Supramolecular Architectures of Dendritic Amphiphiles in Water

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Supramolecular Architectures of Dendritic Amphiphiles in Water Bala N. S. Thota,* Leonhard H. Urner, and Rainer Haag Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin 14195, Germany ABSTRACT: Dendritic molecules are an exciting research topic because of their highly branched architecture, multiple functional groups on the periphery, and very pertinent features for various applications. Self-assembling dendritic amphiphiles have produced different nanostructures with unique morphologies and properties. Since their selfassembly in water is greatly relevant for biomedical applications, researchers have been looking for a way to rationally design dendritic amphiphiles for the last few decades. We review here some recent developments from investigations on the self-assembly of dendritic amphiphiles into various nanostructures in water on the molecular level. The main content of the review is divided into sections according to the different nanostructure morphologies resulting from the dendritic amphiphiles’ self-assembly. Finally, we conclude with some remarks that highlight the self-assembling features of these dendritic amphiphiles.

CONTENTS 1. Introduction 2. Self-Assembly of Amphiphiles 3. Self-Assembly of Dendritic Amphiphiles 3.1. Unimolecular Micelles, Persistent Micelles, and Supramolecular Aggregates 3.2. Tapes, Fibers, Toroids, and Tubes 3.3. Vesicles, Bilayers, and 2D Networks 4. Concluding Remarks Author Information Corresponding Author Notes Biographies Acknowledgments References

periphery, which set them apart not only from the smaller amphiphilic molecules. Moreover, they show excellent physical properties in the bulk state,35 which was the motivation for further investigation of their assembly properties in solution. Since the resulting structures proved to have enhanced stability, dendritic polymers are more applicable than nanostructures formed by small amphiphilic molecules. Dendritic self-organized architectures also show a high degree of functional groups on their surface. Because they can be modified by different functionalities (ligands, targeting groups, etc.), they can mimic multivalent binding interactions, which is highly desirable.36−41 Dendritic self-assembled nanostructures have therefore become an active area of research that addresses several different issues with biomedical relevance. In the present context of the review, we will discuss different types of nanostructures that have been generated by dendritic amphiphilic systems to date. Rich amounts of literature are generally available that address the topic of “self-assembly of dendritic amphiphiles.” Therefore, we have limited our discussion to the formation of different nanostructures in aqueous media. For more detailed information about the selfassembly and self-organization features of dendritic molecules, we recommend the excellent review by Percec and co-workers.35 In the second section of this review, we will give a brief introduction of the concept “self-assembly of amphiphiles in water.” Furthermore, we have classified the third section into different parts based on the structural similarities of different morphologies/nanostructures. Here, we will discuss the most important literature available to date in detail. Finally, we conclude our discussion with remarks on the learning curve in

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1. INTRODUCTION The self-assembly of amphiphilic molecules, which is a commonplace phenomenon in nature, results in many different complex and ordered structures. Various forces, such as hydrophobic interactions, hydrogen bonding, and metal−ligand interactions, generally drive the self-assembly process.1−4 Amphiphilic molecules self-assemble in aqueous solution mainly because of hydrophobic interactions. Inspired by nature and the complexity of the ensuing architectures, many artificial molecules have been developed in the last few decades.5−19 Investigation of these systems has paved the way for the rational design of building blocks that can mimic natural assemblies. Most artificial nanostructures from small amphiphilic molecules that mimic natural systems display inherent drawbacks in terms of stability, which makes them inappropriate for further applications. Dendritic polymers have attracted much attention in the field of nanoscience5,20−34 because they have unique structural characteristics such as a high degree of branching and a multiple number of end groups at the © 2015 American Chemical Society

Special Issue: Frontiers in Macromolecular and Supramolecular Science Received: July 17, 2015 Published: December 16, 2015 2079

DOI: 10.1021/acs.chemrev.5b00417 Chem. Rev. 2016, 116, 2079−2102

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Figure 1. Dependence of nanostructure morphology on the packing parameter (p) of an amphiphile (v is the volume of the hydrophobic chain, a0 is the optimum area of the hydrophilic headgroup, and lc is the critical length of the alkyl chain).

Figure 2. Schematic representation of different dendritic architectures.

packing parameter for the amphiphiles and predict the morphology of the nanostructure formed in solution (Figure 1). This approach is even valid for common amphiphilic block copolymers. Discher and Einsenberg have elucidated the selfassembly of amphiphilic block copolymers on the basis of hydrophilic volume fractions of the polymers.52

the development of dendritic amphiphiles for functional applications.

2. SELF-ASSEMBLY OF AMPHIPHILES Self-assembly of amphiphilic systems is one of the most commonly observed phenomenon in biological systems.42 Cellular membranes, for example, have a bilayer of natural lipids. The desire to mimic these natural self-assembled systems has prompted the development of different classes of synthetic amphiphiles and investigations of their self-assembly processes. The most widely studied classes are amphiphiles with comparatively small molecular masses and amphiphilic block copolymers.7,9,10,18,43−55 Generally, amphiphilic molecules consist of two structural segments, a hydrophobic and a hydrophilic part. Depending on their structure, concentration, solution environment, and temperature, they self-assemble into a wide variety of morphologies.10,54,56 The formation of aggregates in aqueous solution, however, is mainly governed by the attractive hydrophobic interactions between the lipophilic segments and repulsive steric or electrostatic interactions between the hydrophilic head groups.57,58 Israelachvili et al. developed a model-based theory that can explain the aggregate morphology depending on the geometrical considerations of the individual molecules.59,60 According to this approach, one can calculate the

3. SELF-ASSEMBLY OF DENDRITIC AMPHIPHILES As was observed for classical amphiphiles, the self-assembly of dendritic amphiphiles has resulted in different morphologies such as micelles, cylindrical micelles, vesicles, toroids, tubes, and helical fibers. This research area has emerged as an interdisciplinary field of interest, since the unimolecular micellar systems were introduced as stable containers for small molecules in different solution environments.61−63 The interesting features of these macromolecules have led to a further development of various subclasses, including dendrimers, hyperbranched polymers, hybrid systems, etc. (Figure 2). More importantly, their assemblies combine advantageous features from both polymeric and small molecular systems because they are as highly stable as polymeric assemblies and display membrane properties like in the small molecule assemblies. Thereafter, our discussion will be divided into sections depending on the structural similarity of the morphologies that have resulted from their self-assembly in water. 2080


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3.1. Unimolecular Micelles, Persistent Micelles, and Supramolecular Aggregates

Micelles are self-assembled nanostructures derived from amphiphiles, which are characterized by a hydrophobic core surrounded by a hydrophilic headgroup of amphiphilic molecules. The early literature on dendritic amphiphiles mainly consisted of amphiphilic dendrimer and hyperbranched polymers, which resulted in unimolecular micelles. By definition, dendrimers and hyperbranched polymers are three-dimensional (3D), globular molecules with a high degree of branching and a maximum number of functional groups at the periphery.25,33 Modifying the surface functionalities of a hydrophobic dendrimer or hyperbranched system with water-soluble groups introduces amphiphilicity into these molecules; their structure resembles a micelle with a covalently connected hydrophobic core in aqueous media. Newkome et al. reported the first unimolecular micelle from dendrimers,61 which consisted of 36 carboxylic groups on the periphery and alkyl chains in the interior of the dendrimers. Later on, several other groups constructed such dendrimer-based, unimolecular micellar systems and demonstrated their ability to encapsulate hydrophobic molecules in the interior of the dendrimers in aqueous solutions.63,64 The classical examples of dendrimer-based unimolecular micelles constructed by divergent and convergent methodologies are shown in Figure 3. One major advantage of such unimolecular systems over conventional micelles is their stability when diluted. Apart from a terminal group replacement strategy, one can also produce amphiphilic structures by coupling a linear polymer or a small molecule that is opposite in nature to the terminal functionalities of a dendritic molecule. By applying this methodology, new classes of dendritic architectures have been generated and termed dendritic core−shell (CS) or core− multishell (CMS) systems.65 Although there are a few examples of CS and CMS systems that display unimolecular behavior in the transport of guest molecules,66−70 most of them show supramolecular aggregation in water, which will be discussed below. Chen et al. reported on the formation of a unimolecular micelle from a core−shell system consisting of a branched polyethylene core and PEG shell.68 Very recently, Popeney et al. reported an amphiphilic core−shell system based on a hyperbranched polyethylene core and polyglycerol shell that displayed unimolecular transport behavior for hydrophobic molecules in water and demonstrated the advantage of a unimolecular transporter over supramolecular assemblies (Figure 4).67 However, most amphiphilic CMS systems show supramolecular aggregation behavior. Burakowska et al. demonstrated unimolecular micellar behavior for a coredouble-shell architecture that consisted of a hyperbranched polyglycerol core (Figure 5), a long hydrophobic inner shell, and a hyperbranched polyglycerol-based outer shell. The major structural difference compared to earlier CMS systems is an outer shell of hyperbranched polymer that influences the supramolecular aggregation of these molecules.69 Early investigations on the self-assembly of dendritic amphiphiles, however, were mainly focused on dendrimers. Hyperbranched systems have appeared more prominently in the literature since Zhou and Yan et al. reported on the supramolecular self-assembly of an amphiphilic HBPO-starPEO that demonstrated unprecedented self-assembly features of amphiphilic HBPs.71−74 Mai et al. reported on the formation of larger micelles (100 nm) by the self-assembly of HBPO-starPPO.75 In this report, they investigated the self-assembly of

Figure 3. Classical examples of unimolecular micelles reported from dendrimers synthesized by divergent (1) and convergent (2) strategies.

amphiphilic HBPs with various molar ratios of poly(propylene oxide) (PPO) to poly(3-ethyl-3-oxetanemethanol) (HBPO) core. Although the structural features of these macromolecules were similar to HBPO-star-PEO-based HBPs,71,76 the difference in amphiphilicity between the core and the arms was comparatively less. Investigation into the self-assembly of such poorly amphiphilic molecules requires special care, especially since the sample preparation method is very important in such cases. These investigations revealed the formation of larger micelles (greater than 100 nm) by these amphiphilic HBPs. Most importantly, the size of these larger micelles could be controlled by changing the molar ratio of PPO to HBPO. The size decreased with an increase in the ratio of PPO to HBPO, which indicated a similarity with amphiphilic block copolymers. 2081


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Figure 4. Schematic of unimolecular micelles forming PE−PG core− shell systems and demonstration of the superiority of the unimolecular transport system over supramolecular transport systems. Reprinted from ref 67. Copyright 2012 American Chemical Society.

Figure 6. Schematic of a proposed multimicelle aggregate (MMA) model. Reprinted from ref 75. Copyright 2005 American Chemical Society.

proposed MMA model using a new series of amphiphilic HBPs consisting of a HBPO core and poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) arms. Different amphiphilic HBPs were synthesized from the same core of HBPO with varying degrees of polymerization for the arms and studied for their self-assembly in water. CMC measurements of these compounds unambiguously indicated formation of larger micelles above a critical concentration, below which the CMC of the molecules behaved like unimolecular micelles. The size of the larger multimolecular micelles varied with the length of the arms, which provided a way to fine-tune the size of the larger micelles by adjusting the polymer composition. The morphology of the large multimicellar aggregates was similar to that of larger compound micelles (LCMs) observed in block copolymers,45,47 but there were differences in the structure of these larger micelles. In the case of LCMs, the primary aggregation was caused by the microphase segregation phenomenon in block copolymers and these primary micelles aggregated to LCMs. In the case of large MMAs from hyperbranched copolymers, the unimolecular micelles further aggregated to large micelles and no phase separation was observed at any step. Yan and co-workers also investigated the influence of the degree of branching in the core of the amphiphilic hyperbranched polymers on their self-assembly, which clearly showed that the amphiphiles self-assemble into vesicles, wormlike micelles, and micelles upon a decrease in the degree of branching, respectively.79 From the knowledge gained on the self-assembly of amphiphilic hyperbranched systems, the group then developed several nanocarriers for drug delivery applications.80−85 A recent review on the biomedical application of dendritic amphiphiles is available for further reading on this subject.86 As mentioned above, the Haag group also demonstrated the formation of larger aggregates by amphiphilic HBPs as a consequence of supramolecular aggregation.78 In their work,

Figure 5. Molecular structure of unimolecular micelles forming coredouble shell amphiphiles. Reprinted from ref 69. Copyright 2009 American Chemical Society.

The formation of these larger micellar structures suggested a more complex mechanism for the aggregation of these molecules. Mai et al. proposed a multimicelle aggregate (MMA) model for the formation of larger aggregates (Figure 6). In this model, they proposed that the amphiphilic HBPs first self-assemble to smaller micelles with a HBPO core and PPO shell and that association of these smaller micelles through Hbonding and van der Waals interactions resulted in larger aggregates. Later on, the Yan group 77 and the Haag group 78 independently proved that the supramolecular aggregation mechanism for amphiphilic HBPs yielded large micellar aggregates. Yan and co-workers provided proof of their 2082


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supramolecular systems above their critical aggregation concentration (CAC). To demonstrate the efficiency of these CMS architectures for biomedical application and to understand their self-assembly, the Haag group also developed several CMS systems consisting of a polyglycerol-based hyperbranched core with different inner and outer shells.69,87−89 All these amphiphilic HBPs (CMS) displayed a similar behavior in their aggregation, with a few exceptions. Hybrid dendritic architectures, including dendronized polymers, linear−dendritic polymers, dendritic−linear−dendritic polymers, etc., are another important class of dendritic amphiphilic systems that have commonly formed supramolecular aggregates.90−94 Much attention has been given to such hybrid systems from the early developmental phases of dendritic chemistry.95−98 However, these hybrid systems have shown interesting selforganization in bulk phase. Their self-assembly mostly results in micellar aggregates that are ideal for biomedical applications, especially for drug delivery.99−101 The major benefit of these assemblies is that they combine the high degree of functionality from dendrimers with the high loading capacity of polymers. Recently, Gupta et al. reported in a study of nonionic dendronized polymeric micelles for biomedical applications that uniform micelles formed from dendronized polymers and that the guest encapsulation capacity of these micelles could be well-tuned by the choice of the dendron generation.102 Drawing inspiration from natural biological systems like protein that contain quaternary structures composed of various subdomains and often combine several different properties, environments, and functions in close proximity, the concept of multicompartment micelles has emerged.103−105 Although micellar nanostructures with segregated hydrophobic cores would be interesting for nanobiotechnology applications, generating such architectures is more challenging. Mao et al. reported the formation of multicompartment micelles of an amphiphilic copolymer generated from a hyperbranched core (HBPO) with a block copolymer (PDMAEMA-b-POFPMA)based arms.106 All the newly reported systems have the same hydrophobic segments, hyperbranched core, fluorinated parts, and various lengths of PDMAEMA. Self-assembly of these amphiphilic HBPs resulted in multicompartment micelles in aqueous acidic solution (Figure 8) and the size of these micelles varied with the PDMAEMA chain lengths. Although micelles are considered to be the most accessible nanostructures for aggregation of amphiphiles, obtaining micelles with precise structure and stability is a major challenge

they synthesized different amphiphilic core−multishell architectures based on a hyperbranched PEI and demonstrated the encapsulation of different guest molecules that varied from hydrophobic to hydrophilic in nature. The advantages of Haag’s CMS architecture compared to the earlier reported amphiphilic HBPs are that it mimics the structure of a liposome on a molecular basis and transports both polar and nonpolar guests into their nonsolvents (Figure 7). The formation of supra-

Figure 7. Schematic of (a) liposome inspired core−multishell architectures and (b) their aggregation. Adapted with permission from ref 78. Copyright 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

molecular aggregates from dendritic multishell molecules was unambiguously demonstrated through cryo-TEM experiments, which showed the coexistence of both unimolecular and

Figure 8. Schematic of a HBPO-star-PDMAEMA-b-POFPMA aggregation with different PDMAEMA chain lengths in acidic aqueous solution. Reprinted from ref 106. Copyright 2007 American Chemical Society. 2083


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Figure 9. Representative molecular structures of persistent micelle forming amphiphiles. Adapted with permission from ref 110. Copyright 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

in the design of amphiphilic molecules. Hirsch and co-workers reported the formation of structurally persistent micelles from a series of dendritic amphiphiles. Their molecular design involved either a calixarene or a fullerene unit, upon which hydrophilic Newkome dendrons of different generations and alkyl chains were attached in a well-designed fashion.107−114 Kellermann et al. reported for the first time the formation of structurally persistent micelles from a dendritic amphiphilic system.107 The amphiphilic molecule (4, Figure 9) consisted of a calixarene ring that was functionalized on one side with two hydrophilic second-generation Newkome dendrons and on the other side with four alkyl chains that self-assembled into well-defined micelles in aqueous solution. The unique highlight of this report was their structural persistency; the micelles were formed by a fixed number of seven amphiphilic molecules that were arranged in such a way to construct the micelles. These persistent micellar aggregates were characterized by DOSY and cryo-TEM experiments. 3D Reconstruction methods were employed to determine the structural details of the persistent micelles (Figure 10). Hirsch and co-workers also investigated the influence of different parameters, such as the counterion of the carboxylic groups and encapsulation of a hydrophobic guest upon the structure of the shape persistent micelles.108,109 The higher stability of the heptameric micelles in the sodium buffer compared to potassium buffer indicated that the high concentration of the contact ion pairs on the surface of the micelles was necessary for the stability of the heptameric micelles. In the presence of hexane, as a guest molecule, the aggregation number of the micelles increased from 7 to 12 molecules, and these micelles with an encapsulated hexane were stable in both sodium and potassium buffers. To spectroscopically investigate the aggregation behavior of such persistent micelle-forming amphiphiles, Becherer et al. designed another

Figure 10. (a) Representative electron micrograph of calixarene micelles embedded in vitreous ice (bar is 100 Å). (b) Row 1 shows class averages representing different spatial views of the micelles. Reprojections (row 2) into the 3D volume (row 3) at corresponding Euler angle directions illustrate the fit with the experimental data (bar is 50 Å). (c) Stereo view of the isosurface rendered 3D structure (bar is 25 Å). Reprinted with permission from ref 107. Copyright 2004 WileyVCH Verlag GmbH & Co. KGaA.

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amphiphile that consisted of four fluorescent terephthalic benzamide units.110 In addition to the self-labeled feature, this modification also provided better contrast in the cryo-TEM due to the increased rigidity of the molecule. TEM images showed the coexistence of both cylindrical and spherical micelles at neutral pH with different diameters, which suggested a different packing of the amphiphiles in both the structures. The internal structure of the spherical micelles was investigated by reconstructing the micelle from TEM images. A 3D density map of the structure indicated formation of D2 symmetric micelles from 12 molecules of amphiphiles. The aggregation of the amphiphile was investigated at different pH values of the aqueous solutions, which showed the formation of smaller spherical micelles at pH 9 and precipitation of the amphiphiles at pH 4. Most interestingly, the precipitate obtained from the aqueous solution at pH 4 revealed porous membrane structures in TEM images. As mentioned earlier, Hirsh and co-workers also investigated the self-assembly of dendritic amphiphiles based on a fullerene-C60, which are called dendrofullerenes.111−114 One of the earlier examples of fullerene-based dendritic amphiphiles self-assembled in water into vesicles and cylindrical micelles at a neutral pH.111 Later on, Burghardt et al. modified the structure of the amphiphile by introducing amide bonds and studied the pH dependent, supramolecular selfassembly of the new amphiphile (5, Figure 9).112 The new amphiphile showed formation of rod-like morphologies at neutral pH with a diameter that was twice the length of the molecule. Increasing the pH of the solution resulted in the formation of globular micelles with various diameters and a distinct internal structure, similar to one of their earlier reports on persistent micelles. The successful reconstruction of the 3D structure of globular micelles indicated that the globular micelle consisted of 8 amphiphilic molecules with a C2 symmetrical arrangement. The switching of the nanostructure morphology upon a change in the pH of the aqueous solution was a result of the partial and complete deprotonation of the dendritic carboxylic groups of the amphiphiles, which changed the electrostatic repulsions and solvation interactions. In further studies, Schade et al. designed another new amphiphile that was structurally more diverse compared to their earlier systems.113 However, the new amphiphile consisted of the same number of carboxylic groups as their earlier amphiphile and was generated from the Newkome G1 dendrons by increasing the number of anchoring positions, which resulted in more diffused hydrophilic groups on the surface of fullerene. Another important difference in the structure of the new amphiphiles was their lack of long alkyl chains. More densely packed micelles with changed aggregation numbers were envisioned for such a structural modification of the amphiphiles, and the TEM images showed that even the smallest persistent micelle had D3 symmetry. Recently, the Haag group reported on the formation of persistent micelles from a new class of nonionic dendritic amphiphiles.115 They investigated the self-assembly of glycerolbased nonionic amphiphiles consisting of single alkyl chains of different lengths that were conjugated to the dendron through a single or biaryl group. The self-assembly of these amphiphilic molecules in water produced wormlike and spherical micelles depending on the dendritic headgroup generation. Most interestingly, careful investigation of one of the spherical micelles, containing the biaryl unit, showed a well-resolved internal structure of the micelle, similar to the persistent micelles. The formation of the structured micelle by amphiphilic dendrons was further supported by a 3D reconstruction of the

micelle, which indicated that these micelles were constructed from trimeric building blocks of the amphiphiles (Figure 11).

Figure 11. (a) Schematic of a generation dependent self-assembly of amphiphilic glycerol-based dendrons and representative TEM images of the self-assemblies, (b) 3D reconstruction of the persistent micelles with different orientations, and (c) arrangement of trimeric blocks of the G2 amphiphile within the reconstructed micellar volume. Reprinted from ref 115. Copyright 2010 American Chemical Society.

This was the first example of a structurally persistent micelle from a nonionic amphiphilic system. After that, Haag et al. developed several different series of amphiphilic dendrons for functional applications and studied their self-assembly.116−125 Very recently, they demonstrated a possible way to engineer various self-assembled nanostructures with a rational design for these amphiphilic dendrons and have shown that the shape of the amphiphiles influences their self-assembly more than the hydrophilic−lipophilic balance in the molecule.124 3.2. Tapes, Fibers, Toroids, and Tubes

One-dimensional (1D) self-assemblies, such as tapes, fibers, toroids, and tubes, require special directional interactions between the amphiphiles along with hydrophobic interactions to self-assemble in a specific direction.13 Aromatic interaction could provide this kind of directionality through π−π stacking in water. With this hypothesis, Lee and co-workers developed a broad range of dendritic amphiphilic systems, which they termed rod amphiphiles.51,126−130 In their early investigations, the aromatic rods were factionalized only at one end with dendrons and these amphiphilic systems self-assembled to spherical morphologies.131,132 Later on, they functionalized both ends of an aromatic rod segment with hydrophilic dendrons that resembled a dumbbell.133−137 The amphiphiles’ self-assembly could be well-tuned by an interplay of attractive interactions between the rod segments and repulsive interactions between 2085


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the bulkier dendritic head groups. Bae et al. reported on the formation of helical nanofibers by amphiphilic dumbbells consisting of dodeca-p-phenylene rods and aliphatic chiral polyether dendrons (6, Figure 12).133 The formation of helical

Figure 12. Molecular structures of the amphiphilic dumbbells.

Figure 13. (a) Schematic of reversible self-assembly of amphiphilic dumbbells in the presence of guest molecules, and TEM images of dumbbell amphiphile (7) in the absence (b) and in the presence (c) of guest molecules. Reproduced with permission from ref 136. Copyright 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

cylinders was confirmed by light scattering, circular dichroism, and TEM experiments. The TEM studies showed a diameter of molecular length scale with left-handed helices for the cylinders and also revealed the further assembly of these helical cylinders to super helical fibers. The formation of helical fibers is considered an interplay of attractive and repulsive forces between the aromatic and dendritic segments of the molecule, respectively. One of the major applications of amphiphilic self-assemblies in water is to encapsulate hydrophobic guest molecules. This kind of process is very interesting in the above-mentioned case due to the fact that the intercalation of hydrophobic, aromatic guest molecules between the helix forming amphiphiles affects the interaction between the amphiphilic molecules and therefore influences the morphology of the self-assemblies. Ryu et al. reported on the reversible transformation of amphiphilic dendritic-rod dumbbells between nanohelices and nanocapsules triggered by guest intercalation.136 The reported dendritic rod dumbbell self-assembled into a left-handed helical fiber in water. Remarkably, these helical fibers readily transformed into spherical capsules with the addition of 4-bromonitrobenzene (Figure 13). These structural transitions on guest intercalation were investigated by light scattering and electron microscopy experiments, and the formation of hollow capsules was demonstrated by encapsulation of a hydrophilic fluorophore, calcein. Later on, Huang et al. reported on the influence of the hydrophilic dendron’s size on the molecular packing of dumbbell amphiphiles in their fibrillar aggregates using two different amphiphiles consisting of a carbazole end-capped phenanthrene as rod segment and hydrophilic dendrons with different amounts of chiral oligoether chains.137 However, both amphiphiles self-assembled into nonchiral fibers at room temperature; the dumbbell amphiphile with fewer oligoether chains switched into a chiral state with preferred handedness upon heating above the LCST. Furthermore, the same group investigated the self-assembly of asymmetric dumbbell amphi-

philes.134,135 In these efforts, they functionalized one end of the rod segment with a hydrophilic dendron and the other end with hydrophobic dendrons with different alkyl chain lengths. This kind of modification in the dumbbell architecture strengthens the attraction between the amphiphiles with hydrophobic interactions. The morphology of the self-assemblies formed by these asymmetric dumbbell amphiphiles varied from spherical micelles to toroids to wormlike micelles with an increase in the length of the alkyl chains in the hydrophobic dendritic segment.134 The unique feature of the reported self-assembly of asymmetric dumbbells was that the toroids formed an intermediate structure between spherical micelles and cylindrical micelles with changes in the structure (Figure 14). The authors attributed this to a combination of stronger hydrophobic interactions and anisotropic aggregation of rod segments. Facially amphiphilic molecules constitute a different class of amphiphiles because of the differences in their mode of aggregation compared to most of the other classes of amphiphiles. Thayumanavan and co-workers reported facially amphiphilic dendrons for the first time in the literature138 and demonstrated an interesting aggregation behavior for this new class of amphiphiles.139,140 Functionalizing hydrophobic rods laterally with hydrophilic dendritic groups constitutes a different strategy to generate facially amphiphilic systems that are interesting for self-assembly in water due to the unique selfassembly observed for facial amphiphiles and dendritic-rod amphiphiles. Hong et al. reported on the self-assembly of facially amphiphilic dendritic-rod amphiphiles with laterally extended rod segments and oligo(ethylene oxide)-based dendrons. These amphiphilic molecules self-assembled in water into elongated nanofibers with a diameter equal to the bilayer of molecules.141 Later on, they modified the structure of these laterally grafted 2086


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bilayer length of molecules and showed transition in their structure above LCST due to the dehydration of oligo(ethylene glycol) chains. The remarkable feature of these laterally grafted dendritic-rod amphiphiles is that these two-dimensional (2D) sheets transformed into tubes, unlike the dumbbell amphiphiles in which the 2D sheets closed to capsules.142 The authors attributed this uniqueness into a structural feature of the laterally grated rod amphiphiles’ self-assembly. The morphological transition from flat sheets to ribbons upon increasing the hydrophilic fraction of the rod amphiphile suggests that increasing the hydrophilic fraction may result in further nanostructures with increased curvature to reduce the repulsive interactions between the dendritic groups. They investigated the possibility of such a transformation in the morphology by a coassembly of amphiphiles 11 and 12 in the presence of amphiphile 13 that contained the same heptaphenyl rod unit but had only been functionalized with hydrophilic dendron.143 The coassembly resulted in a decrease in the size of the nanostructures formed by amphiphiles 11 and 12 with an increase in the concentration of amphiphile 13. TEM investigation of these coassemblies showed formation of toroids with a hydrophobic interior, which was quite unusual. The application of these toroids to solubilize fullerene molecules in their interior through hydrophobic interactions was investigated, which resulted in the formation of 1D tubes in TEM. The formation of these tubes could be explained by stacking of the supramolecular rings with fullerene molecules in between to reduce exposure of the hydrophobic parts in aqueous solution (Figure 15). One of the more elegant methods to construct tubular morphologies is to replace the rod segment of such amphiphiles with a rigid macrocycle that causes stacking of these molecules in a controlled fashion through self-assembly. Ryu et al. introduced water-soluble dendritic groups on the periphery of a rigid macrocycle and studied their self-assembly in bulk and

Figure 14. (a) Molecular structures of the asymmetric dumbbell amphiphiles and (b) schematic and TEM image of toroids formed by the self-assembly of asymmetric dumbbell amphiphile (9). Reprinted from ref 134. Copyright 2006 American Chemical Society.

dendritic-rod amphiphiles to investigate further features of their self-assembly.142,143 The newly designed molecules (11 and 12, Figure 15) consisted of a heptaphenyl rod unit that was functionalized at the middle phenyl ring with hydrophobic and hydrophilic dendritic groups on either side of the rod. These studies showed that the molecules (12) with longer oligo (ethylene glycol) chains self-assembled into ribbons and the ones with shorter ethylene glycol chains (11) created large sheets. Both these nanostructures had a thickness equal to the

Figure 15. (a) Molecular structures of laterally grafted dendritic rod amphiphiles (11−13) and (b) schematic illustration of 1D-toroid stacking upon addition of C60 guest molecules. Reprinted from ref 143. Copyright 2009 American Chemical Society. 2087


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Figure 16. Representative molecular structures of dendritic bent-shaped amphiphiles, schematic, and TEM images of their self-assemblies. Reprinted from ref 129. Copyright 2013 American Chemical Society. Reprinted with permission from ref 145. Copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted with permission from ref 146. Copyright 2012 Americal Association for Advancement of Science.

aqueous solution.144 Self-organization of this molecule in the bulk clearly indicated a columnar structure with a hydrophilic exterior and suggested a way to form tubular nanostructures in solution. Indeed, TEM images of the compound in aqueous solution indicated formation of cylindrical aggregates with diameters of around 10 nm, which is in agreement with the molecular dimensions and confirmed the 1D stacking of the amphiphiles. Furthermore, solubilization of single-walled carbon nanotubes (SWNT) in the hydrophobic interior of these tubular nanostructures was demonstrated by fluorescence and TEM experiments. Later on, Kim et al. reported on the formation of tubular nanostructures from dendritic-rod amphiphiles that formed shape-persistent macrocycles through noncovalent interactions.145 They constructed the noncovalent macrocycle from a bent-shaped, stiff segment with hydrophilic oligo (ethylene glycol)-based chiral dendrons at the apex (14, Figure 16). These noncovalent macrocycles further stacked over each other into tubular structures. The structural parameters of these supramolecular self-assemblies were calculated with different experimental techniques, in combination with molecular dynamics simulations. The good agreement between all these studies indicated the formation of hexameric macrocycles from the amphiphiles and stacking of these macrocycles with a twist. As a result, helical tubules were created with aromatic walls and hydrophilic dendrons that had been exposed to water. Since the interior of these tubes were functionalized with nitrile groups from the amphiphiles, Kim et al. envisioned that these tubes could encapsulate hydrophobic silver salt through silver−nitrile interactions and consequently studied the interaction of these supramolecular helical tubes with silver salt. These studies indicated disassembly of the helical tubes into discrete nanostructures (Figure 15a). The dynamic behavior of the tubes was investigated by TEM, which indicated the formation of a toroidal structure due to the dissociation of helical tubes that still had supramolecular chirality. However, a similar conservation of supramolecular chirality for tubes as well as discrete nanostructures was reported for dendritic liquid crystalline systems, but there was no precedent of such behavior for self-assembled nanostructures in aqueous systems. In the quest to understand the ability of bent-rod amphiphiles to form different supramolecular nanostructures and in the development

of responsive nanostructures, new bent-shape dendritic systems were designed.146−149 Huang et al. reported on the formation of helical tubules that underwent reversible expansion and contraction in response to temperature using a new amphiphile (15, Figure 16) that contained a pyridine unit at the apex of the bent segment.146 The new amphiphile self-assembled into larger toroids compared to a similar type of molecule from their earlier reports. The large size of the toroids was explained by J-type stacking of the aromatic units in the amphiphiles from the formation of water clusters at the nitrogen atom of the pyridine. The J-type stacking of the aromatic units was further confirmed by UV−vis and fluorescence experiments. These larger toroids aligned over each other to construct helical tubules with an increase in concentration of the amphiphile. The helical nature of these tubules was clearly manifested by CD experiments. Huang et al. also investigated the structural changes in the selfassemblies from the thermoresponsive nature of the helical tubules using both microscopic and spectroscopic methods, which indicated that the arrangement of the bent aromatic core changed from a J-type stacking to H-type stacking upon increase of the temperature. Notably, this reversible change in the structure of tubules was accompanied by an inversion in the chirality. Later on, they also developed a few more responsive bent-shaped dendritic-rod amphiphiles that self-assembled into nanofibers149 and two-dimensional sheets148 in water. These primary self-assemblies transformed into tubular structures under the influence of H-bonding interactions with the guest molecule or from coordinative interactions with metal salt. Nanostructures with responsive behavior are of utmost importance in the development of functional self-assemblies. Introducing such a responsive nature into the structure of an amphiphilic dendron is more interesting because these amphiphiles are well-defined and form stable assemblies. Haag and co-workers designed several azobenzene-based photoresponsive amphiphilic dendrons and demonstrated their use for different applications.116,118,150 An interesting feature of such azobenzene-based dendritic amphiphiles is that they show a more pronounced change in the geometry of the amphiphile than linear structures due to the switching process.116 However, most of these photoresponsive amphiphiles self-assembled into spherical micelles in water. Recently, Haag et al. reported a new 2088


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system consisting of dendritic bolaamphiphiles containing a photoresponsive azo-benzene functionalized with an alkyl chain and a dendron.125 The switching behavior of the new amphiphile (16) was investigated in the gas phase using ion mobility-mass spectrometry and in solution by TEM experiments. The latter revealed that the new amphiphile in trans state readily self-assembled into twisted tape morphologies and that photoirradiation of the solution resulted in the complete disappearance of the tape morphology (Figure 17), which emphasizes the application of such molecules in the development of responsive drug delivery systems.

from vesicles to spherical micelles with an increase in the generation number of the PPI dendron, following a regular transition depending on the hydrophilic−hydrophobic balance of an amphiphile. Schenning et al. reported on the supramolecular self-assembly of amphiphilic PPI dendrimers to vesicles in acidic aqueous solutions.155 They studied aggregations of three classes of PPI-based amphiphilic dendrimers consisting of different hydrophobic units: simple alkyl chains, alkyl chains consisting of diazobenzene units, and adamantyl groups. These studies showed that amphiphilic dendrimers can alter their conformation and self-assemble into defined supramolecular structures and that their self-assembly depends on the flexibility of the peripheral hydrophobic groups. Amphiphilic dendrimers with flexible alkyl chains self-assembled in aqueous acidic solution, which afforded vesicular structures. This was the first report presenting an unconventional view on the conformational freedom of dendrimers. Later on, Menger et al. investigated the aggregation of fourth-generation poly(amidoamine) (PAMAM) dendrimers containing different numbers of alkyl chains and demonstrated the minimum number of alkyl chains on the periphery of the dendrimer needed for their self-assembly.156 Wang et al. studied the selfassembly of different generations of amphiphilic PAMAM dendrimers (G0-G5) consisting of hydrophobic chromophores on the periphery and demonstrated the formation of vesicles from these amphiphiles at lower generations (G0-G3).157,158 Most interestingly, they observed that vesicles aggregated because of outer membrane interactions, which led to twin and quin aggregates (Figure 18). Very recently, Hung et al.

Figure 17. Molecular structure of (a) dendritic bolaamphiphile and (b−d) photoresponsive switching of its self-assembly. Reproduced with permission from ref 125. Copyright 2015 the Royal Society of Chemistry.

Figure 18. Schematic of the self-assembly of amphiphilic PPI dendrimer to vesicles and interaction between the vesicles through their outer membrane layers. Reprinted from ref 157. Copyright 2004 American Chemical Society.

investigated a similar aggregation phenomenon using amphiphilic PAMAM dendrimers containing hydrophobic aniline pentamer as the shell in various pH milieu.159 Paolino et al. reported on the self-assembly of amphiphilic glycodendrimers into higher hierarchical nanostructures, necklace-, and donutlike structures.160 Amphiphilic glycodendrimers from partially functionalized PPI dendrimers with phenyl and adamantyl units were synthesized and studied for self-assembly in water. However, the admantyl-functionalized dendrimers did not show any different aggregation from the glycodendrimers; the phenyl functionalized dendrimer aggregated into spherical particles, which resulted in hierarchical structures upon sonication and incubation.

3.3. Vesicles, Bilayers, and 2D Networks

Supramolecular self-assembled vesicles have attained much importance in the last few decades due to their application in many fields of research, especially for biomedical applications as drug delivery systems.49,50,53,151−153 Several amphiphilic systems, such as lipids, surfactants, and amphiphilic block copolymers, have produced vesicles which are classified into different classes depending on the constituting amphiphilic systems, for example, liposomes and polymersomes. Meijer and co-workers did some of the early work on the formation of vesicles from dendritic amphiphiles.154 This seminal work demonstrated a change in the morphology of the self-assemblies 2089


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Although hybrid systems commonly result in supramolecular micellar aggregates, one can achieve different morphologies by rationally designing these systems. Meijer and co-workers investigated the self-assembly of amphiphilic dendritic-linear polymers constructed from different generations of PPI dendrons and polystyrene polymer.96,154 Later on, several other groups investigated similar hybrid dendritic systems161,162 and demonstrated that the morphological transition of these self-assemblies follows the theory proposed by Israelachvili et al. Recently, del Barrio et al. reported the self-assembly of linear dendritic amphiphiles containing PEG polymers of different lengths as water-soluble linear segments and diazobenzenefunctionalized dendrons of different generations as hydrophobic segments.163 This kind of structural design produced a series of amphiphilic linear−dendritic polymers with different hydrophilic/hydrophobic ratios. The self-assembly of these amphiphilic polymers led to various morphologies, including nanofibers, 2D sheets, tubular micelles, and vesicles, with increased generations of the hydrophobic dendrons. Shao et al. reported the self-assembly of jellyfish-shaped amphiphilic dendrimers from a cyclodextrin core, by functionalizing its primary alcohols with PEG chains of different lengths and secondary alcohols with hydrophobic dendrons of different generations.164 The selfassembly of these amphiphiles resulted in vesicles and micelles with an extremely narrow size distribution. Very recently, Haag and co-workers reported the formation of micelles and vesicles from a similar construct consisting of a cyclodextrin core functionalized with 14 alkyl chains on one side and seven PG dendrons of different generations on the other. The selfassembly of these molecules yielded vesicles and micelles as the dendron generations increased.123 Although vesicle forming amphiphilic systems have been known for decades, most of them are prepared from welldefined molecular architectures such as lipids, block copolymers, and dendrimers. Zhou et al. were the first to find that vesicles formed from hyperbranched amphiphilic structures.76 They reported the synthesis and self-assembly of different HBPO-starPEO copolymers that had different hydrophilic fractions. In contrast to their earlier self-assembling HBPO-star-PEOs,71 these systems readily self-assembled in water into giant vesicles (5−100 μm) (Figure 19). The self-assembly of these amphiphilic HBPs to vesicles is very unique due to the fact that the constituting amphiphiles have a relatively high hydrophilic fraction (>60%) compared to amphiphilic block copolymers, which often forms wormlike micelles and spherical micelles above 40% hydrophilic fraction. These systems’ giant vesicles, which are called branched polymersomes (BPs), are rather astonishing and have special advantages. Microscopic investigations have indicated that these BPs have good control over the size of giant vesicles with respect to the hydrophilic fraction and that the size of the vesicles decrease upon an increase in the hydrophilic fraction of the polymer. An easier approach using amphiphiles HBPs with different compositions allows one to control the size of these giant vesicles. Although all the amphiphilic molecules form giant vesicles in water, the structure of the vesicle wall differs depending on the hydrophilic/hydrophobic fraction of the polymer. The vesicle walls showed a monolayer of molecules for relatively hydrophilic polymers and a bilayer of molecules for hydrophobic systems. Since giant vesicles are ideal systems for cytomimetic chemistry, one of their systems was investigated for cytomimetic behavior.165 The studies showed that the membrane of branched polymersomes behaved similarly to the membranes

Figure 19. (a, c, and d) Optical micrographs and TEM image of giant vesicles formed by HBPO-star-PEOs. The scale bars represent 25 mm in (a), (c), and (d), and 250 nm in (b). Reprinted with permission from ref 76. Copyright 2004 Wiley-VCH Verlag GmbH & Co. KGaA.

of liposomes and surfactant vesicles, which emphasizes that branched polymersomes are a good alternative to liposomes. One of the ways to increase the complexity in the selfassembled systems is hierarchical self-assembly, which operates with diminished interactions between the self-assemblies. This hierarchical self-assembly by vesicles, although limited to the microscope scale, is one of the most interesting features for applications in drug delivery. Large compound vesicles that hierarchically self-assemble are analogous to aggregated bubbles. Block copolymers have formed LCVs, but most of their systems are also microscopic. Mai et al. reported on the self-assembly of branched polymersomes to LCV by HBPO-star-PEO polymers with a relatively low fraction of PEO.166 Astonishingly, these hierarchical self-assemblies were on the mesoscopic scale, which provided an opportunity to investigate their dynamics and formation mechanisms with an optical microscope. These investigations revealed that small vesicles formed first from the thin film of the compound and then fused with nearby vesicles to produce perfect giant vesicles that later self-assembled into three-dimensional vesicle stacks (Figure 20). The fusion in the initial stage slowed down over time due to a few defects in the larger vesicles. A cross-section analysis of the stacks at different heights clearly showed an interconnected vesicle at each height. Breakage of these stacks by external force resulted in large

Figure 20. Hierarchical self-assembly of LCV. Reprinted with permission from ref 74. Copyright 2012 the Royal Society of Chemistry. 2090


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Figure 21. Polymerization-like hierarchical self-assembly of binary vesicles triggered by solution pH. Reproduced with permission from ref 74. Copyright 2012 the Royal Society of Chemistry.

broad range of pH, unlike most of the earlier reported peptosomes. Very recently, Fan et al. reported on the self-assembly of hyperbranched polymeric ionic liquids into vesicles. They prepared HBPO-star-PEO (HsP) functionalized with 1methyl-imidazole (MIM) group with methyl orange (MO) as a counterion. The polymer (HsP-MIM/MO) readily selfassembled into pH-indicative and colorful vesicles in water. An interesting feature of these vesicles is their facile anionexchange ability, which was demonstrated by replacing the MO with rhodamine-B (RB) labeled BSA protein.169 Stability is a major issue in the development of functional vesicles. Therefore, cross-linking is generally employed to stabilize vesicles under different environmental conditions. Wang et al. reported on the preparation of stable and surface-engineered polymeric vesicles from a dopamine-grafted HBPO-star-PEO (HSP-DA).170 They employed a “precrosslinking and postfunctionalization” method to develop surface-engineered vesicles. The polymeric vesicles were obtained by simply solubilizing polymer in water, whereupon the vesicles self-polymerized under alkaline conditions by adjusting the pH of the solution. The formation of vesicles, and the stability of the vesicles during and after selfpolymerization, were confirmed by different electron and optical microscopic techniques. Successful surface functionalization of cross-linked vesicles was demonstrated using gold nanoparticles, proteins, nucleic acids, etc. Recently, supramolecular dendritic amphiphiles have attracted much attention due to their dynamic nature and unique physical and chemical properties.171,172 Zhou and co-workers reported on the self-assembly of linear-hyperbranched supramolecular amphiphiles constructed from a hyperbranched polyglycerol grafted cyclodextrin and adamantane functionalized alkyl chain.173 The supramolecular amphiphiles readily selfassembled in water into unilamellar vesicles which demonstrated very good ductility. This vesicle ductility was attributed to a unique property of the supramolecular amphiphile. The same group also reported on the self-assembly of Janus hyperbranched polymers constructed from similar host−guest interactions between two different hyperbranched polymers functionalized with a cyclodextrin unit and an azobenzene unit. The formation of supramolecular amphiphile and its further light-responsive self-assembly into vesicles as well as the reversible disassembly process were studied by DLS and different microscopic techniques. One interesting feature of

compound vesicles. The unique feature for this hierarchical selfassembly was the strong cohesion between the vesicles, which depended on intervesicular attractive and repulsive forces. Another approach to achieve a hierarchical self-assembly of vesicles is to introduce polymeric patchy vesicles, similar to patch nanoparticle self-assembly. This kind of hierarchical selfassembly can only be achieved by introducing anisotropic interactions between the self-assembled systems. The primary structures formed by the polymer self-assembly are isotropic soft materials, which limits their further self-assembly to hierarchical structures. One of the ways to achieve anisotropic polymeric nanoparticles is by mixing immiscible corona forming polymers. Jin et al. introduced a similar strategy to achieve anisotropic vesicles by the coassembly of two hyperbranched copolymers, HBPO-star-PEO and HBPO-star-PDMAEMA.167 HBPO-starPEO forms vesicles and HBPO-star-PDMAEMA forms micelles in aqueous solutions, whereby the latter is pH responsive. At lower pH, both polymers are miscible and produce isotropic vesicles. The hierarchical self-assembly of these vesicles was investigated at different pH of the solutions. These vesicles did not show any further self-assembly below the isoelectric point of PDMAEMA. Between a pH of 10−14, however, the vesicles displayed a polymerization-like hierarchical self-assembly behavior starting from anisotropic vesicles with two or three hydrophobic patches to linear, branched vesicle chains or vesicle networks upon an increase in pH due to a microphase separation of PDMAEMA chains, and these vesicle chains further changed into linear tubes, branched tubes, circular tubes, and network tubes, respectively, through the fusion of the vesicles along the chains (Figure 21). Peptosomes, vesicles formed by peptides, are of particular interest for biomedical applications due to their intrinsic biocompatibility and biodegradability. Noncovalent methods for the formation of peptosomes have been recently investigated to reduce the tedious effort required to produce them. Most of these approaches make use of a template-assisted concept, which has a drawback concerning the stability of the peptosome during the removal of the template. Guo et al. reported a noncovalent approach to form a peptosome without any template. 168 They reported a one-step preparation of peptosomes by a complex self-assembly of a mixture of anionic hyperbranched polymer and PLL. They termed these vesicles complex peptosomes (CPs). These CPs were stable over a 2091


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the reported self-assembly was the narrow size distribution of the vesicles formed from the supramolecular amphiphiles.174 A major application of synthetic vesicles is to mimic biological membrane processes, which has blossomed into a new research field, cytomimetic chemistry.74,175 As mentioned earlier, branched polymersomes with a cell-like size are ideal systems for cytomimetic chemistry and they have demonstrated membrane fusion and fission like cellular membranes.165,176 Recently Jin et al. reported on a large-scale vesicle aggregation, similar to cell aggregation, using BPs as building blocks.177 They achieved vesicle aggregation by using host−guest interactions between different HBPO-star-PEO vesicles that had been doped with cyclodextrin (CD) and azo-benzene-functionalized HBPs. The reversible light responsive host−guest interactions between CD and azobenzene units triggered the aggregation and disaggregation of vesicles. Simultaneously, they also observed membrane fusion of the vesicles through host−guest interactions. This is the first report on a mimicking of the cell aggregation process on the macroscopic level. Furthermore, Jin et al. reiterated the strength of the multivalent host−guest interaction between the different BPs in the construction of the vesicle aggregates by using cyclodextrin and adamantanefunctionalized BPs.178 The same group also reported the formation of stable vesicle aggregates through covalent crosslinking under click reaction conditions.179 To demonstrate the aggregation process and study the dynamics of the vesicle membrane during the cross-linking process, different BPs were prepared from HBPO-star-PEO and investigated by optical and fluorescence microscopy. These investigations revealed that there were two stages involved in the cross-linking of BPs containing alkyne and azide functionalities. During the first stage, the formation of multimers was observed, which was accompanied by a lateral phase separation of the vesicular membrane, and in the second stage, larger aggregates formed with increased vesicle size due to fusion of the vesicle membranes. To control the vesicle fusion during aggregation, azide-functionalized BPs were replaced with azide-functionalized micelles, which resulted in stable vesicle aggregates. Percec et al. reported the self-assembly in water of a new class of dendrimers, which are called Janus dendrimers (Figure 22).180 In this seminal work, they presented an easy way to prepare stable dendrimersomes in water using 11 different libraries consisting of 108 Janus dendrimers. These bilayer capsules are remarkably uniform in size and impermeable to encapsulated molecules. These dendrimersomes have a quite unique structure and properties and show a stability and mechanical strength similar to polymersomes and the biological function of stabilized liposomes. Another highlight in the report is the ease with which these nanostructures can be prepared, because all these dendrimersomes are produced by a simple injection of their solution in a water-miscible solvent into water or buffer. Furthermore, Percec et al. investigated the selfassembly of whole libraries of Janus dendrimers in detail to compare the size and physical properties of the dendrimersomes with the primary structure of the amphiphiles and with the morphology of their periodic arrays self-organized in bulk state.181 They found that there was a clear correlation between their self-assembly in water and their self-organization in bulk state. Most of the Janus dendrimers that formed lamellar phases in bulk also built dendrimersomes in water. On the other hand, Janus dendrimers that exhibited columnar or cubic phases in bulk were more likely to create micellar structures in water. The few deviations that were observed could be explained by all the

Figure 22. Representative cryo-TEM images of different morphologies obtained by self-assembly of Janus dendrimers; (a) polygonal dendrimersomes, (b) bicontinuous cubic particles coexisting with low concentration of spherical dendrimersomes, (c) micelles, (d) tubular dendrimersomes, (e) rod-like, ribbon, and helical micelles, and (f) disklike micelles and toroids. Reproduced with permission from ref 180. Copyright 2010 American Academy of Arts and Sciences.

different possible interactions during their self-assembly in both their bulk and solution states. The branching pattern in the primary structure of the dendrimer affects the thickness of the layers that self-organize into lamellar structures and the thickness of the vesicle wall. The wall thickness of the dendrimersomes is dependent on the substitution pattern of the hydrophobic part, and an inverse proportionality between the thickness of the vesicle wall and the diameter of the vesicle was observed (Figure 23). There is good correlation between the primary structure of the Janus dendrimers and the way they self-assemble in bulk and solution, however. Most of these twin−twin dendrimers require a greater synthetic effort to synthesize. To minimize the synthetic effort to develop functional dendrimersomes, another new class of Janus dendrimers, single−single Janus dendrimers, was developed and studied for their self-assembly.182 The single−single and twin−twin notation refers to compounds constructed from single hydrophilic and single hydrophobic dendrons and twin hydrophilic and twin hydrophobic dendrons, respectively. These single−single Janus dendrimers selfassemble in aqueous media and result in different nanostructures similar to the twin−twin dendrimers, including dendrimersomes, solid lamellae, rod-like micelles, dendrimer aggregates, and cubosomes. Multidendrimersome dendrimersomes have a novel morphology, which has only been observed in single−single dendrimers. More importantly, the branching pattern of the hydrophilic dendritic part has considerable influence on the self-assembly of single−single Janus dendrimers. Most of the dendrimers with a 3,4,5-branching pattern tend to form dendrimersomes, and dendrimers with only two oligoethylene glycol chains do not produce dendrimersomes except in a few cases. Furthermore, the branching pattern in the hydrophobic part of the dendrimers has been shown to influence the membrane flexibility of the dendrimersomes. Janus dendrimers with a 3,5- and 3,4,5-hydrophobic pattern exhibit lower phase transition in bulk and self-assemble into soft dendrimersomes in water. Percec and co-workers also analyzed the structural parameter of self-organized and self-assembled structures in bulk and solution states, which indicated that, similar to twin−twin dendrimers, these dendrimers also form 2092


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Figure 23. Schematic of the self-assembly of Janus-dendrimers into dendrimersomes. Reprinted from ref 181. Copyright 2011 American Chemical Society.

Figure 24. Representation of a normal dendrimersome and an onion-like dendrimersome and a cryo-TEM image of onion-like dendrimersomes. Reproduced with permission from ref 183. Copyright 2014 PNAS.

Figure 25. Dendrimersomes and glycodendrimersomes self-assembled in water from amphiphilic Janus dendrimers with different topologies and selected examples of hydrophilic and hydrophobic dendrons and carbohydrates used as building blocks. Reprinted with permission from ref 185. Copyright 2015 the Royal Society of Chemistry.

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larger dendrimersomes in solution when they have smaller dspacing in bulk. One interesting point to be noted for these molecules is that ester core dendrimers show smaller d-spacing in bulk than the dendrimers with amide bonds in their core. The observed difference in the d-spacing value for the dendrimers in bulk was attributed to the formation of hydrogen bonding between the molecules in the case of an amide core, which limited their interdigitation. Further extension of the single− single Janus dendrimers libraries with amide cores resulted in another interesting morphology, onion-like dendrimersomes (Figure 24).183 The size of these multibilayer onion-like dendrimersomes also exhibited a similar concentration dependency to all the other dendrimersomes that were reported. A direct correlation between these dendrimersomes and the primary structure of the dendrimers has not been investigated, although it has been clearly demonstrated that the amide bonds in the core of the Janus dendrimer produce onion-like dendrimersomes with ester core dendrimers as the control, which results in simple dendrimersomes. Vesicles decorated with carbohydrates can mimic biological cell membranes. Motivated by the unique features of the Janus dendrimersomes and the well-defined self-assembly of Janus dendrimers, Percec and co-workers took up the challenge to prepare glycodendrimersomes that mimic biological cell membranes.184,185 They consequently synthesized several libraries of Janus dendrimers with monosaccharides D-mannose and D-galactose and the disaccharide D-lactose in their hydrophilic part. All these Janus glycodendrimers are different structurally in terms of the carbohydrate unit used as a hydrophilic part, substitution pattern in the hydrophobic parts, structure of the alkyl chain (linear or branched), and the spacer group used to improve the flexibility and solubility of the dendrimers. These Janus dendrimers self-assemble in water and buffer, which results in a diversity of hard and soft assemblies including glycodendrimersomes, glycodendrimer micelles, glycodendrimer cubosomes, and solid lamellae (Figure 25). Percec’s group then compared the structural variations in the various assemblies to the primary structure of the Janus dendrimers. Screening seven libraries of 51 glycodendrimers yielded ten molecules that formed soft dendrimersomes with programmable dimensions for applications, which were stable both in water and buffers. With the knowledge gained from the formation of glycodendrimersomes, more libraries of glycodendrimers have been synthesized with different topologies and studied to learn how these glycodendrimersomes’ topology influence the lectin binding. It was found that dendrimersomes of twin-mixed topology bound lectins more efficiently than twin−twin and single−single topologies.186 Very recently, the Percec group reported on the potential of glycodendrimersomes to understand fundamental structure−activity relationships in carbohydrate−lectin interactions.187 Lee and his co-workers have reported on the excellent selforganization of rod−coil systems into lamellar, cylindrical, and discrete nanostructures depending on the relative volume fractions of the rod segments.51 To investigate such a welldefined self-assembly in water, they designed dendritic rod amphiphilic systems which they called molecular trees because they resembled the shape of a tree.132 They synthesized two amphiphilic molecules (Figure 26) with octa-p-phenylene as the rod segment and ethylene glycol based dendrons as the flexible head groups. Both these molecular trees (17 and 18), however, showed different self-organization patterns in bulk and had vesicle morphologies in aqueous solution. The major difference

Figure 26. Schematic of nanocapsules formed from tree molecules and a TEM and FE-SEM image. Reprinted with permission from ref 126. Copyright 2008 the Royal Society of Chemistry.

observed in the self-assembly of these molecular trees was the size of the vesicles. The molecules with larger dendritic groups had smaller vesicles than the ones with smaller dendrons. These results showed a possible way to control the size of the selfassemblies through the rational design of dendritic-rod amphiphiles. Self-assembly of synthetic molecules into 2D networks is another underexplored area. The unique features offered by the self-assembly of dendritic-rod amphiphiles make them ideal systems for constructing uncommon morphologies with rationally designed molecules. Kim et al. synthesized a new type of amphiphilic asymmetric dumbbell with relatively high hydrophobic fractions to generate 2D networks and studied the mechanism of their formation.188 These investigations revealed that amphiphiles with shorter rod segments formed micelles at the initial stage of their self-assembly in water, which eventually transformed into perforated bilayers with hexagonal packing of the holes. During the transformation of spherical micelles into 2D networks, formations of branched cylinders, toroids, and planar sheets with lateral holes of several tens to few hundreds of nanometers in diameter were observed as the intermediate structures. The self-assembly of amphiphiles with longer rod segments, on the other hand, resulted in closed 2D sheets, which was explained by a decrease in the interfacial curvature with an increase in the rod length. In order to investigate the influence of the relatively hydrophobic fraction of these rod amphiphiles upon the morphology of their self-assemblies, Lee et al. subsequently synthesized a series of asymmetric dumbbells containing the same rod segment and hydrophilic dendron and systematically varied the length of the alkyl chains in the hydrophobic dendron from ethyl, hexyl, decyl to tetradecyl groups.135,189 The asymmetric dumbbell with the ethyl group readily self-assembled in water into spherical micelles and the hexyl-derivative produced toroids. A further increase in the length of the alkyl chain resulted in 2D nets and vesicles for decyl and tetradecyl derivatives, respectively. These results indicated that systematic variations in the structure of the rod amphiphiles provided a wide variety of nanostructures in water. Later on, Kim et al. also investigated the influence of the rod segment’s stiffness upon the morphology of the self-assemblies by using a series of amphiphiles with conjugated aromatic units 2094


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Figure 27. Molecular structures of asymmetric dumbbell amphiphiles.

Figure 28. Representative molecular structures of asymmetric dumbbell amphiphiles and the thermoresponsive transition in their morphologies (H and C correspond to heating and cooling processes). Reprinted from ref 129. Copyright 2013 American Chemical Society. Reprinted with permission from ref 189. Copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted with permission from ref 190. Copyright 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

(19-21, Figure 27) and varied the length of the rod segments.190 The self-assembly of these amphiphiles was investigated with fluorescence and electron microscopy, which indicated formation of 2D sheets with regular lateral pores from the amphiphiles with shortest rod lengths. An increase in the rod length transformed the morphology from a 2D porous sheet to porous and closed vesicles. Astonishingly, a solution of porous capsules exhibited a thermoreversible phase transition at 60 °C, which was due to the LCST behavior of the PEG-based dendrons. cryo-TEM investigation of these samples indicated that the porous capsules readily transformed into closed

capsules without any considerable change in the spherical shape, and these closed capsules started opening over a period of 7 days with considerable hysteresis (Figure 28). The application of these thermally gated capsules for controlled guest release was demonstrated by encapsulation of a fluorescent molecule in the closed capsules. Self-assembled capsules with such gated openings are rarely observed in synthetic systems, which highlights the uniqueness of the reported systems. As mentioned in an earlier section, rigid macrocycles functionalized with hydrophilic dendrons are ideal building blocks for the construction of 1D tubules.144 With the right 2095


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Figure 29. (a) Molecular structures of the amphiphilic rigid macrocycles and (b) schematic of their self-assembly. Reproduced from ref 191. Copyright 2009 American Chemical Society.

Figure 30. (a) Molecular structure of the amphiphilic aromatic macrobicycle and (b−d) schematic of guest-dependent self-assembly of amphiphile 26. Reproduced with permission from ref 192. Copyright 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission from ref 193. Copyright 2015 Wiley-VCH Verlag GmbH & Co. KGaA.

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systems. Investigations on the self-assembly of simple amphiphilic dendrons and dendritic rod amphiphiles have yielded a through fundamental understanding of the selfassembly process and rational design of amphiphiles with which different nanostructures including complex morphologies could be engineered. Recent investigations on the self-assembly of Janus dendrimers have provided very interesting morphologies. All the above-mentioned features highlight the ever growing interest in the self-assembly of dendritic amphiphiles toward biomimicry, which is a long-standing goal of the scientific community.

macrocyclic ring, however, one can influence their self-assembly. To demonstrate the influence of a macrocycle’s ringlike shape on the self-assembly of rigid macrocyclic amphiphiles, Kim et al. investigated a new series of elliptical macrocyclic amphiphiles with different molecular lengths for the macrocycles, whereby a range of self-assemblies formed from spherical micelles and helical coils to vesicles by increasing the molecular length of the elliptical macrocycle (Figure 29).191 They also noticed a thermoreversible transition of helical coils to rods due to the LCST behavior of oligo(ethylene oxide) chains. Flat disk-shaped aromatic molecules stack together because of face-to-face interactions that result in nanofibers. Grafting hydrophilic chains on such disk-shaped hydrophobic molecules makes amphiphiles interact laterally and leads to 2D selfassembly. With this idea, Lee and his co-workers functionalized an aromatic macrobicycle with hydrophilic dendrons (26, Figure 30).192 As envisioned, the cryo-TEM experiments showed formation of a flexible porous sheet through self-assembly of compound 26 in aqueous solution. Careful investigation of these 2D sheets revealed that the sheets resulted from the lateral interaction of small, discrete micelles. The diameter of these micelles was about twice the length of the molecules, which suggested that dimerization of these molecules was a primitive process in the self-assembly of compound 26 into porous sheets. The formation of dimeric micelles was independently proven by VPO. The encapsulation capacity of these planar nanostructures was investigated by coronene solubilization experiments, which indicated intercalation of the flat guest molecule between the dimeric micelles. Microscopic investigation of the coronene encapsulated samples, however, showed that the 2D-sheet morphology was preserved, as they became stiff and the size of the dimeric micelle decreased. To understand this structural change in the presence of the guest molecule, molecular modeling experiments were performed on the dimeric micelles with and without coronene. These studies showed that the plane of the dimeric micelles slipped to decrease steric repulsions between the middle benzene ring in the absence of the guest. In the presence of the guest, the benzene ring moved to other side of the plane and the amphiphiles and the guest lay on top of each other (Figure 30). Realizing the significant influence of guest molecule interactions in the self-assembly of these disctype aromatic amphiphiles, they subsequently constructed a supramolecular capsule by self-assembly of the same amphiphile in the presence of corannulene, a bucky-ball fragment.193

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected] and [email protected]. Notes

The authors declare no competing financial interest. Biographies

Dr. Bala N. S. Thota received his Ph.D. from the Department of Organic Chemistry, Indian Institute of Science, Bangalore, under the supervision of Prof. Uday Maitra. The focus of his thesis was on the synthesis and aggregation properties of bile acid derived oligomers. He is currently a postdoctoral fellow in the group of Prof. Rainer Haag and working on engineering self-assembled nanostructures using dendritic amphiphiles. His research interests are self-assembly of amphiphilic molecules and development of novel drug delivery systems.

4. CONCLUDING REMARKS Development of functional self-assemblies for different applications is one of the focus areas in nanoscience research. Self-assembly of amphiphiles from small molecules and linear polymers have provided nanostructures of different morphologies through a bottom-up approach; however, both these classes of self-assemblies have their pros and cons. Dendritic amphiphiles have gained considerable interest in this context due to the fact that their self-assemblies are stable like polymeric systems and function like small molecular systems. One unique feature of the dendritic amphiphiles is their enriched topologies. They have been further classified on the basis of their topology, and each class has shown a unique self-assembly behavior. For instance, unimolecular systems obtained from globular dendritic amphiphiles are ideal systems for drug delivery applications. Persistent micelle forming amphiphiles have displayed a very well-defined packing of dendritic amphiphiles in their selfassemblies, which is not commonly observed in synthetic

Leonhard H. Urner received his Master of Science degree in Chemistry from the Freie Universität Berlin, Germany, in 2015. He is currently working with Prof. Kevin Pagel and Prof. Rainer Haag on his Ph.D. His research interest is mainly focused on synthesis and investigation of dendritic azobenzene-based amphiphiles in solution and gas phase. 2097


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Prof. Dr. Rainer Haag obtained his Ph.D. with A. de Meijere at the University of Göttingen in 1995. After postdoctoral work with S. V. Ley, University of Cambridge (U.K.), and G. M. Whitesides, Harvard University, Cambridge, MA (U.S.A.), he completed his habilitation at the University of Freiburg in 2002. He then became associate professor at the University of Dortmund and in 2004 was appointed full Professor of Organic and Macromolecular Chemistry at the Freie Universität Berlin. One of his main research interests is the mimicry of biological systems by functional dendritic polymers, with particular focus on applications in nanomedicine.

ACKNOWLEDGMENTS The authors gratefully acknowledge financial assistance from Deutsche Forschungsgemeinschaft (DFG) through grants from the Collaborative Research Center (SFB) 1112 and from the Indo-German Science & Technology Centre (IGSTC), which is supported by the Bundesministerium fü r Bildung und Forschung (BMBF) and the Department of Science & Technology (DST), Delhi, and University of Delhi, Delhi. Dr. Pamela Winchester is acknowledged for language polishing the manuscript, and Dr. Wiebke Fischer is acknowledged for her support in the preparation of the manuscript. REFERENCES (1) Whitesides, G. M.; Grzybowski, B. Self-Assembly at All Scales. Science 2002, 295, 2418−2421. (2) Boncheva, M.; Whitesides, G. M. Making Things by SelfAssembly. MRS Bull. 2005, 30, 736−742. (3) Percec, V.; Ungar, G.; Peterca, M. Self-Assembly in Action. Science 2006, 313, 55−56. (4) Lehn, J.-M. Toward Complex Matter: Supramolecular Chemistry and Self-Organization. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 4763− 4768. (5) Wooley, K. L.; Moore, J. S.; Wu, C.; Yang, Y. Novel Polymers: Molecular to Nanoscale Order in Three Dimensions. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 11147−11148. (6) Bowden, N. B.; Weck, M.; Choi, I. S.; Whitesides, G. M. MoleculeMimetic Chemistry and Mesoscale Self-Assembly. Acc. Chem. Res. 2001, 34, 231−238. (7) Klok, H.-A.; Lecommandoux, S. Supramolecular Materials via Block Copolymer Self-Assembly. Adv. Mater. 2001, 13, 1217−1229. (8) Zhang, S. Emerging Biological Materials through Molecular SelfAssembly. Biotechnol. Adv. 2002, 20, 321−339. (9) Ikkala, O.; ten Brinke, G. Functional Materials Based on SelfAssembly of Polymeric Supramolecules. Science 2002, 295, 2407−2409. (10) Jain, S.; Bates, F. S. On the Origins of Morphological Complexity in Block Copolymer Surfactants. Science 2003, 300, 460−464. (11) Elemans, J. A. A. W.; Rowan, A. E.; Nolte, R. J. M. Mastering Molecular Matter. Supramolecular Architectures by Hierarchical SelfAssembly. J. Mater. Chem. 2003, 13, 2661−2670. 2098


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Supramolecular Architectures of Dendritic Amphiphiles in Water

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