1 [1]. Since they exhibit unique hierarchically self-assembled structures both at interfaces, including air/water (Langmuir–Blodgett, LB, film) and liquid/solid, and in solutions, the synthesis and application of bolaamphiphilic molecules has been extensively studied. In the last two decades, various synthetic methods have been developed to produce functional bolaamphiphiles which mimick their natural counterparts. More attention has been given to studies of their hierarchally organized structures

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and applications in various fields, including drug delivery, gene delivery, electronics, medical imaging, etc. In the gene delivery application, one end of the bolaamphiphilic molecules functionalized with amine groups interacts with negatively charged nucleotides (in DNA and RNA) and assembles vesicle structures through amphiphilic properties. Other research has focused on the development of nanoelectronics. Due to their bio-compatibility and controllable morphologies, peptide-based bolaamphiphiles have drawn considerable attention in nanoelectronics for their potential as soft templates for production of nanobuilding blocks with different properties such as metallic, and seminconducting. By comparison, carbon nanotubes, also showing great potential in this area, have well-known separation issues that present barriers to their further applications, in both semiconducting and metallic applications. In this account, we define our subject, bolaamphiphilic molecules, as molecules that have hydrophobic repeating units connecting hydrophilic head groups at the two ends of the molecule, symmetrically or unsymmetrically. Therefore, our subject compounds include unsymmetrical bola-molecules as well. As shown in Fig. 1(b), a bolaamphiphile has two hydrophilic head groups: carboxylic acid and a glucose moiety. The hydrophobic connector consists of methylene repeating units which connect the two hydrophilic groups. As shown in Fig. 1(c), amphiphilic molecules, which have only one hydrophilic head group in the molecule, are not considered to be bolaamphiphilic molecules scope in this account. Bolaamphiphilic molecules in the definition of this account will be reviewed broadly focusing on their assembly structures and applications. Progress in the synthesis of such molecules is not a primary focus of this review. The review is divided into two main sections: Assembly (Section 2) and Applications (Section 3). 2. Assembly

Fig. 1. (a) Photograph of an Argentinean bola with leather balls; (b) schematic drawing of defined bolaamphiphiles. Chemical structure below the diagram is an example of an unsymmetrical bolas; (c) a schematic drawing of an amphiphilic molecule which is not in the range of compounds of discussed here [1]. Copyright 2004. Reproduced with permission from ACS.

Bolaamphiphilic molecules can self-assemble and form various hierarchal structures both at interfaces and in solutions since they possess both hydrophilic and hydrophobic portions. At interfaces, including air/liquid and liquid/solid, their assembly structures differ from those in a solution. Because of the special affinity of the hydrophilic groups in one phase, most important studies of bolaamphiphilic molecules at interfaces are particularly focused on monolayer formation at air/liquid or liquid/solid interfaces. For example, one-end-thiol-functionalized bolaamphiphilic molecules are widely studied on the formation of monolayer on gold substrate (Fig. 2). In addition, due to the molecules’ amphiphilic properties, they can also

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3 COOH

HOOC

O NH N H COOH

O

COOH

Bola-1.

Fig. 2. Self-assembly monolayer formation of one end-thiol functionalized bolaamphiphilic molecules on liquid/solid surfaces [1]. Copyright 2004. Reproduced with permission from ACS.

Bola-2.

form monolayers at the air/water interface [2]. The Langmuir–Blodgett technique is applied to create hierarchical structures such as nanotubes (Fig. 3). In comparison, more diverse assembly structures are observed in solutions of bolaamphiphiles. Therefore, we focus our discussion on the assembly structures of the bolaamphiphilic molecules in solution. 2.1. Assembly at air/water and liquid/solid interface Since hydrophilic groups of bola form amphiphiles [2,4], such as X (CH2 )n X, where X is a hydrophilic

Bola-4.

group such as COOH, can form hydrogen bonds or dipole–dipole/dipole–polar via interactions with the aqueous phase, bolaamphiphilic molecules are inclined to not only assemble to the monolayer crystalline formation from U-shaped chainlike molecules (Fig. 4(I)–(III)), but also form multilayer formations on the aqueous surface with the addition of transition ions (Fig. 5) [2]. A monolayer of these bolaamphiphilic molecules (Bola-1–Bola-4) constructs a U-shaped conformation if they have flexible hydrophobic chains at the core, whereas with rigid moieties at the core

O O

P

OH

OH O O O

O

O O

P

OH

OH

Bola-3.

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Fig. 3. Illustration on the possible formation of the helical structures of the bolaamphiphile at the air/water interface through compression: (a) monolayer anchored on water surface before the plateau region. (b) After compression over the plateau region, an intermediate monolayer with one end anchored on water and the other extruded to the air. (c) The intermediate monolayer rolled into helical nanotube. (d) AFM and TEM images of the as-formed EDGA organogel with 1:1 water/ethanol mixture [3]. Copyright 2006. Reproduced with permission from ACS.

Fig. 4. Schematic illustrations for bolaamphiphiles I-IV (Bola-2, Bola 3, Bola-27 and Bola-28) conformations at the air–water interface. The I, II, and III are believed to assume a U-shaped configuration while IV forms monolayers that are standing in an upright configuration [4]. Copyright 2000. Reproduced with permission from ACS.

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Fig. 5. Schematic illustration of HOOC (CH2 )22

5

COOH multilayer on lead chloride solution [2]. Copyright 2001. Reproduced with permission from ACS.

Bola-5.

Bola-6.

they appear to possess an upright conformation (Bola-5) at the air–water interface. The diacid HO2 C (CH2 )22 CO2 H bolaamphiphilic molecule on pure water forms a multilayer with the chain axes parallel to the water surface with the addition of transition ions. Grazing incidence Xray diffraction (GIXD) determined different organizations of these molecules on the surface of aqueous phases containing divalent Cd2+ and Pb2+ ions. The diacid groups react with the ions and form the corresponding salt. In this selfassembled structure, their hydrocarbon chains are parallel to the water surface. The crystalline films are about 50 A˚ thick. The crystalline multilayers were transferred to glass, and reacted with H2 S and yielded quantum dots that had a diameter from 2 to 4 nm for both the cadmium and lead salts. acid based bolaamphiphile, N,Nl-Glutamic eicosanedioyl-di-l-glutamic acid (EDGA) [3,5,6] (Bola-1) assembled at the interface of air/water as a U-shape structure, as shown in Fig. 3. After the bolaamphiphile molecules were spread to form an LB monolayer film by controlling the pH, this film at the air/water interface was compressed and created helical spherical nanotubes through rolling of the monolayer due to the chiral selection of l-glutamic acid head groups (Fig. 3). The nanotubes can be constructed by compression of the membrane via the LB technique [3]. Bolaamphiphiles with 4-hydroxycinnamoyl head groups (Bola-6) assembled in the air/water interface to form LB films [7]. The effect of various lengths of the alkyl spacers (n = 6–12) on the film formation was investigated. The bolaamphiphilic molecules assembled differently

with changes of methylene units between hydrophilic groups. With the increase of methylene units from 6 to 12, the assemblies transformed from J-aggregate to H-aggregate. The bolaamphiphilic molecules assembled to form a nanorod structure for an even number of methylene units. For an odd number of methylene units they formed nano-spirals or nano-fibers. The different assemblies of the molecules were stabilized by forces including H-bonds between the phenolic hydroxyl and the amide groups, ␲–␲ stacking, as well as the hydrophobic interactions of the alkyl spacer, as shown in Fig. 6. The mechanism behind this odd–even-number-effect on self-assembly can be explained as follows. In the self-assembly of bolaamphiphiles in both bulk solution and self-assembled monolayer at the interface between air/water, the interactions between both the head groups and the spacers become important driving forces. Due to variety of head groups and spacers, the driving forces for the assembly of the molecules are different. Therefore, the effects of the odd and even numbers of oligomethylene groups on there self-assembly are discussed briefly in the following for both Bola-6 and Bola-17. The self-assembly structure of Bola-6 at air/water interface is dependent on the cooperative interactions between the H-bonds of the OH among phenolic groups and with amide groups, hydrophobic interactions of the hydrophobic spacer, and the ␲–␲ stacking of the ␲-conjugated end groups. As shown in Fig. 6, the amide H-bond plays a different function for the assembly of the even and odd-spacered bolaamphiphiles. In the even bolas assembly, the amide H-bond align antiparallel, whereas those in odd bolas’ assembly align parallel, with different distances separating the chains in these two cases. Therefore, linear hydrogen bonds cannot be formed. In addition, the hydroxyl H-bonds among the odd bolas assemblies are weaker than those among the even assemblies. Therefore, the even-spaced bolaamphiphiles are easily assembled into 3D nanorods, whereas a one-dimensional nanofiber structure is formed for the odd-spaced ones.

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Fig. 6. Packing models of Bola-6 at the interface of the air and water [7]. Copyright 2012. Reproduced with permission from ACS.

At the interface of water and solid, synthetic bolaamphiphilic molecules functionalized with a thiol group at one end tended to form extended planar monolayers on the surface of water or on smooth gold solids [1] (Fig. 2). Mostly this type of bolaamphiphilic molecules formed a monolayer, changing the surface properties of the substrates. A special thiol head group bolaamphiphile (HS(CH2 )n N3 ) [8] was developed for “click chemistry”. Click chemistry [9] has expanded the possibilities of all fields of science, including materials science, biological science, and organic chemistry, based on high reactivity and mild reaction conditions. The thiol head group at one end of the bolaamphiphilic molecule can attach to a metal substrate (Au, Ag, etc.) and form a monolayer; the azide head group at the other end is highly reactive and can react with other organic compounds to generate a bilayer film/vesicle [10], or with surfactant-capped metal nanoparticles to produce high-functionalized metal nanoparticles [8,10–14]. Fig. 7(A) shows a three-step method to graft molecularly imprinted polymer (MIP) thin films onto Au electrodes. In the first step, propargyl acrylate is ‘clicked’ onto an azidoundecanethiol (HS(CH2 )12 N3 )/decanethiol mixed SAM. Then, by applying UV light (365 nm) in the presence of N,N -methylene bis(acrylamide) (MAAM) and azobisisobutyronitrile (AIBN) as the radical initiator, polymerization was carried out directly on the electrode surface in the presence of an electroactive template molecule [10]. Fig. 7(B) shows Au nanoparticle network formation with a functionalized spacer group via click chemistry and various dialkyne derivatives [13]. 2.2. Assembly in the solution 2.2.1. Assembly of unsymmetrical bolaamphiphilic molecules in solution At present, two different types of theories have been used to explain the tubular architectures from

low-molecular-weight amphiphiles. First, the molecular packing of Lipid Nanotubes (LNT) from amphiphiles possessing hydrophilic and hydrophobic groups at opposite ends has been explained by molecular chirality-based theories [15]. In theory, chiral interactions are the main reason for constituent molecules to pack at a nonzero angle with respect to their nearest neighbors (Fig. 8). Also, the solid bilayer membrane assembled from the amphiphilic molecules has preferential orientation due to the chirality of the molecules. This induces twisting of the bilayer membrane and yields the formation of a hollow cylinder. The elastic theories of tilted chiral bilayer structures describe the distinct geometries of lipids and partly describe LNT structures with the assembly of lipid molecules in a chiral manner. The elastic theory discusses LNT structures in liquid crystals. Fig. 8 shows three phenomenological terms: splay, twist, and bend, describing molecular packing in a liquid crystal based on the elastic theory assumption. Second, packing directed self-assembly is mostly applied in assembly of bolaamphiphilic molecules, including symmetrical and unsymmetrical, in solutions. In this case, no chiral morphologies such as helically twisted or coiled ribbons occur. The second growth mechanism of self-assembled molecular building blocks can facilitate the self-assembly of tubular architectures. In this process no intermediate chiral assemblies were formed; instead, tubular structures are produced directly in a single step. Unsymmetrical bolaamphiphiles experience this packing-directed self-assembly and form nanotubes based on their unique molecular shape. Most self-assembled nanotubes have identical functional groups inside and outside of tubes since the bolaamphiphiles are assembled as a bilayer structure. Unsymmetrical bolaamphiphiles with two hydrophilic moieties of different size are usually assembled as two types of polymorph depending on

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Fig. 7. (A) Preparation of molecularly imprinted polymer (MIP) modified Au electrodes showing the ‘click reaction’ between azidoundecanethiol and propargyl acrylate, the grafting of the methacrylate polymer to the SAM, and the extraction and rebinding of hydroquinone from the MIP; (B) Scheme of synthesis of alkyne derivative link to azidoalkyl-Au NPs [13]. Copyright 2010. Reproduced with permission from RSC.

Fig. 8. Chiral molecular assembly of amphiphilic molecules packed at a nonzero angle with respect to their nearest neighbors. Geometrical definitions:  the director c, and the tilt angle ; (b) the radius r and the pitch angle  of the helical ribbon [15]. Copyright 2005. Reproduced with (a) the director d, permission from ACS.

the molecular packing of symmetrical and unsymmetrical monolayer membranes. An additional two types of polymorph are produced by the stacking motif of each monolayer membrane (head-to-head and head-to-tail). Four different types of monolayer membranes are shown in Fig. 9. Among the four types, only the unsymmetrical monolayer membrane with head-to-tail stacking exclusively produces organic nanotubes having inner and outer surfaces covered with different functional groups. The wedge-shaped bolaamphiphiles (Bola-7) with a relatively large glucose moiety and smaller carboxylic group at each end, asymmetric single-chain bolaamphiphiles, are studied for their self-assembly of the Bola-7 with a variety of oligomethylene chains. They are found to produce a mixture of two types of nanotube, which have different outer diameters of approximately 30 and 200 nm. Conventional centrifugation is applied to separate the resulting smaller and larger nanotubes (Fig. 9).

An asymmetric bolaamphiphilic l-Glu-Bis-3 molecule (Bola-8) consists of a diacetylene unit [16,17] at the hydrophobic core, an l-glutamic acid head group on one hydrophilic end of the molecule, and a carboxyl group on the other. The bolaamphiphilic molecules have pH responsive properties due to their three carboxylic groups. When the bolaamphiphilic molecule is assembled, the stability of the structure can be strengthened through polymerization of the diacetylene units. The assembly process of the bolaamphiphilic molecules is quick and the assembled structure is stable under mild conditions. Fig. 10 shows bolaamphiphilic diacetylene molecule (Bola-8) forming right-handed helical ribbon structures under mild conditions, with micron scale length and nano scale thickness. Bisfunctional polydiacetylenes (PDAs) are formed in the assembled structures through the polymerization of the diacetylene unit, leading to enhanced stability of the resulting structures. With exposure to UV-irradiation, the color of

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Fig. 9. Four possible types of monolayer lipid membranes (MLMs) from wedge-shaped bolaamphiphiles [24]. Copyright 2001. Reproduced with permission from RSC.

Bola-7.

Bola-8.

the solution containing the assembled materials turns dark blue within seconds. The rapid polymerization indicates a highly ordered assembly and well-aligned diacetylene units. A transmission electron microscopy (Fig. 10) study allowed direct observation of the assembly process of the molecules from flat sheets to helical ribbons and tubes. The rupture of flat sheets along domain edges and the peeling off between stacked lipids explains the assembly mechanism of the formation of the helical ribbons. The model was invoked to explain both morphological change and chromatic transition with change of pH. Hexagonal cells on the surface of the polymeric helical ribbons observed by contact-mode AFM study show the hexagonal cells on the surface of the helical ribbons formed by packing of the three carboxyl groups. The polymer solution shows different colors at different pH values. It became blue at pH < 6 and red at pH > 7.5. The reason for the color change of the

solution is that electrostatic repulsion between the carboxylate groups produces a shorter conjugation pathway and a blue shift because of strain and backbone distortion. Self-assembly of heteroditopic ␣,␻-amphiphiles with different head groups [18–23] formed nano-tubular structures. The unsymmetrical bolaamphiphiles (Bola-9) [22] have been assembled into tubular assemblies. As shown in Fig. 9, if the unsymmetrical bolaamphiphiles pack in antiparallel fashion in the tubular formation, they form symmetrical monolayer lipid membranes (MLMs). If reversed, they form unsymmetrical monolayer lipid membranes (MLMs). For example, bolaamphiphile (Bola-7) [19,24–28] with one galactose head group and one carboxylic head group packs in a parallel fashion to form an unsymmetrical MLM. Unsymmetrical bolaamphiphiles (Bola-7) possessing d-glucose and carboxylic acid head groups assemble as nanotube structures [25]. Bola-10

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Fig. 10. Cross-linked diacetylene bolas with a glutamic acid and a carboxyl head groups produce ribbons with beautifully ordered surfaces (AFM; contact mode); (b) TEMs show networks of fibers [16]. Copyright 2001. Reproduced with permission from ACS.

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Bola-9.

Bola-10.

Bola-11.

molecules are usually assembled to form fiber structures [18]. Assembly morphology of Bola-11 and Bola-12 [21] depend on parameters such as pH, the structure of the amphiphile and position of the connecting links on the imidazole moiety. They can form from vesicle to ribbons through hydrogen-bonding and the morphologies of the assembly may be controlled by adjusting the three parameters. Bola-13 is also an unsymmetric peptide bolaamphiphile, possessing (1-glutamyl)3 glycine at one terminus and either tetraethylene glycol or aspartic acid at

the other end, self-assembled into nanofibers in hydrogels [23]. The unsymmetrical bolaamphiphiles (Bola-14 and Bola15) [29–31], with one amino acid (d- and l-lysine or dand l-ornithine) head group and one ammonium chloride head group (Fig. 11), assembled as rod micelles and nanotubes. It is uncertain whether the amino acid groups of the molecules arrange asymmetrically or not. However, in some vesicles structures, smaller amino groups have been found on the inner surface. 2.2.2. Assembly of symmetrical bolaamphiphilic molecules in solution Another common assembly process is invoked to explain the nanotube formation of dumbbell-shaped peptide amphiphiles or symmetrical bolaamphiphilic

Bola-12.

Bola-13.

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Bola-14.

Bola-15.

Bola-16.

molecules with dicarboxylic acids at both ends (Bola16–Bola-18). High-resolution atomic force microscopy revealed that the peptide head groups pack in a distorted hexagonal fashion orienting, parallel to the normal of the microtube membrane surfaces. On the other hand, the dumbbell-shaped amphiphiles possessing the l-Val-lVal residue as a hydrophilic region, with typical ␤-sheet hydrogen bonding, only self-assembled into nanofibers, and never formed tubular structures. Shimuzu et al. [32] studied oligopeptide-based bolaamphiphiles with dicarboxylic head groups at both ends. Among the bolaamphiphiles, the symmetric bolaamphiphilic molecules formed tubes with a diameter of about 2 ␮m. The tubes included a large number of vesicles (Fig. 12) [1,32–34]. The dicarboxylic oligopeptide bolaamphiphiles containing Gly-Gly (Bola-16) and Gly-Gly-Gly (Bola-17) residues in both oligoglycine head groups selfassembled into vesicle-encapsulated microtubes with even numbers of methylene units [32]. Optical microscopy images (Fig. 12) showed that microtube structures with closed ends and a uniform diameter (about 1–2 ␮m) were formed. Fig. 12 explains the vectorial formation of both acid-anion dimers and interpeptide hydrogen-bond networks in the microtubes [35]. The bolaamphiphile with two glycine residues at each end formed thinner tubes with 1–2-␮m diameter, as compared with the bolaamphiphiles with three glycine residues at each end. No tubes were found when the methylene units of glycyl-glycine bolaamphiphiles were 7, 9 or >11. However, other groups [36,37] reported that glycylglycylglycine based bolaamphiphiles (Bola-17) with odd-numbered methylene spacing groups such as 3 [36] and 7 [37] formed tubes. The bolaamphphiles with head groups of sarcosylsarcosine, Lprolyl-l-proline, glycyl-l-prolyl-l-proline, or glycylsarcosylsarcosine (Bola18) did not form tube structures in aqueous solutions, even after several months [32]. The self-assembled structure of the l-glutamic acid based bolaamphiphile, N,N-eicosanedioyl-di-l-glutamic acid (EDGA) [5,6] (Bola-1), shows “helical sphericalnanotube”. The lengths of the tubes were up to tens of micrometers and 40.0 nm diameters (Fig. 3). The AFM

Fig. 11. (a) TEM image of molecular monolayer nanotubes (pH 10.5, negatively stained with 2% phosphotungstate). (b) Schemes of nanotubes in (a) showing the 4 nm monolayer membrane. (c) The model of the nanotube assumes a statistical arrangement of head groups with preference for the smaller amino head groups on the smaller inner surface (bottom) [29]. Copyright 2004. Reproduced with permission from ACS.

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Bola-17.

Bola-18.

image indicated that the nanotubes are left-handed helical structures, originating from curved helical ribbons (Fig. 3). The assembled structure was formed in 1:1 ratio mixtures of ethanol–water or methanol–water. The benzoic diacid diamide molecule [38] (Bola-19) has a structure that is similar to peptide-based bolaamphiphilic molecules (Bola-16–Bola-18). Its assembly mechanism is shown in Fig. 13. In a solution with pH 8, benzoic diacid

diamide molecules self-assembled into 1 ␮m microspheres during 48-h assembly process. In a solution with pH 7, the benzoic diacid diamide bolaamphiphilic molecule (Bola-19) assembled into nanotubes. After a 12-h incubation, the nanotubes (50 nm in diameter) were detected as a linkage between the microspheres. The two assembly structures for the two different pH conditions are shown in Fig. 13. First, the benzoic diacid diamide molecules self-assembled into microspheres in a solution with pH 8. When the pH was changed to 7, the self-assembled structures reassembled into nanotubes through connecting microspheres. acid-ω-carboxylate bolaamphiphilies ␣-Glutamic (Bola-20) with diacetylenic centers was assembled to form helical ribbons in water. The assembled structure formed

Fig. 12. Several peptide bolas with connecting alkane chains produced tubules which en-trapped vesicles made of the same material upon acidification [15]. Copyright 2005. Reproduced with permission from ACS.

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13 OH

O

H N O

O N H

O OH

Bola-19.

OAc O

AcO AcO

H N

OAc

H N AcO

(H 2C)3

(CH 2)3

AcO O

OAc OAc

O

O Bola-20.

HOOC H

COOH HOOC

H

H

H N

N

N

H

N

H

H

H COOH

N

N

N

N

n

n

Bola-21.

Bola-22.

Bola-23.

nanoscale fibers after UV-induced polymerization [39–41]. The gel assembled from bis-glucosidetetraacetate containing diacetylene units turned red after UV irradiation (max = 506 and 546 nm), which indicated polymerization without change of the fiber appearance in TEMs (Fig. 14).

Urocanic acid-based bolaamphiphilies (Bola-21) [42] are considered to be very important molecules for photobiology. Self-assembled structures of symmetrical bolaamphiphiles derived from (E) urocanic acid (3-[1Himidazolyl-(4)-yl]-propenoic acid) are vesicles and rods in water, but they did not show any change under UV

Bola-24.

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irradiation. The pH, structure, and position of the connecting links were found to be the main parameters for controlling self-assembly of these bolaamphiphiles in aqueous solutions. Only N-alkylated bolaamphiphilic molecules formed vesicles in all pH ranges. In contrast, Oalkylated derivatives with an ester linkage self-assembled into a spherical shape. With an amide linkage, the assembled structures of O-alkylated derivative bolaamphiphiles depend on pH. Under acidic conditions, the molecules self-assemble into rings and vesicles, whereas, under neutral and basic conditions, they form irregular multilayered sheets. Hydrogen bonding is the major driving force for the formation of the assembly. Shimuzu et al. [43] explored nucleotide-appended bolaamphiphilic molecules. In this series of molecules, each end of a long n-alkyl chain has a thymine or adenine derivative attached. These molecules include the complementary 1,␻-thymine, 1,␻-adenine, and 1,␻-(thymine, adenine) bolaamphiphiles, [N,N -bis[3-(2,4-dihydroxy5-methylpyrimidine-1-yl)propionyl]1,n-diaminoalkane [T-n-T (n = 10–12)] (Bola-22), N,N -bis[3-(6-aminopurine9-yl)propionyl]1,n-diaminoalkane [A-n-A (n = 10–12)] (Bola-23), and N-[3-(2,4-dihydroxy-5-methylpyrimidine1-yl)propionyl], N -[3-(6-aminopurine-9 yl)propionyl]1,ndiaminoalkane [T-n-A (n = 10–12)] (Bola-24), respectively]. Among them, the T-10-T bolaamphiphile assembled into double-helical ropes. The rope was 1–2 ␮m wide and several hundred micrometers long. In contrast, the A-10-A form microcrystalline solids in 10% ethanol aqueous solutions. The equimolar mixture of T-10-T and A-10-A was assembled into fibers with 15–30 nm in width (Fig. 15) [43]. In the T-10-T assemblies, natural light induced photopolymerization of the thymine fragments for the chiral rope formation. In T-12-A bolaamphiphile assemblies of supramolecular fibers, hydrogen bonds between the thymine–adenine heterobase pairs prevented the photoreaction and led to the formation of a non-chiral rope.

Fig. 14. (a) TEM of a typical organogel as obtained from an ethyl acetate/nhexane mixture. (b) Irradiation with ␥-rays produced the polymer without changing the fiber’s appearance drastically [39]. Copyright 1668. Reproduced with permission from ACS.

Fig. 13. Illustration of (a) microsphere and nanotube fabrications [38]. Copyright 2002. Reproduced with permission from ACS.

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Fig. 15. TEM image of (a) a double-helical T-10-T rope and EF-TEM images of (b, c) the double-helical ropes (bar = 1 ␮m), (d) nanofibers as a constituent of the helical ropes (bar = 1 ␮m), (e) nanofibers formed from an equimolar mixture of T-10-T and A-10-A (bar = 200 nm), and (f) nanofibers formed from the heteroditopic T-12-A (bar = 1 ␮m) [43]. Copyright 2001. Reproduced with permission from ACS.

Assemblies of T-n-T and A-n-A presented a multilamellar organization. Trans(1R,2R)1,2Cyclohexanedi (11aminocarbonylundecylpyridinium) hexafluorophosphate (Bola-25) [44] assembled into three-dimensional fibrous networks or rods. Intermolecular hydrogen-bonding among the amide groups was responsible for the formation of the assembly structures. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images in Fig. 16 show the self-assembled rods in ethanol with diameter of 50–300 nm. These molecules (Bola-25) assemble to form rods by intermolecular hydrogen-bonding. The symmetric bolaform molecule (Bola-26) consists of two identical 1-glucosamide head groups. These glucosamide- and dipeptide-based molecules incline to self-assemble into crystalline needle-like/right-handed helical/flexible fibers or planar monolayers stabilized by various hydrogen-bonds, summarized in Table 1 [45]. The morphology of self-assembly is determined by the length of the alkyl chain, or the number of methylene repeating units. Reported self-assembly structures include fibers

and planar platelets, depending on the strength of hydrogen bond networks (Fig. 17). Self-assembly structures of hydrogels and thin fibers can compete in this kind of bolaamphiphile, depending on the concentration of the bolaamphiphile, cooling speed and preparation method [46]. The FTIR and X-ray diffraction data are commonly used for the development, identification, and further study of new bolaamphiphile molecules having similar structures [47–53]. Cholesterol-based organogelators [54] possessing monoaza-18-crown-6 and 1,10-diaza-18-crown-6 moieties are reported to have tubular structures with 45–75 nm wall thickness and 170–390 nm inner diameter in cyclohexane. Microscopic observation showed that these tube structures assemble, first as curved lamellar sheets, then into paper-like rolls. In the formation of nanotubes, the bolaamphiphiles in aqueous media assembled as linear ribbons first, then into metastable intermediate helical ribbons, and finally nanotubes. The bolaamphiphilic molecules, cholesterol-based organogelator bearing a dibenzo-30-crown-10 moiety [54–56] (Bola-27), first

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Table 1 Physical properties of 1-glucosamide bolaamphiphiles and the obtained representative morphologies of the self-assemblies from saturated aqueous solutions [45]. Bolaamphiphile Glc-NC(6)CN-Glc Glc-NC(9)CN-Glc Glc-NC(10)CN-Glc Glc-NC(11)CN-Glc Glc-NC(12)CN-Glc Glc-NC(13)CN-Glc Glc-NC(14)CN-Glc

n 6 9 10 11 12 13 14

Mp (◦ C)

Solubility in water (w/v %)a ◦

207.5–208.3 (dec) 212.6–217.6 (dec) 222.2–224.9 (dec) 213.4–220.4 (dec) 220.2–224.0 (dec) 226.3–227.3 (dec) 227.0–229.4 (dec)

>50 (at 25 C) ndb ndb 0.52 (at 36 ◦ C) 0.78 (at 36 ◦ C) 0.11 (at 50 ◦ C) <0.1 (at 70 ◦ C)

Morphology Needle-like Amorphous solid Long thin fiber or gel fiber Twin and platelet Helical fiber Amorphous solid “Bow-tie”-like fiber or thin fiber

Reproduced with permission from ACS. a Solubility was determined using constant-composition methods. b Not determined.

Bola-26.

Fig. 16. SEM (A) and TEM (B) images of self-assembled formed by trans-(1R,2R)-1,2-Cyclohexanedi(11structure aminocarbonylundecylpyridinium) hexafluorophosphate in ethanol [44]. Copyright 2000. Reproduced with permission from ACS.

formed helically coiled ribbon structures in the assembly process. The lipid containing a 1,2-bis(tricosa-10,12-diynoyl)sn-glycero-3 phosphocholine moiety also self-assembled to form an archaeal membrane lipid macrocyclic lipid (Bola-5) [57]. Tubular structure tubes and fibers were constructed by assembly of single-chain bolaamphiphiles containing two Schiff base rigid segments connected by an oxydipheny-

Bola-25.

lene chromophore group, N,N-bis[4-trimethylammonium bromo dodecyloxysalicylaldehyde] diamines (Bola-28) in dilute aqueous solutions [58]. In this molecule, when the rigid oxydiphenylene moiety in the rigid segment center is connected with a flexible chain of methylene repeating units, the self-assembled morphologies are transformed from linear aggregates to spherical vesicles. To change the morphology of the bolaamphiphile monolayer, it is important to control the connector structure. A tetraether bolaamphiphile (Bola-2) is made of two similar bipolar head groups. The tetraether bolaamphiphile [59–61] is the core structural model for archaebacterial membranes. These molecules assemble into a monolayer membrane lipid that accounts for 80–95% of the overall membrane lipid [59] and helps the microorganism to maintain the membrane integrity in a severe environment. In the last twenty years, various structures of tetraetherstructure bolaamphiphile molecules have been discovered, synthesized and explored including those with symmetrical and asymmetrical polar head groups [9,62]. These molecules had the ability to self-assemble to supramolecular structures. The structures could be monolayered or bilayered, and the morphology could be vesicles, disks or crystallized fibers, depending on whether symmetrical or asymmetrical lipids were used, the chain length of the linker repeating units, and the nature of the polar groups. These self-assemblies could be monitored and characterized by optical microscopy (OM), electron microscopy (EM), and dynamic light scattering (DLS).

Bola-27.

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Bola-28.

Fig. 17. (a) Needle-like fibers made of Glc-NC(6)CN-Glc, (b) right-handed fibers from Glc-NC(12)CN-Glc, (c) twin crystal formed with Glc-NC(11)CN-Glc. All were observed using polarized light microscopy (at 25 ◦ C in water) [45]. Copyright 1997. Reproduced with permission from ACS.

Glycerol dibiphytanyl glycerol tetraethers (GDGTs) are one important kind of tetraether bolaamphiphiles, and are synthesized by methane-metabolizing archaea [59,63]. GDGTs and their self-assemblies are quite stable and resistant to oxidation or degradation in geological formations. The compound was recently discovered to be a biomarker to indicate marine gas hydrates, especially methane hydrates in seafloor sediments [63]. Monolayered lipids formed by caldarchaeol–PO4 (Bola3) can anchor to the surface of silicon wafers and form stable mono-molecular films that can be detected and monitored by AFM and ellipsometry [64]. This monolayer film is resistant to rinsing by organic solvent and physical treatments such as ultrasonication. The film stability under hydrophobic effects can potentially be used in medical or industrial fields. Asymmetric bolaamphiphiles (Bola-4) derived from tetraester or tetraether are prone to assemble to vesicles (Fig. 18) instead of fibers or tubes [65–67]. The vesicles are formed from monolayer membranes and have high physical and mechanical stability that is dependent on the stabilizing polar groups, or hydrogen-bonding within the hydrophobic domain or the interface between the hydrophilic domains and the hydrophobic domains of the bolaamphiphile molecules. The self-assembly formed from tetraester derivative macrocyclic bolaamphiphiles (Bola-29) acts as an

artificial cation channel that mimics the biological ion channels of cells [68–70]. Typically these cationic channels come from the vesicle membrane or planar membrane via asymmetric bolamolecules. They are ion-selective depending on ion competition, particularly the alkali cation species [68], and they are controlled by the polar head-groups of the molecular structures [69]. Some vesicles from asym-

Fig. 18. Transmission electron microscopic image of negatively stained vesicles formed by bolaamphiphile molecules (R1 = R2 = S CH2 COO− Na+ ) [67]. Copyright 1986. Reproduced with permission from ACS.

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Bola-29.

Bola-30.

metric bolamolecules are highly membrane-active ion transporters [71]. The nano-sized vesicles assembled from vernolic-acidbased-bolaamphiphiles (Fig. 19) [72,73] (Bola-30) are also a kind of cationic vesicle. They have another important application in the medical field in the targeted delivery of drugs to certain lipid-abundant tissues, especially the brain. Their nano-size dimension leads to higher efficiency in vivo and can overcome problems of regular liposome delivery [72]. The targeting mechanism relies on the hydrolysis of the bola head groups through a certain enzyme abundant in the target tissue, followed by release of the encapsulated drug at the target site. Because cationic surface groups combining with the vesicles enhance the penetration that allows the vesicles to cross the cell membrane, cationic vesicles will have a longer circulatory lifetime and good permeability, to facilitate delivery to the target place after intake. A multi-step synthesis gave a novel bolaamphiphilic (Bola-31) fullerene structure with two ammonium head

groups [74]. This novel structure was used as a model molecule for understanding the conditions necessary for self-assembly of this type of bolaamphiphile. Bola-31 shows the molecular structure of the bolaamphiphile. Different assembly structures are observed, as shown in Fig. 20 [74]. Vesicles with various shapes and sizes are present in the assembly system. A bilayer membrane model was also proposed for the formation of vesicle structures by the bolaamphiphilic fullerene structure. Controlling aggregation of these structures in solution is of great importance for the development of functional materials. Dequalinium dichloride was described in a study on its application as an antimicrobial agent. Stable MLM vesicles are formed by the assembly of the dicationic dequalinium dichloride bolaamphiphiles as shown in Bola-32. Applications include nontoxic vehicles for DNA delivery to mitochondria [75]. A bis-macrocyclic bolaamphiphile (Bola-33) was synthesized by multi-step synthesis [76]. These molecules

Bola-31.

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rigid linkage structure than that of the latter. As a result, the assembly structures are also different: Bola-39 shows a fiber/ribbon assembly structure, while Bola-38 shows a vesicle structure [58]. Slight changes in stereochemistry of the head groups can lead to major differences in the assembly structure of bolaamphiphiles [43,77–83]. Helical fiber structures are observed for bis-glucoside bolaamphiphiles (Bola-40 and Bola-41), with a stiff diazobenzene bisamido core in concentrated DMSO/water solutions [78,83–85]. These helical fibers converted to vesicles with the interaction between poly(l-lysine) boronate and bis-glucoside bolaamphiphile (Fig. 21). Fiber shaped structures as shown in Fig. 22 are observed in the assembly of asymmetric bolaamphiphiles such as (16-carboxy hexadecyl)trimethylammonium bromide Bola-42. 3. Applications of bolaamphiphilic molecules 3.1. Bolaamphiphilic molecule templates for synthesis of nanomaterials

Fig. 19. Transmission electron microscopic images of the nano-sized vesicles from vernolic-acid-based bolaamphiphile molecules [72]. Copyright 2010. Reproduced with permission from John Wiley & Sons.

Bola-32.

were designed for creating pores for ion transport. To create a stretched conformation, the ideal amphiphiles for this application are molecules with a long hydrophobic core to cross the lipid membrane and with polar head groups at the ends of the bolaamphiphile. Most interestingly, the ion channels have ion-selective pores and can transport both cations and anions by designing different polar headgroups of the structures. Comparing the two bolaamphiphiles Bola-38 and Bola39 [58], the central linkage structure of the former has more

Since bolaamphiphilic molecules show excellent hierarchal assembly structures, they can be utilized as a template for fabrication of nanomaterials. Recently, symmetrical bolaamphiphilic molecules formed ring shell structures with certain precursors under some conditions. So far, several metal [86], and metal oxide nanomaterials [87,88] have been successfully synthesized. Hollow titania nanotubes (Fig. 23) were fabricated using a bolaamphiphilic molecule (Bola-25) as a template. In this fabrication, a bolaamphiphilic compound (Bola-25) containing cationic charges self-assembled as tubes and electrostatically interacted with titania precursors in the sol-gel polymerization process of Ti[OCH(CH3 )2 ]4 . In basic conditions, the precursor solution was composed of Ti[OCH(CH3 )2 ]4 , the bolaamphiphilic molecule (Bola-25), ethanol and an ammonium hydroxide aqueous solution. In acidic conditions, NH3 in the precursor solution was replaced by hydrochloric acid. First, Ti[OCH(CH3 )2 ]4 and the bolaamphiphilic molecule were mixed with half of the prescribed amount of ethanol. Ammonium hydroxide aqueous solution (25%) or HCl aqueous solution (2 M) as a catalyst was added to the other half of the prescribed amount of ethanol. A mixture of the two solutions was then heated at 80 ◦ C. Lastly, the mixture solution was further calcined at 450 ◦ C for 2 h to remove the template and completely convert the product into pure hollow TiO2 nanotubes. For the synthesis of metal nanotubes, a nanotubeassembled structure of l-glutamic-acid-based bolaamphiphile, N,N-eicosanedioyl-di-l-glutamic acid (EDGA) [89] was applied to fabricate double- and multi-wall silver

Bola-33.

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Bola-34.

Bola-35.

Bola-36.

Bola-37.

Bola-38.

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Bola-39.

Fig. 20. TEM micrographs of dispersed vesicles at various magnifications [74]. Copyright 2000. Reproduced with permission from ACS.

Fig. 21. Morphological differences between the assembly structures of bolaamphiphiles with head groups of different stereochemistry: A–C are TEM images of the assembly structure of Bola-40 and Bola-41, respectively [78]. Copyright 2002. Reproduced with permission from RSC.

Bola-40.

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nanotubes. In the fabrication process for silver nanotubes, the gel was formed from the mixture of AgNO3 and the bolaamphiphilic molecule (Bola-1) in water/ethanol. The silver(I) cations electrostatically bound to both the inner and outer surfaces of the EDGA nanotubes. Photoirradiation was then used to reduce silver cations into silver metal and double-wall silver nanotubes with two silver layers and one EDGA layer (Fig. 24). This gel nanotube can be used as a template to react with a metal precursor such as AgNO3 to form metal particle coated nanotubes. Single-wall (SW), double-wall (DW), triple-wall or even more-layer-wall nanotubes are acquired by controlling the reduction time [89]. The mechanism for the formation of multiple walls is as follows: EDGA molecules on the outside surface of nanotubes are dissolved into solvent in the reduction process, allowing more free metal ions to be absorbed onto the newly formed tube surface. The free EDGA molecules then bind to the metal, and a new tubular layer forms. This procedure can occur again and again for the formation of multi-wall nanotubes, as shown in Fig. 24. For the controlled synthesis of gold nanomaterials, bolaamphiphilic monomers (Bola-16) are mixed with the water-insoluble trimethylphosphinegold chloride (AuPMe3 –Cl) for 5 days in the dark (Fig. 25). After ring-shaped nanostructures were formed, 20 min of UV irradiation was applied to reduce Au ions in the nanodoughnuts (Fig. 25). Au nanocrystals are generated inside

Fig. 22. Fiber morphology of assembled Bola-42 [1]. Copyright 2004. Reproduced with permission from ACS.

Bola-42.

Fig. 23. SEM images of the dried samples prepared under acidic (A) and basic (B) conditions [44]. Copyright 2000. Reproduced with permission from ACS.

Bola-41.

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Fig. 24. (A) Possible mechanisms for template synthesis of double wall (DW) and multi wall (MW) Ag NT: (a) bolaamphiphilic nanotube. (b) Formation of a DWSNT. (c) Self-assembly of the bolaamphiphilic EDGA molecules and Ag on the surface of the formed DW Ag NT. (d) Formation of a three-layered Ag NT. (B) (a) TEM image of the synthesized silver nanoparticles (EDGA/AgNO3 in a 3.5:5 weight ratio), exposed to daylight for 17 h with stirring. (b) TEM image of the synthesized SNTs (EDGA/AgNO3 in a 0.35:1 weight ratio) exposed to daylight for 17 h without stirring [89]. Copyright 2006. Reproduced with permission from ACS.

the cavities of nanodoughnuts (Fig. 25). The shell of the doughnut structure was destroyed by long UV irradiation for the formation of gold nanoparticles. The average diameter of the Au nanocrystal is 12 nm. The same synthesis approach was applied to fabricate ferroelectric barium titanate at room temperature. A ringshaped assembly of the peptide bolaamphiphiles (Bola-16) provides a unique template for the synthesis of ferroelectric nanoparticles under environmentally benign conditions. Due to the effect of a depolarization field, it is difficult to synthesize ferroelectric nanoparticles at room temperature [90,91]. A ring structure was applied to suppress effects from side depolarization field in this synthesis. Ferroelectric nanoparticles were synthesized for the first time at room temperature using an assembly of peptide bolaamphiphilic molecules as a template [88]. A ring-shaped assembly of bolaamphiphilic molecules has been applied to synthesize other oxides such as gallium oxides under environmentally benign conditions [87]. Peptide bolaamphiphilic tubes are widely utilized as templates in the synthesis of nanomaterials including metal and semiconductors [35,36,92–96]. In this approach, peptide sequences that can catalyze the synthesis of materials are attached to the side walls of peptide bolaamphiphilic molecule (Bola-16) assembled tubes so that the peptides optimized from naturally-observed mineralizing sequences not only catalyze the material synthesis

under mild conditions, but also direct the growth of a particular crystalline structure, shape, and size depending on the experimental conditions. The crystalline, size and shape of the nanomaterials on the bolaamphiphilic tube template can be relatively well-controlled by biomimetic material growth. For example, biomineralizing functional peptides with a high affinity for Cu coated on the tubes can grow monodispersed Cu nanoparticles, and the size of Cu nanoparticles on the nanotube is directly related to the conformation of the peptide (Fig. 26). The shape of Ag nanocrystals may be optimized by peptides that can slow down or catalyze the growth on certain crystalline faces over others due to characteristic amino acid sequences. 3.2. Sensors Acetylene-based bolaamphiphilic systems are widely exploited in sensing applications since the solution containing the bolaamphiphilic molecules changes color in response to external stimulus [97,98]. These sensors are developed by incorporating molecular recognition and signal transduction into a supramolecular assembly that will respond with a color change via binding events (Fig. 27). These colorimetric sensors can provide device-free on-site detection of biological hazards and have great potential application for a variety of medical or household purpose diagnosis. As shown in Fig. 27 [17] in PDA based DNA sensor

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Fig. 25. (A) Scheme for the peptide nano-doughnut self-assembly as a nanoreactor: (a) nano-doughnut assembly in the presence of organic Au salts, (b) Au ions in the peptide ring are reduced by short UV irradiation (<20 min). (c) Longer UV irradiation (>10 h) destroys the nano-doughnut to release the Au nanocrystal. (B) (a) AFM and (b) TEM images show the nanodougnut assembly of peptide bolaamphiphilic molecules containing gold ion precursor in the middle of the rings. (C) (a) AFM image of the gold nanoparticles after long UV irradiation, (b) Phase image from AFM showing bright gold nanoparticles, (c) histogram of nanoparticles [86]. Copyright 2004. Reproduced with permission from ACS.

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Fig. 26. (a) Proposed structure of the Cu nanocrystal–HG12 peptide complex on a template nanotube. The conformation change of peptides influences the nucleation and growth rate to control Cu nanoparticle domains on bionanotubes. (b) Cu nanocrystals grown on a bionanotube at pH 6; (top-left) TEM image. (Top-center) electron-diffraction pattern, (top-right) size distribution, (inset) the TEM image in higher magnification. (Bottom) (c) Cu nanocrystals grown on a bionanotube at pH 8; (bottom-left) TEM image. (Bottom-center) electron diffraction pattern. (Bottom-right) size distribution. (Inset) the TEM image at higher magnification (scale bar = 100 nm) [96]. Copyright 2003. Reproduced with permission from NAS.

Fig. 27. Schematic illustration of colorimetric PDA sensors shows surface ligands and their interactions with target molecules [17]. Copyright 2008. Reproduced with permission from ACS.

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Fig. 28. Time-dependent UV–vis spectra of 10-layer LS films from (a) HCDA6, (b) HCDA7, (c) HCDA8, (d) HCDA9, (e) HCDA10, and (f) HCDA11 under 254 nm UV irradiation. (g, h) Plot of the peak at 315 nm as a function of irradiation time [7]. Copyright 2012. Reproduced with permission from ACS.

systems, PDA films and vesicles functionalized with carbohydrates and immobilized with probe DNA molecules undergo a blue-to-red colorimetric transition upon binding with complementary strands of DNA, enabling them to be used as colorimetric DNA sensors. The same strategy was also applied for the detection of the influenza virus [99], cholera toxin [100], and Escherichia coli (E. coli) [101]. Bolaamphiphiles containing a single-headed cinnamoyl could (Bola-6) [7] in LB films were investigated for photodimerization under UV irradiation. The effect of different packing of bolaamphiphiles on the photochemistry of the cinnamoyl groups in organized films was studied and the films showed spectral change both with and without photo-irradiation (Fig. 28). However, these films showed behavior that depended on the spacer length. Furthermore, both the length and odd–even number of the spacers can subtly affect both the molecular packing and photochemistry. The assemblies changed from J-aggregate to H-aggregate as the number of methylene units changed from 6 to 12. The molecule with even-numbered methylene units inclined to form nanorod structure at the air/water

interface. However, the molecule with odd-numbered methylene units formed nanospirals and nanofibers. The interaction between H-bond in the phenolic hydroxyl and the amide groups, ␲–␲ stacking as well as the hydrophobic interactions of the alkyl spacer was applied to explain the spacer effect in the assembly. A system consisting of the polyacetylene (PDA) based bolaamphiphilic molecules (Bola-19) investigated in aqueous media underwent blue-to-red color transitions at or below 70 ◦ C and became red color at ca. 90 ◦ C [40]. In repeated heating-cooling cycles, interactions between strong head groups in the PDAs are critical factors for colorimetric reversibility. The carboxyphenylanilido groups of the molecules at both ends of the DA monomer show stronger head group interactions in the resulting PDA. The color of the PDA supramolecules (Fig. 29) shows no apparent change even in boiling water. Bolaamphiphilic polydiacetylene (BPDA)-based colorimetric sensors [97] were studied based on nanoscopic morphological transformations with chromatic transitions. As shown in Fig. 30 [97], one end of a diacetylene containing

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Fig. 29. (A) Scanning electron microscope (SEM) image of PDA supramolecules prepared with the bolaamphiphilic diacetylene in ethylene glycol. (B) Photographs of PDA suspensions in ethylene glycol during thermal cycles [40]. Copyright 2009. Reproduced with permission from John Wiley & Sons.

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a lipid [16,102], 10,12-docosadiynedioic acid, was modified with l-aspartic acid, l-lysine, l-serine, and ethanolamine through an amide linkage to form the bolaamphiphiles (series of Bola-7) BPDA-1, BPDA-2, BPDA-3, and BPDA4, respectively (Fig. 30). These surface residues differed in their charge and hydrogen bonding capabilities. The diacetylene unit was placed at the center of all four bolaamphiphiles to promote the proper alignment of diacetylenes irrespective of their packing arrangement (i.e., parallel or antiparallel). The compounds BPDA-1–BPDA-4 (Fig. 30) were polymerized assemblies and studied for their optical properties. As shown in Fig. 30(A) and (B), after a 0.1 J/cm2 irradiation, BPDA-3, possessing l-serine surface residues, absorbed mainly at 630 nm and gave a blue color (Fig. 30(A)). The other three BPDAs, terminated with ethanolamine, l-lysine, and l-aspartate residues on one end of the bolaamphiphilic lipids, absorbed more intensely at 540–550 nm (the “red phase”), displaying various shades of blue (for BPDA-2 and BPDA-4) and purple (for BPDA-1) (Fig. 30(B)). For these BPDA systems, different pH- and temperatureinduced Colorimetric Responses (CR) were investigated with dramatic morphological transformations at nanoscale. The CRs of BPDAs with temperature change are shown in Fig. 31. A similar trend for pH-induced CR was also found for all BPDAs. The most sensitive response to temperature increases was found in BPDA-1 (80% at 60 ◦ C). The other three BPDAs are relatively less responsive, with 10% CR at 50 ◦ C. Among all the systems, at 80 ◦ C BPDA-3 was most resistant to the thermal change, maintaining a colorimetric response less than 20%. As shown in Fig. 31, the blue-to-red CR most sensitive to pH value change was also BPDA-1 with a 20% CR at physiological pH (pH 7.4). At pH 8.5 and pH 11, the colorimetric changes of BPDA-1 increased dramatically to 50% and 80%, respectively. However, the other three BPDAs showed no response between pH 6 and pH 7.4 (Fig. 31). CRs for BPDA2 and BPDA-3 with a 50% increase required the pH of the solutions to be 10.5 and 10, respectively. The CR of BPDA-4

Fig. 30. (A) Visible spectra of BPDAs formed with 0.1 J/cm2 UV irradiation: BPDA-1 (green); BPDA-2 (pink); BPDA-3 (blue); BPDA-4 (red). a.u. arbitrary units. (B) BPDAs formed with 0.1 J/cm2 UV irradiation display various shades of blue (BPDA-2, BPDA-3, and BPDA-4) and purple (BPDA-1) at ambient conditions [97]. Copyright 2004. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.) Reproduced with permission from ACS.

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Fig. 31. (A) BPDAs show color changes with various temperatures. (B) pH induced color change of all BPDAs formed with 0.1 J/cm2 irradiation at 254 nm [97]. Copyright 2004. Reproduced with permission from ACS.

was the least responsive one, with no CR increase even at pH 14. The preparation of label-free sensor systems was based on the fluorogenic properties of the conjugated polymer polydiacetylene (PDA) [17]. PDA has been extensively investigated as a sensor matrix, owing to a brilliant blueto-red color transition that takes place in response to environmental perturbations. Bolaamphiphilic molecules (Bola-1) have been studied for optical sensor applications (Fig. 32) [5]. The two enantiomeric glutamic acid-based bolaamphiphiles were self-assembled into chiral nanotubes in hydrogels with opposite helicities. After mixing with an azobenzene derivative, 4-(phenylazo) benzoic acid sodium salt (Azo), the bolaamphiphiles or nanotubes co-assembled to possess the function. Various assembly methods were tried to construct the azo-containing hierarchical nanotube structure. One approach was the assembly of the Azo with the prepared chiral nanotubes. In the second approach, Azo was mixed with the bolaamphiphiles in solution at elevated temperature first, then the mixture was cooled to form the co-gel. In both methods, the chirality of helical tubular structures and the supramolecular structure were examined. The two different assembly methods provide different functions. In the first method, when the strong exciton-type Cotton effect was examined, supramolecular chirality was found to be irreversible under alternative UV–vis irradiation; however, the system had a reversible absorption because Azo exhibits cis-trans isomerizations. In the second approach, the system demonstrated reversible changes in both UV–vis and CD spectra under alternative UV–vis irradiation. This result revealed that the system had a simultaneous formation of an optical and chiroptical switch and demonstrated a feasible method for tuning the function of the lipid nanotube systems.

Fig. 32. (A) Molecular structures of the hydrogelators HDGA and Azo, (B) gels formed by l-HDGA in water in the absence and presence of Azo, respectively [6]. Copyright 2011. Reproduced with permission from RSC.

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Fig. 33. Impedimetric pathogen biosensors assembled from peptide nanotubes; (a) antibody modified nanotubes concentrate virus at the gap between two electrodes, leading to increased impedance at high frequency; (b) peptide nanotube biochips for the multiplexed detection of bacterial cells via agglutination on an array of impedimetric transducers [104]. Copyright 2010. Reproduced with permission from RSC.

Symmetrical bolaamphiphilic molecule (Bola-17) based tubes were applied as building blocks for bio-sensors. In both the detection and the identification of viruses, specific interactions among peptides and proteins have been exploited to develop sensors. In particular, the functional bolaamphiphilic nanotubes with antibodies have been prepared to detect viruses [103,104] (Fig. 33). In this sensor, as shown in Fig. 33 [104,105], antibody attached bolaamphiphilic nanotubes (Fig. 33) were aligned to link to two electrodes through positive dielectrophoresis. In this sensor, if the low permittivity virus binds to the antibodymodified nanotubes, the impedance at the gap between the electrodes will increase at high frequency. The capacitance of the solution was measured in order to detect the binding effect between the nanotube and virus [106]. In the design of a reusable pathogen biochip for bacteria detection, the detection platform of the biochip consisted

of an array of 36 pairs of transducers; each transducer had peptide nanotubes attached to bind to specific types of bacteria. When bacteria were absorbed by peptidemodified nanotubes, the impedance of the electrodes will increase rapidly. As a result, E. coli and Salmonella typhimurium cells were successfully differentiated by the peptide nanotube multisensor in the range from 102 to 104 cells. A similar peptide nanotube detection strategy to that used for pathogen sensing was also applied as a platform for the detection of heavy ion elements [104]. In that approach, after the target heavy ion binded to the metalbinding-peptide-coated-nanotube electrodes at the most sensitive location on the transducer, the attached heavy metal ion was further reduced by a reducing agent. The resulting metallic junction of the specific peptide-coated nanotube between the electrodes served as a resistor in

Fig. 34. Strategy for the detection of ultralow levels of Pb2+ with the peptide nanotube detection platform; (a) in the absence of Pb2+ ; (b) in the presence of Pb2+ , peptides nucleate the crystallization of Pb; (c) conductance (G) of the peptide nanotube between the electrodes after the incubation with varied heavy metal ions; concentrations are indicated on each bar [105]. Copyright 2011. Reproduced with permission from John Wiley & Sons.

Bola-43.

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Fig. 35. Scheme to assembly of two different antibody nanotubes, anti-mouse IgG-coated nanotube and anti-human IgG-coated nanotube, into a cross-bar geometry using biomolecular recognition (left). AFM image of the two antibody nanotubes assembled in cross-bar geometry (right). Scale bar = 200 nm [110]. Copyright 2008. Reproduced with permission from John Wiley & Sons.

the equivalent circuit (Fig. 34). However, in this configuration, other heavy metal ions not specific to the peptide were not detected. As a result, other ions do not form crystalline depositions even after the reduction step. 3.3. Electronics Miniaturization of logic circuits is a practical way to develop powerful electronic devices in the future. Biological interactions between antigens and antibodies can be used to align nano-building blocks for electrical circuits. For example, the assembly of proteins onto targeted areas on electrical substrates has been applied to construct a metal–oxide semiconductor (MOS) device [106]. Nanowires modified with various antibodies were aligned on complementary-protein-patterned areas on the electric substrates, allowing the fabrication of the desired electrical device structures [107] (Fig. 35). Many techniques have been developed for the fabrication of nanoscale electronic circuit [108,109] in combination of both bottom-up and top-down approaches. Biomimetic approaches are one of these recent approaches. Specific interactions between antigens and antibodies were applied to align bolaamphiphilic tubes (Bola-16) as building blocks for logic gate modules. Nuraje et al. [107] aligned peptide tubes with

antibodies onto antigen-patterned surfaces, demonstrating that mouse-IgG-immobilized-peptide-tubes selectively attached onto antimouse-IgG-patterned areas, and never absorbed human-IgG-patterned areas. Similarly, cross-bar assembled modules were achieved as shown in Fig. 35 [110]. Chemical approaches have also been applied to immobilize the bolaamphiphilic tubes onto selective locations [111,112]. alkanedisulfide Tetracyanoquinodimethane (TCNQC10 S)2 (Bola-43) can form a self-assembled monolayer (SAM) onto a metal substrate surface (Fig. 36) [113]. This (TCNQC10 S)2 SAM can be fabricated to a metal/SAM/SAM/mercury electronic-junction that has the ability to rectify an electric current. These junctions represent a particularly useful model system for electrical rectification by organic thin films for three reasons: (i) they do not contain a donor-acceptor compound or an embedded molecular dipole, (ii) neither electrode is formed by a process involving evaporation of metal atoms onto organic molecules, and (iii) the thickness of SAM on the mercury electrode can be varied systematically without extensive synthetic efforts [113,114]. Other bolaform compounds with thiol head groups, such as tetraphenyl molecules (Bola-44), can also be fabricated to a single-molecule diode as shown in Fig. 37 [115].

Fig. 36. Schematic illustration of the fabrication of the metal-SAM insulator–metal junction [113]. Copyright 2002. Reproduced with permission from ACS.

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Bola-44.

Fig. 37. Break junction measurements for a tetraphenyl molecule that behaves as a molecular diode [115]. Copyright 2011. Reproduced with permission from ACS.

3.4. Drug delivery A monolayer of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol forming at the air/water interface has been used as a model. Simultaneously, derivatives of synthetic urocanic amphiphiles (Bola-21) were studied using rat skin

on a flow-through diffusion cells. This study showed both the flux and the cumulative amounts were similar in the DPPC/cholesterol monolayer and epidermal lipids using incorporation and diffusion methods. The model membrane from Langmuir–Blodgett technique is suitable for the study of primary screening of amphiphilic compounds [116]. The nanotube consisting of unsymmetrical bolaamphiphile, N-(2-aminoethyl)-N -(ˇ-d-glucopyranosyl)icosanediamide [19] (Bola-9), was applied for detection of the encapsulation of guest molecules after modification of the inside of nanotubes with a fluorescence donor dye. Fluorescence resonance energy transfer (FRET) from the fluorescence donor on the inner surface to the fluorescence acceptor allowed visualization of the encapsulation and nano-fluidic features of the ferritin in the nano-channel. A bolaamphiphilic prodrug [117] (Bola-45), containing dual zidovudine, pentadecanedioyl dizidovudine (PDDZ), was vesicular self-assembly prepared by injecting a methanol solution of PDDZ into water. Hydrophobic interaction was the main driving force for the molecular self-assembly. In combination with the nonionic surfactant Tween 20, the physical stability of self-assemblies was much improved due to the formation of surfactant micelles. The mean size of hydroxylpropylmethylcellulose (HPMC) vesicles was 156 nm. A PDDZ self-assembly system improved anti-HIV activity on a MT4 cell model. PDDZ was efficiently spread into the liver, spleen and testis followed by the rapid production of AZT after intravenous injection to rabbits. The bolaamphiphilic PDDZ vesicle demonstrated a promising self-assembled drug delivery system (SADDS). 3.5. Gene delivery

Fig. 38. Schematic presentation of bolaamphiphile, its hypothetic assembly into asymmetric monolayer membranes and formation of DNA complexes, so-called bolaplexes (A). Red and green parts represent cationic and neutral head groups, respectively. Chemical structures of the new bolas (B) [138]. Copyright 2012. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.) Reproduced with permission from Elsevier.

Systems based on Bola-7, Bola-14 and Bola-15 have been studied for gene delivery [18,20,118]. The bolaamphiphilic molecule was prepared by the following steps: the bromine of tetralkylammonium salts containing a long hydrolysable chain and a terminal bromine atom or amino group was substituted by thiomannose, the amine amidated with a mannopyranosyl-gluconolactone. The

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Fig. 39. An assembly mechanism of Cu2+ -l-HDGA nanotubular structure and its asymmetric catalysis for Diels–Alder reaction of aza-chalcone with cyclopentadiene [119]. Copyright 2011. Reproduced with permission from ACS.

Bola-45.

bolaamphiphiles had positively charged tetraalkylammonium and an electroneutral mannose head group that could interact with negatively charged nucleic acids. The tritium labeled bolaamphiphile coating on the 3 P-labeled t-RNA was absorbed by macrophages (Fig. 38) and uncoated t-RNA was not. Bolaamphiphilic molecule Bola-9 based tubular nanomaterials have been studied for nonviral gene transfer vectors because they have a unique morphology and can be functionalized by biological methods [27]. Functionalized organic nanotubes (ONTs) for gene delivery were constructed via co-assembly with bipolar glycolipid, arginine-lipid and PEG-lipid. They protected DNA from enzymatic degradation via efficient complexing with

plasmid DNA. The experimental results showed, although long ONTs with a length of 1 ␮m was difficult to adsorb into cells, those with a length of 400–800 nm effectively convey plasmid DNA into cells and lead high transgenic expression of green fluorescence protein (GFP). This study proved the practicability of functionalized ONT in the gene delivery process. 3.6. Catalytic reaction The formation of helical nanotube or nano-fiber structures from the self-assembly of l-glutamic acid-based gelators (l-HDGA, Bola-1) has been investigated under the

Fig. 40. Lipase-immobilized nanotube fabrication and its enzymatic application [120]. Copyright 2005. Reproduced with permission from ACS.

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Fig. 41. Structure and conformation of a bis(crown ether) bolaamphiphile and the binding mechanism of Ba2+ in a bilayer membrane [1]. Copyright 2004. Reproduced with permission from ACS.

condition of presence of or absence of Cu2+ ions [119]. The self-assembly of the molecule changed dramatically when Cu2+ ions were added. Furthermore, the monolayer nanotube of l-HDGA by Bola-1 transited to a multilayer nanotube with an approximately 10 nm thick tubular wall

in the presence of Cu2+ ion. However, other amphiphiles did not form the gel, forming nanofiber structures instead. These nanostructures containing Cu2+ can be applied as a catalyst for Diels-Alder cycloaddition between cyclopentadiene and aza-chalcone (Fig. 39). This

Fig. 42. The rectification behavior and the schematic structure of the assembly artificial channel by asymmetric bolaamphiphiles [123]. Copyright 2001. Reproduced with permission from ACS.

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nanostructure catalyst not only enhanced the reaction rate, but also improved the enantiomeric selectivity. In summary, the substrate molecules could be immobilized onto the Cu2+ mediated nanotube surface and could form a stereochemically favored alignment. The fabrication and scale-up of the Cu2+ -mediated nanotube appears to provide a new platform for high-efficiency chiral catalysis. Candida rugosa lipase immobilized to the inside channel of peptide tubes (Bola-16) increased their catalytic activity in some applications [120]. In order to evaluate the catalytic activity of enzymes inside PNTs, both the change in the hydrolysis rate of p-nitrophenyl butyrate and the concentration of one product, p-nitrophenol, were measured. The result showed that at room temperature the activity of enzyme inside PNTs was 33% higher than the activity of free enzyme in the solution. At 65 ◦ C, the activity of enzyme inside PNTs increased 70% compared with the free enzyme. Two possible mechanisms were launched based on both the capillary effect and the hydrophobic interactions (Fig. 40). 3.7. Membrane

Fig. 43. Bolaamphiphilic chemical stopper to open and close the ion channel pore reversibly [1]. Copyright 2004. Reproduced with permission from ACS.

The cyclic glycerophospholipid was synthesized by linking the alkyl chain (Bola-5) with two glycerol head groups to form a 64-membered macrocycle [121]. The incorporation of two methylene moieties in the alkyl chains in the lipid was aimed at improving the membrane fluidity. A fluorescence recovery study proved that the membrane containing the methylene-cyclic-lipid had better fluidity than that with a single linear alkyl-chain lipid in an equal ring size at room temperature. Crown ethers (Bola-34), especially 18-crown-6, draw attention for their selective binding to cations. The U-shaped bis(crown ether) conformation of this bolaamphiphile can bind the Ba2+ cation quite effectively [122]. The proposed cation binding process is shown in Fig. 41, in which the interaction occurs between the crown ether head groups and the Ba2+ cations; the U-shaped conformation formed facilitates the disruption of the bilayer. This bis(crown ether) bolaamphiphile can potentially be applied as an ion channel in a bilayer membrane. Supramolecular assembly structures can form from bolaamphiphiles with asymmetric anionic head groups, such as Bola-35 and Bola-36. When incorporated into bilayer lipid membranes these assemblies exhibit clear rectification properties, as shown in Fig. 42. Potassium channels turn to the open status under application of a 100 mV potential. This first rectification property to be observed on a non-peptidic channel provides a prototype for an artificial voltage-dependent channel [123]. Artificial ion channels usually form pores in a bilayer lipid membrane [124,125]. The easiest way to control the opening or closing of a pore is the reversible placement a chemical stopper. A bolaamphiphile, such as ␣,␻-disulfone bolaamphiphile shown in Fig. 43, can be candidates for stopper molecules. Synthetic transmembrane channels containing 18crown-6 or ␤-cyclodextrin units, which integrate holes

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Fig. 44. Zinc porphyrinate molecule was used to absorb the light and induce a charge separation in the bolaamphiphile structure [1]. Copyright 2004. Reproduced with permission from ACS.

within membranes, have been reviewed by Gokel and Murillo [126]. They produced a tris(macrocyclic) channel model system and a steroid bolaamphilphile (Bola37) that stayed at the bilayer membrane mid-plane and stretched the OEG arms to the inner and outer surfaces. Bolaamphiphiles can also used as an electron conductor in a monolayer or bilayer lipid membrane, which otherwise would be an insulator for electrons. A dye-sensitized light absorption and charge separation [127] observed between a quinone bolaamphiphile in a bilayer membrane is shown in Fig. 44. Stiff polyene bolaamphiphiles [128,129] disturbed the fluidity of bilayer lipid membranes and allowed the electron transport across the membrane. Those delocalized aromatic structures played the role of a “conductive wire” for electrons to move forward, as shown in Fig. 45.

Fig. 45. Electron transport along the polyene bolaamphiphiles in bilayer lipid membranes [1]. Copyright 2004. Reproduced with permission from ACS.

Fig. 46. (a) Schematic representation of the fluorescent polyene bolaamphiphile in a phospholipid bilayer; (b) the fluorescence images of giant unilamellar vesicles (diameter 30 ␮m) [130] Copyright 2001. Reproduced with permission from John Wiley & Sons.

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Fig. 47. (A) Hydrophobic ligands of QDs (1) were exchanged with 1H,1H,2H,2H-perfluorooctanethiol (2). The dispersion of these QDs in perfluorocarbon (PFC) liquids was facilitated by the fluorooctanethiol (Bola-48) outer layers (3). Finally, QDs-containing PFC liquids were emulsified in aqueous solutions using various surfactants, such as phospholipids and cholesterols, to provide biocompatibility [137]; (B) TEM image of nanocomposite emulsion [137]. Copyright 2009. Reproduced with permission from ACS.

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Fig. 48. Fluorescence microscopic images and flow cytometry analysis of immunotherapeutic cells labeled with PFC/[CdSe/ZnS QDs] nanocomposite emulsions (10 mg/mL). Macrophage and T cells were labeled with PFDOC/[CdSe/ZnS (525 nm) QDs] and PFDOC/[CdSe/ZnS (596 nm) QDs], respectively. Dendritic cells were labeled with PFOB/[CdSe/ZnS (596 nm) QDs]. The % number represents positive percentage of labeled cells. PFDOC is perfluorodioctylchloride, and PFOB is perfluorooctylbromide [137]. Copyright 2009. Reproduced with permission from ACS.

Bola-46.

3.8. Imaging Polyene bolaamphiphile used as transmembrane fluorescent probe in cell lipid bilayer [130,131] were synthesized as symmetrical bolaforms (Bola-46) with four, five, or more conjugated double bonds in the center of the molecule, linked to terminal carboxylic acid groups.

They are thermally stable if kept in a cool, dark place, with solubility in ethanol or dimethyl sulfoxide (DMSO) in the range of 1–10 ␮M. They can span typical lipid bilayers within a maximum expanded length of 35–43 A˚ [68,130], permitting the carboxyl groups to reach the two opposite membrane surfaces, with the polyene chromophore located right in the center of the bilayers, as shown in Fig. 46(A). Thus they can be utilized as transmembrane fluorescent probes for lipid imaging; in clinical field they could be used to visualize ether lipid in the brain and study brain function [132]. Bolaamphiphile with a thiol head group (Bola-47) can form lipid monolayers on the surface gold nanoparticles in water or toluene solution, providing anticorrosive protection against aqueous 0.1 M cyanide solutions [133–135].

Bola-47.

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Fig. 49. In vivo detection. (a) Black and white image of the mouse injected with three different types of immune cells (5 × 106 –1 × 107 cells/mL) labeled with PFC/[CdSe/ZnS QDs] nanocomposite emulsions: (A) Macrophage cells labeled with PFDOC/[CdSe/ZnS (525 nm) QDs]; (b) T cells labeled with PFDOC/[CdSe/ZnS (596 nm) QDs]; and (c) dendritic cells labeled with PFOB/[CdSe/ZnS (596 nm) QDs]; (b) image obtained by using a green filter (525WB20); (c) image obtained by using a red filter (600WB20); (d) 1H MR image; (e) PFDOC-resonance selective MR image; and (f) PFOB-resonance selective MR image [137]. Copyright 2009. Reproduced with permission from ACS.

4. Perspectives and outlooks

Bola-48.

Fluorinated thiol molecules (Bola-48) (tridecafluoro1-octanethiol, HS(CH2 )2 (CF2 )5 CF3 )) adsorb on the metal surface (Au or Ag) from solution to form oriented monolayer film [8,136]. In recent studies of this short chain molecule, it covered quantum dot (QD) nanoparticles as spherical layer to link to other surfactants to form emulsified QDs. In medical and immunological applications, this nano-composite emulsion can be taken-up by different types of immunocytes (macrophage, dendritic cells, T cells, etc.) in different amounts, distinguished by flow cytometry, as shown in Fig. 47. The uptake differences of immunocytes can be used to identify the immunocyte type (Fig. 48). The nano-composite emulsion could be potentially used as a nano-probe to detect and visualize various immunotherapeutic cells in vivo (Fig. 49) and in vitro tests [137].

Bolaamphiphiles are an extensive family of molecules with interesting chemical structures, organized self -assembly supramolecular architectures and fascinating applications in a wide spectrum of different directions. As discussed in this account, the complexity of bolaamphiphilic systems includes their synthesis, self-assembly, performance in different applications, sometimes in combinations. This review intends to give the reader a clearer perspective in the topic of bolaamphiphiles. Although not the major objective of this review, progress in the synthesis of bolaamphiphiles is of fundamental importance for further studies in this area. Readers can refer to other reviews [1,15] that focus on that subject. The self-assembly architectures of bolaamphiphilic systems is a principal focus of this review. The appropriate approach to generate designed architecture by bolaamphiphiles is to consider and balance the possible interactions in the system. Those interactions include electrical interaction, hydrophilic, hydrophobic, van der Waals, ␲–␲ interactions, etc. These interactions may be used as tools to design the desired functional self-assembly structure and then design the synthesis that structure. A variety of characterization methods may be

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used to study the assembly structure, including optical microscope, electron microscopy, atomic force microscopy, etc. In addition, spectroscopic and electromagnetic scattering methods (laser, X-ray, neutron, etc.) may also be useful tools to characterize the assembly structure. Finally, no matter how interesting the self-assembly architecture may be, substantial attention must also be given to the applications. Thus, a fruitful research projects will depend on not only the synthesis, the self-assembly architecture, but also most importantly the application. This review is intended to give the reader an introduction to the progresses made in this topic in recent years, and guide further research directions on the assembly and application of this fascinating family of molecules. Accordingly, the review considers the assembly and applications of bolaamphiphilic molecules, and gives a brief introduction of the main principles of the assembly structures of bolaamphiphilic molecules both at the interface of air/water or liquid/solid, and in solution. The article may be used as a tutorial for non-experts and also provides valuable information about recent developments in amphoteric materials. Acknowledgements We thank Dr. Michael Surko and Miss Roya Shaji for helping to improve the syntax and phrasing in this manuscript.

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