Supramolecular Amphiphiles Based on Host–Guest Molecular

Review pubs.acs.org/CR

Supramolecular Amphiphiles Based on Host−Guest Molecular Recognition Motifs Guocan Yu, Kecheng Jie, and Feihe Huang* State Key Laboratory of Chemical Engineering, Center for Chemistry of High-Performance & Novel Materials, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China 3.7. Dual Stimuli-Responsive Supramolecular Polypeptide-Based Hydrogel and Reverse Micellar Hydrogel Mediated by Host−Guest Chemistry 3.8. Cyclodextrin-Based Macrocyclic Amphiphiles 3.9. Hybrid Materials Constructed from Cyclodextrin-Based Supramolecular Amphiphiles 3.9.1. Self-Assembly of Supramolecular Amphiphiles as a Tool To Functionalize Nanotubes 3.9.2. Chiral Self-Assembly and Reversible Light Modulation of a Polyoxometalate Complex via Host−Guest Recognition 3.9.3. Self-Assembly of Soft Hybrid Materials Directed by Light and a Magnetic Field 3.9.4. Supramolecular Tubular Nanoreactor 3.10. Supramolecular Amphiphiles as Drug Delivery Vehicles 3.10.1. Intracellular pH-Sensitive Supramolecular Amphiphiles Based on Host− Guest Recognition between Benzimidazole and β-CD as Potential Drug Delivery Vehicles 3.10.2. Polymeric Core−Shell Assemblies Mediated by Host−Guest Interactions: Versatile Nanocarriers for Drug Delivery 3.10.3. Core−Shell Nanosized Assemblies Mediated by an α−β Cyclodextrin Dimer with a Tumor-Triggered Targeting Property 4. Calixarene-Based Supramolecular Amphiphiles 4.1. Supramolecular Amphiphiles from Sulfonated Calixarenes and Single-Chain Surfactants 4.2. Multistate Self-Assembled Micromorphology Transitions Controlled by Host−Guest Interactions 4.3. Hybrid Systems Constructed from Calixarene-Based Supramolecular Amphiphiles 4.3.1. Architecture-Controlled “SMART” Calix[6]arene Self-Assemblies in Aqueous Solution

CONTENTS 1. Introduction 2. Crown Ether-Based Supramolecular Amphiphiles 2.1. Supramolecular Micelles Constructed by Crown Ether-Based Molecular Recognition 2.2. Novel Diblock Copolymer with a Supramolecular Polymer Block and a Traditional Polymer Block 3. Cyclodextrin-Based Supramolecular Amphiphiles 3.1. Photoresponsive Supramolecular Amphiphile Constructed from an AzobenzeneContaining Surfactant and α-Cyclodextrin 3.2. Light-Controlled Smart Nanotubes Based on Cyclodextrin/Azobenzene Molecular Recognition 3.3. Voltage-Responsive Vesicles Based on SelfAssembly of Two Homopolymers 3.4. Supramolecular Amphiphiles Constructed from Hyperbranched/Dendrimeric Building Blocks 3.4.1. Linear−Hyperbranched Supramolecular Amphiphile Based on β-CD and Adamantane Recognition 3.4.2. Multiple Host−Guest Interactions Driven Self-Assembly of Cyclodextrin and Adamantane Modified Hyperbranched Poly(ethylene imine)s 3.4.3. Supramolecular Janus Hyperbranched Polymer 3.4.4. Cyclodextrin-Covered Organic Nanotubes Derived from Self-Assembly of Dendrons and Their Supramolecular Transformation 3.5. Side-Chain-Type and Main-Chain-Type Supramolecular Polymeric Amphiphiles 3.6. Noncovalently Connected Micelles © XXXX American Chemical Society

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Chemical Reviews 4.3.2. Hybrid Self-Assemblies Constructed from an Amphiphilic Calix[4]arene and Au Nanoparticles 4.4. Photomodulated Fluorescence of Supramolecular Assemblies of Sulfonatocalixarenes and Tetraphenylethene 4.5. Photodynamic Therapy System Fabricated from a Calixarene-Based Supramolecular Amphiphile 4.6. Multi-Stimuli-Responsive Supramolecular Amphiphile as a Drug Delivery System 4.7. Cholinesterase-Responsive Supramolecular Vesicles as Drug Delivery Carriers 4.8. Supramolecular Amphiphiles Constructed from Calixarene Analogues 4.8.1. Supramolecular Amphiphile Based on Calix[4]resorcinarene and a Cationic Surfactant for Controllable Self-Assembly 4.8.2. Fabrication of Well-Defined Crystalline Azacalixarene Nanosheets Assisted by Se···N Noncovalent Interactions 5. Cucurbituril-Based Supramolecular Amphiphiles 5.1. Supramolecular Vesicles Formed by Amphiphilc Cucurbit[6]uril and Multivalent Binding of Sugar-Decorated Vesicles to Lectin 5.2. Supramolecular Photosensitizers with Enhanced Antibacterial Efficiency 5.3. Supramolecular Approach To Fabricate Highly Emissive Smart Materials 5.4. Cucurbit[8]uril-Based Ternary Supramolecular Amphiphiles 5.4.1. Spontaneous Formation of Vesicles Triggered by Formation of a ChargeTransfer Complex in a Host 5.4.2. Supramolecular Glycolipid Based on Host-Enhanced Charge-Transfer Interaction 5.4.3. Supramolecular Peptide Amphiphile Vesicles through Host−Guest Complexation 5.4.4. Biocompatible and Biodegradable Supramolecular Assemblies for Reduction-Triggered Release of Doxorubicin 6. Pillar[n]arenes-Based Supramolecular Amphiphiles 6.1. Pillar[n]arene-Based Enzyme-Responsive Supramolecular Amphiphiles 6.2. Bola-Type Supramolecular Amphiphile Constructed from a Water-Soluble Pillar[5]arene and a Rod−Coil Molecule for Dual Fluorescent Sensing 6.3. Cationic Water-Soluble Pillar[6]areneBased Supramolecular Amphiphile 6.4. Photoresponsive Self-Assembly Based on a Water-Soluble Pillar[6]arene and an Azobenzene-Containing Amphiphile in Water 6.5. Four-Armed Supramolecular Amphiphile with Complexation-Induced Emission 6.6. Supramolecular Amphiphiles as Multiwalled Carbon Nanotube Dispersants

Review

6.6.1. pH-Responsive Water-Soluble Pillar[6]arene-Based Supramolecular Amphiphile 6.6.2. UV-Responsive Water-Soluble Pillar[6]arene-Based Supramolecular Amphiphile 6.7. Supramolecular Amphiphiles Constructed on the Basis of Pillararene/Paraquat Recognition 6.7.1. pH-Responsive Supramolecular Amphiphiles on the Basis of Molecular Recognition between Pillar[n]arenes (n = 6, 7, and 10) and Paraquat 6.7.2. Supramolecular Hybrid Nanostructures Based on Pillar[6]arene Modified Gold Nanoparticles/Nanorods and Their Application in pH- and NIR-Triggered Controlled Release 6.8. Water-Soluble Pillar[6]arene-Based Supramolecular Vesicles for Drug Delivery 7. Supramolecular Amphiphiles Constructed by Other Macrocycle-Based Host−Guest Molecular Recognitions 7.1. Switchable Nanoporous Sheets from Aqueous Self-Assembly of Aromatic Macrobicycles 7.2. Multi-Stimuli-Responsive Supramolecular Diblock Copolymers 7.3. Assembly of Amphiphilic Baskets into Stimuli-Responsive Vesicles 7.4. Supramolecular Amphiphiles Constructed from Benzimidazolium-Based Cyclophane 7.5. Porphyrin-Based Supramolecular Amphiphile 7.6. Shuttle-Like Supramolecular Amphiphile 8. Conclusions and Outlook Author Information Corresponding Author Notes Biographies Acknowledgments References

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1. INTRODUCTION Self-assembly, which makes use of molecules rather than atomic units, offers a bottom-up approach to the construction of new materials on multiple length scales.1−9 By precisely organizing relatively simple molecular and macromolecular building blocks in a noncovalent fashion, nature utilizes this approach to create complex functional materials and systems in which the functions of the whole are greater than the sum of its parts.10−13 Protein folding, nucleic acid assembly and tertiary structure, ribosomes, phospholipid membranes, and microtubules, etc. are selective and representative examples of selfassembly in nature that are of critical importance for living organisms.14−22 Phospholipids, a class of amphiphilic molecules, are the main components of biological membranes. The amphiphilic nature of these molecules defines the way in which they form membranes. They arrange themselves into bilayers by positioning their polar groups toward the surrounding aqueous medium, and their lipophilic chains toward the inside of the bilayer, defining a nonpolar region between two polar

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ones.23,24 Another well-known example is DNA, where the selfrecognition of the complementary base-pairs by hydrogen bonding leads to the self-assembly of the double helix. Viruses, such as the rhinovirus, possess a spherical capsid around their nucleic acid. The closed-shell virions are built from smaller proteins via noncovalent interactions, resulting in a structure with icosahedral symmetry. The skeletons of radiolaria and capsid shells of viruses are nature’s expression of the most economical structural solution to a given set of growth conditions. Conventionally, amphiphile is a term describing a chemical compound possessing both hydrophilic and hydrophobic parts linked by covalent bonds.25−27 The interest in amphiphiles arises from their self-assembly in aqueous solution to form welldefined structures, such as micelles, nanotubes, nanorods, nanosheets, and vesicles, which can be applied in many fields ranging from nanodevices, drug/gene delivery, template synthesis, and cell imagings.28−34 The structures and the properties of the self-assemblies formed by amphiphiles are determined by their architectures (interplay between the hydrophilic−hydrophobic balance and geometric packing constraints) and experimental conditions, such as concentration, temperature, pH, and ionic strength.35 For example, bolaform amphiphiles with two head groups linked to one alkyl chain have high thermal resistance and are discovered frequently in the cell membranes of thermophilic bacteria.36 Gemini-form amphiphiles with two head groups located in the middle of the alkyl chain self-assemble in solvents at very low concentration, exhibiting potential applications in gene and drug delivery.37−39 The concept of amphiphile has been extended to polymers. Generally, a polymeric amphiphile is constructed by linking a hydrophilic segment and a hydrophobic segment through a covalent bond.40−42 Compared with low molecular weight amphiphiles, polymeric amphiphiles are endowed with structural diversity and stability. The self-assemblies fabricated using polymeric amphiphiles have a larger capacity for guest molecules and better thermal sustainability. For example, the assemblies from low molecular weight amphiphiles are comparatively dynamic, due to the balance between the aggregated molecules and the dissociated nonaggregated molecules in the bulk solution. For aggregates from polymeric amphiphiles, the stronger interactions as well as the entanglement between the polymer chains prevent quick molecular exchange. The unique property of the polymeric topology has led to applications in drug delivery and templated synthesis of nanomaterials.43−46 However, the syntheses of large amphiphilic molecules by traditional covalent chemistry are typically time-consuming and cost-intensive. An extraordinarily convergent methodology is required to reach the nanoscopic dimensions upward from the molecular level. In the early 1960s, the discovery of “crown ethers”, “cryptands”, and “spherands” led to the realization that small, complementary molecules can be made to recognize each other through noncovalent interactions, such as electrostatic interactions, π−π stacking, hydrogen bonding, and hydrophobic interactions, etc.47−54 In 1987, the Nobel Prize was awarded to Pedersen, Cram, and Lehn for their pioneering studies on host−guest and supramolecular chemistry. Since then, supramolecular chemistry has attracted wide attention from chemists, biologists, and materials scientists. The topics of supramolecular chemistry are focused on the ionic/molecular

recognition and assembly of different building blocks through noncovalent interactions.55−58 By combining supramolecular chemistry and traditional amphiphiles, supramolecular amphiphiles, a novel research field, was born under the widespread attention of scientists. In contrast to conventional amphiphiles, supramolecular amphiphiles referring to amphiphiles constructed on the basis of noncovalent interactions or dynamic covalent bonds are very useful in the fabrication of nanomaterials with a high degree of structural complexity.59,60 Functional groups can be attached to supramolecular amphiphiles by employing various noncovalent interactions, greatly avoiding the tedious covalent syntheses and substrate modifications required for the preparation of traditional amphiphiles. Moreover, the dynamic and reversible nature of the noncovalent interactions endows the resultant supramolecular architectures with excellent stimuli-responsive features. The advance of supramolecular amphiphiles will not only enrich the family of conventional amphiphiles, but also provide a new bridge between the colloidal and supramolecular sciences.61−66 Due to their above-mentioned advantages, supramolecular amphiphiles are being widely and actively investigated in materials and biomedical sciences nowadays. Especially, the applications of supramolecular amphiphiles in biologically and pharmaceutically relevant fields have aroused tremendous interest of researchers in recent years. To date, a number of excellent reviews have been published on supramolecular amphiphiles. For example, Zhang and coauthors comprehensively summarized the recent research progress of supramolecular amphiphiles, covering their definition, syntheses, properties, functionalization, stimuli-responsivenesses, selfassembly behaviors, and potential applications.58−62 Hao and co-workers highlighted recent studies on different strategies in the fabrication of vesicles from supramolecular amphiphiles.63 Various noncovalent interactions can be adopted as driving forces to construct supramolecular amphiphiles, including hydrogen bonding, π−π interactions, electrostatic interactions, and charge-transfer interactions. Among them, supramolecular amphiphiles constructed on the basis of host−guest recognition show distinctive properties by introducing macrocylic hosts into the supramolecular systems. In principle, a host−guest system formed by molecular recognition always consists of a receptor molecule (host) and a ligand molecule (guest) through noncovalent interactions.67−72 The larger host molecule usually has a hydrophobic or hydrophilic cavity in which the guest can be embedded, while organic compounds, their ions, as well as metal ions, and even nanoparticles and biomacromolecules, can serve as guests.73−87 Since the origin of host−guest chemistry (molecular recognition chemistry), a wide variety of synthetic organic receptors like crown ethers, cyclodextrins, calixarenes, cucurbiturils, and pillararenes have been used as molecular receptors to construct supramolecular amphiphiles.88 In the following discussion, supramolecular amphiphiles constructed by host−guest molecular recognition motifs are classified by the types of macrocyclic hosts involved.

2. CROWN ETHER-BASED SUPRAMOLECULAR AMPHIPHILES It has been nearly five decades since Pedersen began his effort to develop a complexing agent for divalent cations. Crown ethers are the first generation of artificial macrocyclic hosts that represent the birth of supramolecular chemistry. The host− guest interactions between crown ethers and guest molecules C

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Figure 1. Top: chemical structures of building blocks 1 and 2 and cartoon representation of supramolecular micelle formation from self-assembly of 1 and 2. TEM images: (a) the micelles formed by the supramolecular amphiphiles at a concentration of 5.0 × 10−4 M in water (pH = 7.0); (b) enlarged image of part a; (c) after adding a small drop of aqueous HCl solution to part a (pH = 3.0); (d) after adding a small drop of aqueous NaOH solution to part c (pH = 7.5). (e) Controlled release of Nile Red encapsulated in a 5.0 × 10−4 M micellar solution at different pH values. Reproduced with permission from ref 112. Copyright 2012 American Chemical Society.

constant (Ka) value of 1.5 × 103 M−1, the negatively charged crown ether host unit of 1 interacted with the viologen dication guest moiety of 2 to form a supramolecular amphiphile 1⊃2. Compared with the crown ether/paraquat molecular recognition in organic solvents, the stability of this supramolecular amphiphile was enhanced effectively upon introduction of electrostatic interactions into this host−guest system. The critical micellar concentration (CMC) of this supramolecular amphiphile was calculated to be ∼7.5 × 10−5 M. Supramolecular amphiphile 1⊃2 self-assembled to form stable dispersed supramolecular micelles about 50 nm in diameter with the decyl group as the core and PEO as the shell in water (Figure 1a,b). Furthermore, the host−guest complexation between the negatively charged BMP32C10 unit and the paraquat moiety can be controlled by adding acid and base, giving pH responsiveness to the supramolecular micelles. The COO− groups were converted into the neutral carboxylic acid groups by adding acid, weakening the complexation between the BMP32C10 unit and the viologen moiety, resulting in the destruction of the micellar structure. A dramatic decrease of the size from 50 nm in diameter to 10 nm (pH = 3.0) was observed upon addition of a small drop of aqueous HCl to the neutral micellar solution. Meanwhile, the spherical aggregates with uniformly dispersed size were destroyed instead by the formation of rodlike aggregates which self-assembled from amphiphilic 2 alone (Figure 1c). Continuous addition of small

(such as paraquat derivatives and secondary ammonium salts) are important secondary interactions not only mimicking natural systems but also constructing new materials.89−98 In the past two decades, crown ether hosts, such as dibenzo-24crown-8 (DB24C8), bis(m-phenylene)-32-crown-10 (BMP32C10 ), and bis(p -phenylene)-34-crown-10 (BPP34C10), were usually involved in affording interesting topological structures, such as rotaxanes, catenanes, polypseudorotaxanes, and supramolecular polymers.99−111 However, crown ethers have rarely been utilized as building blocks to construct supramolecular amphiphiles mainly due to the weak interactions of crown ether-based molecular recognitions in water. Consequently, it is challenging to fabricate aqueous supramolecular amphiphiles driven by crown ether-based molecular recognition between hydrophilic and hydrophobic segments. 2.1. Supramolecular Micelles Constructed by Crown Ether-Based Molecular Recognition

Huang and co-workers employed a hydrophilic poly(ethylene oxide) (PEO) terminated bis(m-phenylene)-32-crown-10 (BMP32C10) host 1 containing two COO− groups and a hydrophobic viologen dication derivative 2 containing a decyl group to fabricate a crown ether-based supramolecular amphiphile with the capability of pH-responsive self-assembly/disassembly in water.112 By utilizing the electrostatic attraction-enhanced host−guest interactions with an association D

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drops of aqueous NaOH solution into the aqueous solution resulted in a recovered aggregate size (Figure 1d), indicating that the reversible transition between the assembled and disassembled structures could be achieved by changing the solution pH. With the pH-responsive complexation between 1 and 2 in hand, the authors utilized this supramolecular system to encapsulate hydrophobic molecules (Nile Red) into their hydrophobic cores under neutral condition and later release the encapsulated molecules in response to a decrease of the solution pH. The host−guest interactions between 1 and 2 were weakened, and the supramolecular micelles disassembled by adding acid (aqueous HCl), resulting in the release of Nile Red from the micelles (Figure 1e). This supramolecular amphiphile based on the crown ether/paraquat host−guest recognition motif demonstrated that the pH-responsive release of hydrophobic guest molecules from the interior of supramolecular micelles could be achieved, making it possible to use these supramolecular micelles as carriers in various fields. 2.2. Novel Diblock Copolymer with a Supramolecular Polymer Block and a Traditional Polymer Block

The morphologies and sizes of the aggregates self-assembled from amphiphilic block copolymers are closely related to the solvophilicity and solvophobicity of different blocks. Typically, it is a challenge to regulate the chain lengths of traditional amphiphilic block copolymers in which the monomers are connected by covalent bonds. Therefore, intricate organic and/ or polymer syntheses are required to adjust the solvophilicity/ solvophobicity ratio of different polymer segments in order to obtain various self-assembly morphologies. Supramolecular polymers are polymers based on low molecular weight monomers held together by directional and reversible noncovalent interactions,113−123 such as hydrogen bonds, metal− ligand bonds, π−π stacking, electrostatic interactions, and hydrophobic interactions. Supramolecular polymers have captured more and more attention from scientists over the past decades, because they combine attractive features of conventional polymers with properties that result from their reversibility.124−136 It should be emphasized that the polymerization degree of supramolecular polymers can be regulated by controlling the monomer concentration in solution due to the concentration-dependence of supramolecular polymerization.137−141 Therefore, the construction of a supramolecular amphiphilic diblock polymer is a novel and effective strategy to adjust the solvophilicity/solvophobicity ratio of the dynamic polymer, and further to control the self-assembly behavior in solution. On the basis of the crown ether/paraquat host−guest recognition, Huang and co-workers constructed a novel diblock copolymer with a supramolecular polymer block as the hydrophobic part and a traditional polymer block as the hydrophilic segment (Figure 2).142 Monomer 3 self-assembled into a supramolecular polymer, and the viologen dication guest moiety was associated with the terminal bis(m-phenylene) 32crown-10 (BMP32C10) host unit on the traditional polymer 4 to form a supramolecular amphiphilic diblock copolymer in N,N-dimethylformamide (DMF) when the concentration of 3 was higher than that of 4. The chain length of the supramolecular polymer could be adjusted by changing the proportion of 3 to 4, resulting in the variation of the hydrophobic/hydrophilic ratio. Consequently, various selfassembly morphologies, such as micelles, disk-like micelles,

Figure 2. Chemical structures of building blocks 3 and 4 and cartoon representations of the diblock copolymer formation and its selfassembly in water. Lsp represents the extended length of the supramolecular polymer, and Ltp represents the extended length of the traditional polymer. TEM images of the self-assembly morphologies of the diblock copolymers in water (pH 7.0) with different concentrations of 3: (a) 20.0 mM; (b) 30.0 mM; (c) 40.0 mM. Here the concentration of 4 was constant at 1.00 mM. Reproduced with permission from ref 142. Copyright 2013 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim.

and vesicles were obtained with the function of controlled release of different molecules. When the concentrations of 3 and 4 were 20.0 and 1.00 mM, respectively, 3 self-assembled into a supramolecular polymer with a medium polymerization degree of 9.5. The chain length of the traditional polymer (Ltp = 28.1 nm) was longer than that of the supramolecular polymer (Lsp = 24.2 nm), and this supramolecular amphiphile produced by noncovalent association between the supramolecular polymer and the traditional polymer 4 self-assembled into micelles (average diameter was about 90 nm) with the PEO as the corona block and the supramolecular polymer as the core block (Figure 2a). Due to the hydrophobicity of the core block, hydrophobic Nile Red molecules could be encapsulated in the micelles. Moreover, controlled release of the dye molecules was achieved by acidifing the solution due to the pH-responsive molecular recognition. The complexation between the BMP32C10 host unit and the viologen dication guest moiety was weakened by adding acid caused by the protonation of the COO− groups into the neutral carboxylic acid groups, resulting in the degradation of the supramolecular polymer and the breakage of the linkage between the supramolecular polymer and 4. The chain length of the supramolecular polymer increased to 29.8 nm, which was similar to the length of the traditional polymer (Lsp ≈ Ltp) when the concentration of 3 was increased E

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to 30.0 mM. The self-assembly morphology of this supramolecular amphiphile was disk-like micelles (Figure 2b), and the size of the nanoaggregates was uniformly dispersed and slightly larger than that of the micelles, attributed to the increased length of the supramolecular polymer. The transition from micelles to disks was caused by the increase of interfacial tension to overwhelm the other free energy terms, giving rise to complete stretching of the core blocks and a flat interface. The chain length of the supramolecular polymer further increased to 34.4 nm (Lsp > Ltp) as the concentration of 3 was further increased to 40.0 mM. Vesicles around 1 μm in diameter formed by this supramolecular amphiphile with the average wall thickness of about 100 nm (Figure 2c), demonstrating the bilayer wall structure of the vesicles. Compared with the micellar aggregates, these vesicles could encapsulate hydrophilic molecules calcein within their interior under neutral conditions and release the molecules in response to a decrease of the solution pH. Furthermore, the morphologies of the self-assemblies could be controlled from vesicles to disk-like micelles and then to spherical micelles by adjusting the solution pH from 7.0 to 6.5 and then to 6.0 due to the dynamic nature of the supramolecular polymer arising from the changing the degree of the polymerization. Therefore, the solvophilicity/solvophobicity ratio of the supramolecular amphiphile was reduced, causing the morphology changes of the self-assemblies.

Figure 3. Typical guest structures for CDs.

Table 1. Some Structural Parameters of Cyclodextrins144,147,148

property no. of glucose units (n) empirical formula (anhydrous) molecular wt min internal diameter (a) (Å) max internal diameter (b) (Å) diameter of outer periphery (c) (Å) height of torus (h) (Å) cavity volume (Å3)

3. CYCLODEXTRIN-BASED SUPRAMOLECULAR AMPHIPHILES That cyclodextrins (CDs) can be obtained from natural products was discovered coincidentally by Villiers in 1891, and their structures were first reported in 1903 by F. Schardinger.143,144 CDs are cyclic oligosaccharides composed of D-glucose units that are connected by α-1,4-glucosidic linkages. α-, β-, and γ-Cyclodextrins are the most common macrocyclic oligosaccharides and are composed of six, seven, and eight D-glucopyranose residues, respectively.145−150 CDs assume a toroidal shape with the diameter of the primary hydroxyl rim of the cavity reduced compared with the secondary one. The exterior of the cavity is highly polar due to the bristling hydroxy groups, while the interior is nonpolar, making them suitable and fascinating hosts for supramolecular chemistry.151−159 Most importantly, the well-documented ability of the parent CDs to form inclusion complexes with a very wide range of guest species in both aqueous solution and the solid state has been widely exploited.160−162 The major driving forces of the formation of CD inclusion compounds are hydrophobic and van der Waals interactions between the inner surface of the CD ring and the hydrophobic sites on the guest. CDs have been extensively employed as not only excellent receptors for molecular recognition but also excellent building blocks to construct nanostructured functional materials.163−168 Due to the discrepancy in cavity size, each cyclodextrin has its own ability to form inclusion complexes with specific guests, an ability which depends on the size-selective complexation between the guest molecule and the hydrophobic cyclodextrin cavity (Figure 3).169−173 The diameter of the hydrophobic part of the guest has to be smaller than the minimum diameter to permit the formation of a stable axial inclusion complex. The values of minimum internal diameter (a), maximum internal diameter (b), diameter of outer periphery (c), and cavity volume are listed in Table 1. For example, dodecyl groups can form inclusion complexes with α-CD, β-CD, and γ-CD with

α-CD

β-CD

γ-CD

6 C36H60O30 972.85 4.4 5.7 13.7

7 C42H70O35 1134.99 5.8 7.8 15.3

8 C48H80O40 1297.14 7.4 9.5 16.9

7.8 174

7.8 262

7.8 427

different stoichiometries caused by the difference in the cavity size. Adamantane (ADA), azobenzene (AZO), phenyladamantane (Ph-ADA), ferrocene (Fc), lithocholic acid (LA), and cholesterol are frequently used as guests. As a pair of model compounds, Ph-ADA exhibits much higher binding affinity (7.6 × 105 M−1) to β-CD than that of ADA (0.4 × 105 M−1), because the hydrophobic phenyl group is conducive to the host−guest complexation and makes the binding site for β-CD deeper than ADA.174,175 Among them, many pairs with binding abilities that are adjustable to external environment, such as pH-change, light, and redox, have drawn great attention, because they could be applied to construct stimuli-responsive supramolecular materials.176−180 Moreover, the binding affinities of different pairs cover a very broad range, providing a good opportunity to realize reversibility of self-assembly just by competition between the guests. On the basis of the host−guest recognition between CDs and these stimuli-responsive groups, a variety of supramolecular amphiphiles have been fabricated, endowing the self-assemblies with interesting functions. 3.1. Photoresponsive Supramolecular Amphiphile Constructed from an Azobenzene-Containing Surfactant and α-Cyclodextrin

Stimuli-responsive supramolecular self-assemblies have attracted much interest due to their potential applications in a broad range of fields, including memory storage, smart supramolecular polymers, drug delivery systems, protein probes, and nanodevices.181−183 Among numerous external stimuli, light is of special interest because it can work rapidly, F

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104 M−1. Upon addition of an equivalent amount of α-CD into an aqueous solution of trans-AzoC10, the vesicle-like aggregates disappeared and some irregular aggregates formed (Figure 4c). Driven by hydrophobic and van der Waals interactions, the hydrophobic trans-azobenzene group of the guest penetrated the cavity of α-CD, destroying the amphiphilicity of trans-AzoC10, thus inducing the disassembly of the vesicle-like aggregates. Upon irradiation with UV light at 365 nm for 500 s, the vesicle-like aggregates formed again with an average diameter of about 200 nm (Figure 4d). The size of the azobenzene in the cis-state was larger than the cavity of α-CD, so it decomplexed, making cis-AzoC10 amphiphilic in the presence of α-CD. Notably, the average sizes and shapes of the vesicle-like aggregates formed by trans-AzoC10 and α-CD⊃cis-AzoC10 were different (Figure 4f). On the other hand, the photoisomerization of the azobenzene group on the hydrophobic segment of the amphiphilic guest had no apparent influence on the self-assembly of AzoC10 although the CAC values of transAzoC10 and cis-AzoC10 were different. Therefore, the reason for the difference between the vesicle-like aggregates was that α-CD interacted with the alkyl chain of AzoC10 as well when trans-AzoC10 was photoisomerized into cis-AzoC10. More interestingly, the aggregates were disassembled by further irradiation with visible light at 450 nm, and were largely recovered on further UV irradiation at 365 nm (Figure 4e); this was attributed to the reversible host−guest complexation between α-CD and the azobenzene group. This photoresponsive supramolecular system certainly has enormous potential applications in various areas, including nanodevices, memory storage, and drug/gene delivery systems.

remotely, cleanly, and noninvasively. Azobenzene has been proved to be especially advantageous for inducing dramatic structural changes in supramolecular systems accompanied by large molecular property changes due to its photoinduced E/Z isomerization.184−186 Photosensitivity is usually accomplished by host−guest interactions between α-CD and azobenzene on the basis of the mechanism of switchable azobenzene isomer under light regulation. Driven by hydrophobic and van der Waals interactions, trans-azobenzene can be well-recognized by αCD, whereas the cis-form azobenzene group rapidly slides out of the cavity because of the size mismatch between the host and guest.187 This photoisomerization can be reversibly switched upon external photoirradiation. On the basis of this host−guest recognition, photoresponsive supramolecular amphiphiles can be constructed. The morphology of the self-assemblies formed by the supramolecular amphiphiles can be regulated reversibly by UV and visible light irradiation. The on/off photoresponsive effect can be applied in drug delivery systems, which allows remote control of drug storage and release. Zhang and co-workers elegantly employed an azobenzenecontaining amphiphile AzoC10 with α-CD to construct a photoresponsive supramolecular amphiphile that underwent reversible assembly and disassembly (Figure 4).188 Due to its

3.2. Light-Controlled Smart Nanotubes Based on Cyclodextrin/Azobenzene Molecular Recognition

Compared to stimuli-responsive zero-dimensional polymer selfassemblies (e.g., micelles or vesicles), one-dimensional polymeric nanomaterials (nanofibers, nanotubes, and nanowires) with intelligent responsivenesses exhibit great potential applications ranging from nanotechnology to bioscience due to their distinctive structural and functional utilities.189,190 Developing novel stimuli-responsive polymeric nanotubes enables their application in biologically and pharmaceutically relevant fields. Generally, polymeric tubes fabricated from block copolymers with different functionalities linked by covalent bonds are short of stimuli-responsiveness. A “block copolymerfree” strategy in which pseudocopolymers are obtained by orthogonal assembly of two or three homopolymers through noncovalent interactions at chain ends, such as H-bonding and metal−ligand bonding,191,192 has been widely employed to construct 1D polymeric nanomaterials. Yuan and co-workers combined the concept of “block copolymer-free” and dynamic host−guest recognition to successfully prepare smart nanotubes possessing reversible self-assembly behaviors upon UV−vis irradiation (Figure 5).193 Two homopolymers, poly(acrylic acid) with single transazobenzene end-capping (PAA-tAzo) and poly(caprolactone) bearing an α-CD terminator (PCL-α-CD), were designed and synthesized. The azobenzene and α-CD units at the ends of the homopolymers formed a 1:1 inclusion complex in aqueous solution with a Ka value of ∼1.32 × 104 M−1. This host−guest complex linked the hydrophobic poly(caprolactone) (PCL) and hydrophilic poly(acrylic acid) (PAA) polymeric segments to form a supramolecular amphiphile PCL-α-CD/PAA-tAzo in

Figure 4. (a) Reversible photoisomerization of AzoC10 upon UV and visible light irradiation, respectively. TEM images: (b) AzoC10; (c) AzoC10 mixed with α-CD (1:1 molar ratio); (d) after irradiation at 365 nm for 500 s; (e) after irradiation at 450 nm for 2500 s, then further irradiation at 365 nm for 500 s; (f) cis-rich AzoC10 mixed with α-CD (1:1 molar ratio). (g) Dependence of the surface tension on the AzoC10 concentration. (h) Illustration of the photocontrolled reversible assembly and disassembly of AzoC10. Reproduced with permission from ref 188. Copyright 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

amphiphilic property, trans-AzoC10 itself self-assembled into vesicle-like aggregates in aqueous solution with an average diameter of about 500 nm (Figure 4b) when the concentration was higher than its critical aggregate concentration (CAC = 3.5 × 10−5 M) (Figure 4g). The azobenzene part at the tail of the hydrophobic alkyl chain of AzoC10 formed a 1:1 inclusion complex with α-CD with an association constant (Ka) of 2.82 × G

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fragmented tubes reverted to similar shapes and sizes as the original ones upon visible light irradiation at 450 nm for 300 s, which demonstrated that the photoresponsive host−guest recognition played a significant role in the fabrication of the supramolecular amphiphile (Figure 5d). The reversible assembly and disassembly processes of the nanotubes were further verified by dynamic light scattering (DLS) measurements (Figure 5e). The photoresponsive self-assembly and disassembly properties were utilized for controlled release of Rhodamine B (RB) encapsulated in the nanotubes. The nanotubes only exhibited a low-level free-release less than 17% within 10 h without UV irradiation. On the contrary, a rapid release curve (∼0.80 h) could be observed upon UV irradiation at 365 nm for 420 s due to the disassembly of the nanotubes. Furthermore, the release rate of RB could be adjusted precisely by controlling the irradiation time. The release percentage of RB all reached ∼100% triggered by UV irradiation for different times (Figure 5f). These results indicated that this supramolecular system PCL-α-CD/PAA-tAzo exhibited excellent capacity as a onedimensional nanocarrier for controlled release of gene or anticancer drugs over a tunable time with precise light control, which compared favorably with other polymeric nanocapsulated systems. 3.3. Voltage-Responsive Vesicles Based on Self-Assembly of Two Homopolymers

Most cells generally function in a reduced state, because they can produce physiologically low amounts of reactive oxygen, nitrogen, and sulfur species, referred as ROS, RNS, and RSS, respectively, in a regulated way and through different mechanisms, which act as signaling molecules in many intracellular or intercellular communication processes (redox signaling).194,195 On the other hand, an imbalance in the metabolism of these reactive intermediates results in the phenomenon known as oxidative stress, that is, ROS or RNS concentrations exceeding the antioxidant capacity of the cell. If left unchecked, these oxidative molecules can cause oxidative modification of cellular macromolecules, modify their function, and eventually lead to cell death.196−198 Therefore, developing new redox-responsive supramolecular systems is conducive to elucidating and biomimicing the biological activities. Construction of voltage-responsive supramolecular selfassemblies is considered significantly attractive because they can be easily controlled using electrochemistry and do not contaminate the system.199 On the other hand, electrical stimulus can reduce redox reactions of the systems without bringing any redox pollution, making it favorable for application in industry and biological systems. In the field of voltageresponsive supramolecular systems, β-cyclodextrin (β-CD), calixarenes, and cyclophanes are used frequently as hosts, while ferrocene (Fc), cobaltocenium, tetrathiafulvalene (TTF), and viologen are common guests.200−202 For the β-CD and Fc host−guest molecular recognition, the neutral Fc moiety is strongly bound in the cavity of β-CD to form a stable inclusion complex mainly driven by hydrophobic interactions, whereas the charged moiety (Fc+) dissociates rapidly. This threading and dethreading switch is reversible and can be precisely controlled by redox potentials.203,204 Yuan and co-workers fabricated a voltage-responsive supramolecular amphiphile based on the β-CD/Fc host−guest molecular recognition motif, which self-assembled into supramolecular vesicles (Figure 6).205 Two end-decorated homo-

Figure 5. Top: cartoon representation of the reversible assembly and disassembly of light-responsive PCL-α-CD/PAA-tAzo nanotubes based on cyclodextrin/azobenzene molecular recognition. TEM images of reversible assembly and disassembly of the nanotubes upon exposure to light: (a) no stimuli; (b) 365 nm UV light for 60 s; (c) 365 nm UV light for 300 s; (d) 450 nm visible light for 300 s. (e) The change of hydrodynamic size of PCL-α-CD/PAA-tAzo aggregates by UV and visible light stimuli. (f) Controllable release of Rhodamine B from the supramolecular nanotubes in response to the light stimulation. Reproduced with permission from ref 193. Copyright 2011 The Royal Society of Chemistry.

water (CAC ∼0.56 mg/mL). TEM revealed that PCL-α-CD/ PAA-tAzo self-assembled into tubular aggregates ∼220 nm in length and ∼90 nm in diameter. These aggregates were stable for at least three months in the absence of stimuli. The wall thickness of the nanotubes was 9−13 nm, close to two molecular lengths of PCL-α-CD/PAA-tAzo, indicating that the supramolecular amphiphile self-assembled in a bilayer packing mode through orthogonal assembly. Upon UV irradiation at 365 nm for 60 s, the bilayers were gradually destroyed (Figure 5b), inducing a partial deaggregation of the nanotubes, because PAA-tAzo underwent photoisomerization to the cis-state (PAA-cAzo) upon exposure to UV light, and the azobenzene unit in the cis-state at the tail of PAA chain dethreaded from the cavity of α-CD, resulting in the breakage of the supramolecular amphiphile. The nanotubes were disassembled completely into small fragments under UV irradiation for 300 s (Figure 5c), accompanied by the appearance of some insoluble PCL-α-CD. Interestingly, the H

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from the cavity of β-CD, resulting in decomplexation of the pseudocopolymer PS-β-CD/PEO-Fc. Moreover, the supramolecular vesicles completely disassembled into small fragments (several nanometers in size) upon +1.5 V voltage stimulus for 5 h, which indicated the total collapse of the vesicles (Figure 6e). It is noteworthly that the small fragments were reassembled to form vesicles with similar shapes and sizes as the original state by exerting a reductive voltage of −1.5 V (Figure 6f), because the Fc+ group was reduced to the neutral Fc, and interacted with β-CD, forming the supramolecular amphiphile PS-β-CD/PEO-Fc again. Cyclic voltammetric (CV) and DLS experiments provided convincing evidence for the voltage-responsive self-assembly and disassembly behavior of the supramolecular vesicles. The average diameter of the aggregates jumped repeatedly from 102 to 7 nm upon alternating potential (+1.5 and −1.5 V), indicating the reversibility of this voltage-responsive supramolecular system. More importantly, these supramolecular vesicles possessing voltage-responsiveness were employed to encapsulate and release RB molecules. Compared with the release curve in the absence of an electro-stimulus, an abrupt release (∼32 min) was observed upon application of high voltage (+4.0 V). The release speed could be accurately controlled by adjusting the external potential through the reversible association and disassociation of the supramolecular connection. The supramolecular vesicles exhibited a relatively slower release (∼120 min) upon lower voltage stimuli (+2.0 V) and the slowest rate (∼450 min) at the lowest voltage (+1.0 V). As a type of intelligent assembly, these artificial voltage-responsive polymeric vesicles are well-suited to drug encapsulation and controlled release, and electrical stimulation is easily applied in cells and the human body. On the basis of β-CD/Fc molecular recognition, Yan, Yuan, and co-workers further constructed a quasi-brush-like supramolecular polymeric amphiphile.206 Poly(ethylene glycol)block-poly(glycidyl methacrylate) grafted with β-CD pendants (GA-CD) and poly(caprolactone) containing end-capping ferrocene (Fc) moieties (L-Fc) were used as the building blocks. The supramolecular polymeric amphiphile selfassembled into micelles around 220 nm in diameter with a CAC value of ∼0.20 mg/mL. Triggered by a positive voltage (+1.0 V) on the pseudocopolymer solution for 8 h, the Fc species was converted into the charged Fc+ state, and dethreaded from the cavity of the β-CD. The host−guest interactions were inhibited, destroying the hydrophilic−hydrophobic balance in the supramolecular amphiphile. As a result, the micelles disassembled completely into small fragments. On the contrary, micelles with similar shapes and sizes formed again under a reductive potential stimulus (−1.0 V) for 8 h arising from the reduction of Fc+ into the neutral state. Owing to the reversible transition between Fc and Fc+ in the presence of an electrochemical redox trigger, the assembly and disassembly behavior of the supramolecular amphiphile was regulated reversibly.

Figure 6. (a) Chemical structures of PS-β-CD and PEO-Fc. (b) Cartoon representation of the reversible assembly and disassembly of voltage-responsive PS-β-CD/PEO-Fc vesicles based on β-CD/Fc molecular recognition. TEM images of the reversible assembly and disassembly of the voltage-responsive vesicles upon electric stimuli: (c) no external voltage; (d) +1.5 V (after 2 h); (e) +1.5 V (after 5 h); (f) −1.5 V (after 5 h). Reproduced with permission from ref 205. Copyright 2010 American Chemical Society.

polymers, poly(styrene) with β-CD end-decoration (PS-β-CD) and poly(ethylene oxide) containing uncharged ferrocene (PEO-Fc), were chosen as the building blocks (Figure 6a). Connected through terminal host−guest interactions between β-CD and Fc, a supramolecular copolymer was obtained with PEO-Fc as the hydrophilic part and PS-β-CD as the hydrophobic segment (CAC ∼0.28 mg/mL). As evidenced by the distinct contrast between the particle skin and the inner pool in a TEM image (Figure 6c), supramolecular vesicles ∼102 nm in diameter were obtained which were stable for 3 months without any external stimuli. The wall thickness of the vesicles was ∼19 nm, in line with the interdigitated molecular length of the PS-β-CD/PEO-Fc supramolecular amphiphile, indicating self-assembly in the bilayer membrane. Interestingly, the vesicles partially disassembled and the membrane started to disrupt within 2 h upon +1.5 V voltage stimulus (Figure 6d), because the Fc group at the tail of PEOFc was oxidized into the charged Fc+ species and dethreaded

3.4. Supramolecular Amphiphiles Constructed from Hyperbranched/Dendrimeric Building Blocks

3.4.1. Linear−Hyperbranched Supramolecular Amphiphile Based on β-CD and Adamantane Recognition. Over the past two decades, two classes of dendritic polymers, dendrimers and hyperbranched polymers, have attracted major attention owing to their interesting properties resulting from the branched architecture as well as the high number of I

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functional groups.207−209 Dendrimers are monodispersed macromolecules with well-defined branched architectures consisting of dendritic cores and peripheral sites, making them fascinating building blocks in host−guest, medicinal, and catalytic chemistries.210,211 In comparison to dendrimers that are prepared in demanding tedious multistep syntheses, hyperbranched polymers are usually accessible in one-step processes and often considered to be ill-defined dendrimers due to their relatively high polydispersity (usually Mw/Mn > 5).212−216 Recently, hyperbranched polymers have received more and more interest in both academic and industrial fields because of their advantages in facile one-pot synthesis, low cost, peculiar structures, excellent properties, and broad applications. Combination of the dynamic/reversible nature of supramolecular polymers with the three-dimensional topological features and multifunctionality of dendritic polymers provides a versatile strategy for preparation of nanostructured functional soft materials. Zhou and co-workers elegantly constructed a linear− hyperbranched supramolecular amphiphile through the noncovalent linkage of an adamantane-functionalized long alkyl chain (AD-C18) and a β-cyclodextrin modified hyperbranched polyglycerol (CD-g-HPG) by specific β-cyclodextrin/adamantane host−guest molecular recognition (Figure 7).217 The adamantane group on AD-C18 penetrated the cavity of β-CD to form a supramolecular amphiphile (C18-b-HPG) with the alkyl chain as the hydrophobic part and CD-g-HPG as the hydrophilic part. The Ka value was calculated to be about 1.7 × 103 M−1, which was lower than the typical Ka value (∼104) between β-CD and ADA groups due to the steric hindrance of the grafted HPG chains. On account of the inherent amphiphilicity of C18-b-HPG, this supramolecular amphiphile self-assembled into vesicles in water with diameters ranging from 60 to 600 nm that showed excellent stability. Scanning electron microscopy (SEM), TEM, and atomic force microscopy (AFM) provided insight into the morphology of the aggregates formed by C18-b-HPG. SEM image showed that the structure of the aggregates was spherical (Figure 7a). Considering the existence of the concave feature (white arrows) among some of the particles, the core of the aggregates was hollow. As confirmed by TEM, vesicles were observed with a contrast difference between the dark periphery and the lighter central part (Figure 7b), in agreement with the result obtained from SEM. The wall thickness of the vesicles was uniform, about 8 ± 1.4 nm from TEM images, almost two extended lengths of C18-b-HPG (∼3.7 nm), indicating that the vesicles possessed a bilayer structure with two hydrophilic HPG shell layers and one hydrophobic alkyl chain core layer. Interestingly, the vesicles formed by the supramolecular amphiphile exhibited great ductility. The vesicles pointed out by white lines in Figure 8c showed an expansion of about 300% in radius when the force of the AFM tip was increased in the tapping-mode AFM experiments (Figure 7c,d). The height-todiameter ratio was calculated to be 1:20 by monitoring the dried particles. On the other hand, the thicknesses of the periphery and the center of the deformed vesicles were calculated to be about 3 and 0.7 nm, respectively, close to the size of a C18-b-HPG molecule and the size of CD-g-HPG, indicating the dynamic nature of this supramolecular amphiphile. 3.4.2. Multiple Host−Guest Interactions Driven SelfAssembly of Cyclodextrin and Adamantane Modified Hyperbranched Poly(ethylene imine)s. The nonviral

Figure 7. Preparation, self-assembly, and disassembly processes of C18b-HPG. Self-assemblies captured by SEM (a), TEM (b), cryogenic transmission electron microscope (cryo-TEM) (inset in b), and AFM (c, d). The force was 2.1 nN on the AFM tip in image d. Reproduced with permission from ref 217. Copyright 2012 American Chemical Society.

transfer of DNA or small RNAs (siRNAs) in vivo represents a prospective approach in gene therapy in the treatment of cancer.218−220 Polymer-based vectors have been explored extensively for the condensation of nucleic acids into nanoscale complexes, which are able to cross biological barriers, protect their payload, and mediate cellular delivery and intracellular release. Cationic polymers, such as polyethylenimines (PEI), poly(L-lysine), PAMAM dendrimers, poly(lactic-co-glycolic acid) (PLGA), chitosan, PEI-alginate nanoparticles, and cyclodextrin oligomers are used frequently as nonviral vectors to deliver siRNA via nonspecific uptake mechanisms. Among them, PEI is well-established as a backbone in artificial enzymes and used as a vector for in vitro or in vivo cases on account of their high gene transfer efficacy.221−226 The high cationic charge density at physiological pH allows PEI to form supramolecular complexes with negatively charged DNA and other nucleic acids, which can be released from endosomes as J

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Figure 8. Structures of CD-PEI, Ada-PEI, CD-Cal, and Ada-Cal. Cryo-TEM of systems A (CD-PEI and Ada-Cal) and B (Ada-PEI and CD-Cal) tubular vesicles prepared from (a) CD-PEI (blue)/Ada-Cal (green) and (b) Ada-PEI (blue)/CDCal (green). Reproduced with permission from ref 227. Copyright 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ada-Cal self-assembled into tubular vesicles ∼30 nm in diameter, which were revealed by cryo-TEM (Figure 8a). Similarly, system B containing Ada-PEI and CD-Cal displayed the formation of tubular vesicles as well. The wall thickness of the tubular vesicles varied from 8 to 16 nm with unilamellar as well as multilamellar domain boundaries (Figure 8b). The average hydrodynamic diameters of the aggregates formed by both systems were 88−163 nm by DLS with polydispersities ranging from 0.16 to 0.24. Additionally, the self-assemblies were quite stable in water for several months over a wide range of pH. The diameters of the nanotubes self-assembled from system B were much larger than those of system A, and the tubular vesicles had a sharp, dark double membrane, because the amphiphilicities of the building blocks in these two systems were different. In system A, a monolayer of the hydrophobic modified fluorescent dye Ada-Cal was enclosed by the

an essential approach for the delivery of the siRNA into the RNAi machinery or the DNA into the nucleus. Compared with linear PEIs, hyperbranched PEIs offer an increased molecular surface for chemical functionalization and superior drug loading capacity, attracting more and more attention over the past few decades. Ritter and co-workers masterfully designed and synthesized two sophisticated hyperbranched PEI derivatives: a cyclodextrin modified hyperbranched PEI (CD-PEI) and an adamantane grafted hyperbranched PEI (Ada-PEI) (Figure 8).227 Moreover, cyclodextrin-functionalized CD-Cal and adamantylfunctionalized calcein Ada-Cal were synthesized to study the supramolecular self-assembly of functionalized PEI in the presence of the corresponding dye (Figure 8). Driven by multiple host−guest interactions between cyclodextrin hosts and adamantane guests, two supramolecular amphiphiles were fabricated: systems A and B. For the former one, CD-PEI and K

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Figure 9. Top: self-assembly and disassembly processes of a supramolecular Janus hyperbranched polymer (JHBP) HBPO-b-HPG. (a) DLS results for the mixed solutions with different water/DMF volume percentage ratios (v/v). (b) Dependence of Dh on the water/DMF ratio. (c) Numberaverage size distribution of the aqueous solution of CD-g-HPG. (d) A solution of HBPO-b-HPG self-assemblies (inset) and the number-average size distribution. (e) The residual transparent solution after UV irradiation (inset) and the number-averaged size distribution. (f) UV−vis spectra of aqueous HBPO-b-HPG solution with different UV irradiation times (λ = 365 nm). Self-assemblies captured by (g, i) SEM, (h) TEM, and (j) AFM. The inset in part g shows SEM images of the particles with holes, and the inset in part h shows the TEM image of the freeze-dried particles. Reproduced with permission from ref 241. Copyright 2013 American Chemical Society.

hydrophilic CD-Cal, resulting in a double layer of fluorescent dye. Due to the existence of calcein in the membranes, fluorescence microscopy was used to display the structure of

hyperbranched polymer with more hydrophilic CD-PEI orientated toward the aqueous phase. For the complementary system B, the hydrophobic Ada-PEI was covered by the L

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the self-assemblies. Wormlike fluorescent structures were observed for system A, in line with the result obtained from cryo-TEM. The hyperbranched PEIs modified through the supramolecular approach exhibited enormous potential for applications in biologically and pharmaceutically relevant fields, such as biosensors, drug and gene delivery systems, protein− protein interactions, and cell imaging. Jiang and co-workers used a β-cyclodextrin-ended poly(Nisopropylacrylamide) (PNIPAM) and an azobenzene modified hydrophobic dendron as the building blocks to construct a dual responsive supramolecular amphiphile which were linked by the β-CD/azobenzene host−guest interactions.228 The noncovalently connected amphiphile self-assembled into bilayer vesicles in water with the hydrophobic dendron inside the walls and the hydrophilic parts (PNIPAM) facing the inner and outer aqueous medium. Optical switching of the assembly and disassembly was realized by alternating visible and UV irradiations due to the photoswitchable cyclodextrin/azobenzene complexation. In addition, the thermally induced coil− globule transition of the PNIPAM chains leads to thermoresponsiveness of the assemblies. 3.4.3. Supramolecular Janus Hyperbranched Polymer. Janus particles, two-faced particles with different surface makeups on opposing sides, have attracted tremendous attention in the past decade.229−233 Their noncentrosymmetry brings distinctive or even incompatible elements (e.g., hydrophobicity/hydrophilicity) into the same unit and therefore endows them with many promising applications ranging from the formation of colloidal superstructures to biomedical imaging.234−237 Most of the previously reported Janus particles focused on the solid state, whereas Janus particles with hollow structures have exhibited more promising applications in various fields such as controlled-release capsules of genes and drugs, optical and magnetic biosensors, protection of biomacromolecules, recyclable catalysts, and so on.238−240 Among various Janus structures, Janus dendrimers (also referred to as “bow-tie” dendrimers), which are composed of two heterogeneous segments, are intrinsically suitable for mimicking primitive biological membranes, configuring into biomimetic nanocapsules, fabricating functional nanomedicines, and so on. Supramolecular modifications can be utilized to construct supramolecular Janus hyperbranched amphiphiles by linking the hydrophobic and hydrophilic parts through noncovalent interactions. Due to the dynamic nature of the supramolecular interactions, the self-assemblies formed from Janus supramolecular amphiphiles certainly possess excellent stimuli-responsivenesses, endowing these self-assemblies with sophisticated functions. Zhou and co-workers reported a photoresponsive supramolecular Janus hyperbranched polymer on the basis of cyclodextrin/azobenzene host−guest molecular recognition (Figure 9).241 A hydrophilic hyperbranched polyglycerol with a β-cyclodextrin apex (CD-g-HPG) and a hyperbranched poly(3-ethyl-3-oxetanemethanol) with an apex of an azobenzene group (Azo-g-HBPO).241 By mixing Azo-g-HBPO and CD-g-HPG (molar ratio of CD:azobenzene = 1:1), a Janus hyperbranched polymer HBPO-b-HPG was obtained. Upon enhancement of the volume percentage of water/DMF from 0% to 26% (Figure 9a), the average hydrodynamic diameter (Dh) of the aggregates increased, accompanied by Tyndall scattering (Figure 9b). Additionally, the Dh value increased from 2.7 to 5.1 nm due to the formation of the Janus supramolecular amphiphile HBPO-b-HPG when the volume

percentage of water was improved from 0 to 15% (the size of the 1:1 inclusion complex of CD-g-HPG and Azo-g-HBPO was about 5.1 nm). Furthermore, a rapid increase in the Dh value to 220 nm was observed by enhancing the volume percentage ratio of water/DMF from 16% to 26% (Figure 9d), which indicated that HBPO-b-HPG self-assembled into larger supramolecular aggregates. Nanoaggregates about 220 nm in diameter were observed by removing DMF from the mixture of water and DMF through dialysis. The stability of the supramolecular self-assemblies was excellent even in the presence of competitive host or guest molecules and in the heating process. The morphology of the self-assemblies was revealed by SEM, TEM, and AFM (Figure 9g−j). From SEM images, spherical particles with a narrow size distribution were observed (Figure 9g,i). On the other hand, the hollow structure of the aggregates was directly seen as holes in the destroyed particles, which demonstrated that these selfassemblies were vesicles, in line with the results obtained from TEM experiments (Figure 9h). The wall thickness of the vesicles was calculated to be 9.8 ± 0.8 nm through the statistical analysis of 30 vesicles by TEM and AFM (Figure 9j); this was about twice the extended length of HBPO-b-HPG (around 4.8 nm), suggesting that HBPO-b-HPG possessed a bilayer packing pattern. Owing to the photoresponsive azobenzene group in HBPOb-HPG, the self-assembly and disassembly processes could be regulated by UV and visible light. Upon UV light irradiation for 15 min, the vesicles diassembled into CD-g-HPG and Azo-gHBPO, respectively. Accordingly, the Dh value decreased from 220 to 2 nm (Figure 9e), associated with the formation of yellow Azo-g-HBPO precipitate (inset of Figure 9e) due to the trans-to-cis photoisomerization of the azobenzene group. A dissipative particle dynamics simulation was also performed to provide convincing insight into the self-assembly process of this supramolecular amphiphile HBPO-b-HPG to understand the dynamics and mechanism of the spontaneous vesicle formation, which indicated that formation pathway of these Janus hyperbranched polymers was similar to that of Janus dendrimers. 3.4.4. Cyclodextrin-Covered Organic Nanotubes Derived from Self-Assembly of Dendrons and Their Supramolecular Transformation. Kim and co-workers utilized β-CD and γ-CD to control the self-aseembly of amphiphilic dendrons 6−9 that were prepared by coupling amide dendron 5 with pyrene derivatives through different spacers (Figure 10a).242 The amide dendrons formed vesicular aggregates in aqueous solution with excellent stability for several months without any precipitation. TEM and environmental scanning electron microscopy (E-SEM) images revealed that the mean diameter of the vesicles was 259 nm [polydispersity index (PDI) = 0.125], 253 nm (PDI = 0.145), 238 nm (PDI = 0.209), and 209 nm (PDI = 0.148) for 6−9, respectively. Upon addition of β-CD (or γ-CD), the transformation of vesicles into nanotubes was achieved due to the formation of a host−guest inclusion complex between the focal pyrene and βCD (or γ-CD), making the focal moiety very hydrophilic, generated from the existence of hydroxyl groups on the CD exterior. A mechanism was proposed to explain the morphological transformation from vesicles for dendrons to nanotubes for CD⊃dendrons. Upon complexation with β-CD (or γ-CD), the hosts inserted into the membrane of vesicles to form 1:1 [2]pseudorotaxanes. The volume ratio of the M

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interactions (Figure 11a), resulting in a dramatic quenching of the pyrene emission caused by photoinduced electron transfer

Figure 10. (a) Structures of the amide dendron-pyrene conjugates. (b) Schematic route to organic nanotubes and the reversible transformation of supramolecular assemblies of dendrons triggered by the motifs of CD inclusion and pseudorotaxane formation. Reproduced with permission from ref 242. Copyright 2003 National Academy of Sciences.

hydrophilic and hydrophobic segments of the building blocks was changed due to the inclusion of hydrophobic pyrene into the cavity of hydrophilic CD, resulting in the helical transformation from vesicles to nanotubes. On the basis of the results from TEM, AFM, and E-SEM, the degree of supramolecular transformation in all cases was calculated to be over 90%. The length of the fully stretched structure of dendron 7 was 5.35 nm, and the wall thickness was 11.5 nm, indicating that the hydrophilic exterior of the inclusion complex at the focal moiety was exposed to the aqueous phase, and the hydrophobic alkyl chains were located in the middle of the nanotubes. The surfaces of the nanotubes could be modified conveniently by the addition of functionalized cyclodextrins (such as per-6-thio-γ-CD) into the vesicular solution, which was demonstrated by TEM and an electron energy loss spectroscopic sulfur mapping image. However, the supramolecular transition could not be induced by the addition of α-CD, because the cavity of α-CD is smaller than the pyrenyl group of the dendron. Interestingly, the focal point hosts could be removed from the nanotubes by PPG1000 (number-average molecular weight = 1000) to form polypseudorotaxanes owing to the competitive complexation with β-CD (or γ-CD), causing a reversible supramolecular transformation between the nanotubes and vesicles (Figure 10b). Furthermore, Kim and co-workers functionalized the surfaces of the supramolecular nanotubes by utilization of C6-modified cyclodextrins.243 Functional groups, such as iodo, amine, carboxyl, and biotin, were introduced on the basis of the hierarchical self-assembly of dendron 7 with functional CDs. These nanotubes were utilized as supramolecular templates to construct hybrid nanotubes. Den-mono-NH2-CD-NTs with a cationic surfaces were obtained using Den-mono-NH2-CD as the host. AuNP-COOH (1.7 ± 0.3 nm) was densely coated on the surface of Den-mono-NH2−CD-NTs through electrostatic

Figure 11. (a) Orientation of metal nanoparticles on the surface of fluorescent Den-CD-NTs. (b) Schematic description showing the preparation of nanotube−nanoparticle hybrids. Detection of proteins using fluorescent Den-CD-NT templates. (c) SA-FITC/Den-biotinCD-NTs and (d) SA-FITC/Den-biotin-C4CD-NTs (scale bar: 5 μm). (e) Schematic representation of the inhibition assay on Den-biotinC4-CD-NTs. Reproduced with permission from ref 243. Copyright 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

from the pyrene units to proximalte AuNPs. On the other hand, hybrid nanotubes were also prepared by reduction of [AuCl4]− adsorbed on the surface of the Den-mono-NH2-CD-NTs via electrostatic interactions (Figure 11b). More interestingly, the nanotubes were functionalized with biotin and further used as a biosensing platform to detect receptor proteins, such as streptavidin and avidin. Driven by the specific biotin−avidin interactions, fibrous images were observed by confocal laser scanning microscopy (CLSM) after culturing the biotin-covered nanotubes (Denbiotin-CDNTs and Den-biotin-C4-CD-NTs) and fluorescein-labeled streptavidin (SA-FITC) (Figure 11c,d). The fluorescence of the nanotubes was quenched effectively upon addition of the streptavidin-AuNP conjugate (SA-AuNP) due to the formation of hybrid SA-AuNPs/Den-biotin-C4-CD-NTs. Owing to the specific binding of SA-AuNP to the biotin on the surface of Den-biotin-C4-CD-NTs, fluorescence changes could not be monitored by incubating avidin-saturated Den-biotin-C4-CDNTs/SA-AuNP or biotin presaturated SA-AuNPs/Den-biotinC4-CD-NTs. The fluorescence intensity of the ternary system N

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Figure 12. (a) Formation of micelles via the inclusion complexes of β-cyclodextrin and adamantyl polyphosphazene-polystyrene block copolymers. TEM micrographs of APN-PS/β-CD micelles with different scale bars: (b) 1 μm; (c) 100 nm. (d) Schematic representation of noncovalent amphiphiles defined by host−guest inclusion, and the molecular structures of their components. TEM images of surface-deposited aggregates from noncovalent amphiphiles above their solution CMC: (e) 10a/11, 1.0 mg/mL; (f) 10a/11, 1.0 mg/mL magnified image; (g) 10a/11, 2.0 mg/mL; (h) 10c/11, 1.0 mg mL−1. Left panel reproduced with permission from ref 244. Copyright 2009 American Chemical Society. Right panel reproduced with permission from ref 245. Copyright 2004 The Royal Society of Chemistry.

distribution, which agreed with the result obtained from TEM images. Interestingly, the molar ratio between β-CD and APN-PS block copolymer played a significant role in the formation of supramolecular micelles. As the molar ratio between the adamantyl group and β-CD increased from 1:0.4, 1:0.6, 1:0.8, to 1:1, the corresponding CMC values changed from 0.645, 0.755, 0.881, to 0.925 mg/L, respectively. The hydrophilicity of the APN block generated from the host−guest complexation exhibited a linear relationship with the concentration of β-CD. This supramolecular strategy provides an opportunity to selectively encapsulate guest molecules that are sensitive to hydrolytic bioerosion to harmless small molecules that can be metabolized or excreted into the micelle core by simply adjusting the portion of the secondary participant such as βCD. Craig and cowokers utilized dihexadecylthio-β-CD 11 and poly(ethylene glycol) modified guests 10a−10c to fabricate main-chain-type supramolecular amphiphiles in aqueous solution (Figure 12d).245 Quasielastic light scattering (QELS) measurements revealed that both the individual components 10a and 11 were soluble in water, and only formed relatively small clusters even when the corresponding concentration was up to 3.0 mg/mL. While the QELS results of the supramolecular amphiphile 10a/11 were indistinguishable from those of the individual components when the concentrations were at and above 0.60 mg/mL, which was indicative of larger aggregates formation. On the other hand, the scattering intensity and Rh distribution returned to that of the individual components within minutes when the concentration was below 0.60 mg/mL, suggesting that the CAC value of this supramolecular amphiphile was 0.60 mg/mL. The size of the aggregates formed by the supramolecular amphiphile 10a/11

containing Den-biotin-C4-CD-NTs, SA-AuNP, and avidin was recovered effectively by increasing the concentration of avidin, because SA-AuNP bound more weakly to biotin than avidin (Figure 11e). This hybrid material exhibited excellent sensitivity; the detection limit for avidin was approximately 1 nM. These results suggested that the Den-CD-NTs “toolkit” might have a great potential for the fabrication of functional hybrid nanomaterials by changing surface functionality of the nanotubes by means of introduction of functional groups into the supramolecular hosts. 3.5. Side-Chain-Type and Main-Chain-Type Supramolecular Polymeric Amphiphiles

Allcock and co-workers designed a block copolymer APN-PS composed of a hydrophobic polystyrene (PS) block and a hydrophobic adamantyl polyphosphazene (APN) (Figure 12a).244 Hydrophilic β-CD was introduced to construct a polymeric supramolecular amphiphile by forming inclusion complexes with adamantane units on APN. This supramolecular modification switched the properties of the diblock polymer from hydrophobic to amphiphilic and further changed the micelle forming characteristics of the block copolymer in aqueous media. The critical micelle concentration (CMC ∼0.93 mg/L) was much lower than that of poly(ethylene glycol)poly(lactide) diblock copolymer (CMC < 2 mg/L) and that of oligo(methyl methacrylate)-poly(acrylic acid) micelles (CMC = 100 mg/L), because β-CD with highly hydrophilic character in the shell layer surrounded the PS core, providing a more stable corona structure in the micelles in a hydrophilic medium. The size and morphology of the micelles were directly revealed by TEM (Figure 12b,c). As measured by DLS, the hydrodynamic volume of the micelles was 193 nm with a narrow size O

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metal oxides, and quantum dots, etc. with surfaces modified by either guests or hosts. Jiang and co-workers used a hydrophilic β-CD-containing polymer (PGMA-CD) and a hydrophobic ADA-containing polymer (PtBA-ADA) to prepare polymeric micelles with PtBA-ADA as the core and PGMA-CD as the shell driven by inclusion interaction between β-CD and ADA (Figure 13).247

(3.0 mg/mL) reduced to those of the individual components when 5 equiv of unalkylated β-CD was added due to its competitive complexation with the adamantane group. Although guest 10b possessed the same PEG chain as 10a, the association constant of the 2-naphthyl end group with βCD (102 M−1) was significantly lower than that of the adamantyl group of 10a (104 M−1). The CAC value of 10b/11 was calculated to be 1.3 mg/mL, higher than that of 10a/11 due to the relatively weaker binding strength. The morphologies of the self-assemblies formed by the supramolecular amphiphiles 10b/11 were explored through TEM by using uranyl acetate as a negative staining agent (Figure 12e,f). Cylindrical micelles were observed with sharp features and widths of 20−50 nm and lengths of 155−480 nm. The selfassemblies of the main-chain-type supramolecular amphiphiles were sensitive to the solution concentration of the components. The aggregates grew to form larger rectangular aggregates when the concentration was up to 2 mg/mL (Figure 12g), while these well-defined aggregates disappeared when the concentration was lower than the corresponding CAC value. Furthermore, the molecular structure of the guests influenced the self-assembly of the supramolecular amphiphiles. Although the CAC value occurred at the same molar concentration as 10a/11 (0.020 mM), 10c/11 with a longer hydrophilic tail selfassembled to form a fine, fibrous network (Figure 12h), different from 10a/11. A mechanism was proposed to explain why the morphologies of the aggregates changed by increasing the length of the hydrophilic chain. The microassembled structure of the aggregates formed by amphiphiles is determined by the curvature of the membrane. The steric hindrance generated upon insertion of larger PEG tails on the surface of a cylindrical aggregate led to the formation of selfassemblies with a greater curvature and a smaller cylinder diameter.

Figure 13. (a) Chemical structures of PGMA-CD and PtBA-ADA. (b) TEM image and (c) height-contrast AFM image of PGMA-CD/PtBAADA micelles. (d) TEM image of cross-linked micelles and (e) AFM and (f, g) TEM images of the corresponding hollow spheres. (h) An illustration of PGMA-CD/PtBA-ADA micelles and their characters. Reproduced with permission from ref 247. Copyright 2006 American Chemical Society.

3.6. Noncovalently Connected Micelles

The size of the resultant micelles depended on the molar ratio of β-CD to ADA (Figure 13b,c). The particle size of the micelles decreased first and then increased when the β-CD/ ADA ratio increased from 0.33 to 2.17, because hydrophilic PGMA-CD acted as a stabilizer for the hydrophobic core of PtBA-ADA. In the first step, the more PGMA-CD added, the smaller the core was when the molar ratio of β-CD to ADA was low ( 650 nm).268 However, these porphyrin-based photosensitizers tend to form inactive aggregates due to hydrophobic interactions, decreasing their ability to photosensitize 1O2 as the stacked molecules and release the absorbed energy as heat. Ravoo and cowokers designed and synthesized an adamantane-functionalized, hexaanionic water-soluble zinc(II) phthalocyanine (15), and utilized β-CDVs to prevent it from forming inactive aggregates (Figure 15d).269 A significant drop of the ζ-potential was monitored upon addition of 15 which had been deprotonated by an equivalent amount of NaOMe due to the host−guest complexation between β-CDVs and the hydrophobic adamantane residues of the PC, confirming the immobilization of the adamantane-functionalized PC on the βCDVs’ surface. Compared with the bare β-CDVs, the size of the vesicles was unchanged after complexation with the functional guests due to the repulsive forces among the functionalized vesicles. The host−guest interactions compensated the free energy of aggregation and overcame the stacking effect of 15. The percentage of active photosensitizer molecules on the βCDVs was calculated to be about 25%. Consequently, the singlet oxygen quantum yields of β-CDVs⊃15 were dramatically higher than that of free 15 in aqueous solution. This supramolecular method enhanced the photosensitizing ability of the PC-based derivative and provided a sophisticated photoactive platform for the construction of phototherapeutic agents.

macrocyclic amphiphiles were prepared by introducing alkyl chains (C12 or C16) on the secondary face of the CDs and oligoethylene glycol units on the primary face. Unilamellar bilayer CD vesicles (CDVs) with a diameter of 100−150 nm were obtained in buffer at pH 7.2 by extrusion (Figure 15a, I and IV). In order to minimize the exposure of the hydrophobic alkyl chains, the macrocyclic amphiphiles self-organized in a molecular bilayer in aqueous medium with CDs embedded in the surfaces of the vesicles, providing binding sites for hydrophobic guests, such as adamantane, tert-butylbenzene, and azobenzene units. By simply mixing the CDVs with functional guest molecules, modified CDVs (α-CDVs or βCDVs) can be employed in various fields. A ternary supramolecular system was constructed with the ability of light-responsive capture and release of DNA.265 Azobenzene−spermine conjugate 12 was chosen as a guest to decorate CDVs (α-CDVs or β-CDVs) through inclusion of the hydrophobic trans-azobenzene group (Figure 15a). The Ka values of the host−guest complexes (α-CD⊃12 and βCD⊃12) were measured to be 6 × 103 and 4 × 103 M−1, respectively. The surfaces of the CDVs were appended with multiple positively charged spermine groups which exhibited high-affinity multivalent interactions with negatively charged DNA, resulting in the formation of a supramolecular lipoplex (Figure 15a, II and III for α-CDV and V and VI for β-CDV). The conjugate trans-12 was photoisomerized into cis-12 and detached from the vesicle surfaces upon UV irradiation. The multivalent display of spermine groups was disrupted, and DNA was effectively released from the ternary system due to the low-affinity between monovalent spermine units and DNA. Conversely, the cis-form guest was isomerized back to the transstate upon visible-light irradiation, and the ternary lipoplex reformed. The photoresponsive formation and dissociation of the ternary complex caused light-induced capture and release of low molecular weight DNA reversibly. Spermine·4HCl acted as a competitive monovalent guest to trigger the release of DNA from the ternary system. On the other hand, the ternary complex was dissociated by the addition of enzyme DNase I (30 U/ml) due to enzymatic hydrolysis of the captured DNA. However, the ternary complex containing CDVs, trans-12, and double-stranded DNA (dsDNA) lost photoresponsiveness and could not be used as a platform to capture and release the high molecular weight DNA, because the kinetic stability and binding affinity were enhanced effectively. Novel functions could be achieved by replacing spermine by carbohydrates (Figure 15b).266 Azobenzene-based guests (13 and 14) containing lactose and maltose, respectively, were employed. The high density of carbohydrate ligands on the surface of the vesicle led to high-affinity binding of lectins. Moreover, these two ternary complexes selectively bound peanut agglutinin (PNA) (Figure 15b, II) and concanavalin A (ConA) (Figure 15b, III) due to specific carbohydrate−protein interactions. These ternary complexes also exhibited photoresponsive capture and release of proteins caused by the photoinduced transition from a high-affinity, multivalent state to a low-affinity, monovalent state. Driven by orthogonal interactions, including host−guest interactions in the β-CDVs bilayer and hydrogen bonding between the peptides, β-sheet domains were easily obtained by decorating the surface of β-CDVs with adamantane modified octapeptide 16 at pH 5.0 (Figure 15c).267 However, peptide 16 did not form a β-sheet conformation in the presence of β-CDVs at pH 7.4, or in the absence of β-CDVs at either pH 7.4 or 5.0

3.9. Hybrid Materials Constructed from Cyclodextrin-Based Supramolecular Amphiphiles

Hybrid materials are composites commonly consisting of two constituents: one is inorganic, and the other one is organic in nature at the nanometer or molecular level. They have attracted increasing attention over the past decades.270,271 Different from traditional composites whose constituents are at the macroscopic (micrometer to millimeter) level, in hybrid materials the components are mixed at the microscopic scale, leading to more homogeneous materials that show either properties between the two original phases or even new properties. Moreover, the processability of the hybrids can be improved effectively by combining both organic and inorganic parts that differ enormously from those of their separate parts. 3.9.1. Self-Assembly of Supramolecular Amphiphiles as a Tool To Functionalize Nanotubes. Liu and co-workers S

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nanotubes were composed of about 10 bilayers of the supramolecular amphiphiles. After modification of β-CD with an amino acid (L-tryptophan) with green fluorescence emission, the modified host (18a) also interacted with guest 17. This new supramolecular amphiphile 18a⊃17 self-assembled into similarly sized nanotubes as those of β-CD⊃17 (Figure 16g). As depicted by fluorescence microscopy and confocal laser scanning microscopy, the periphery of the aggregates with a clear green fluorescence emission was verified, which further confirmed the hollow nanotube structure. In order to functionalize the gaint supramolecular nanotubes, catalytic moieties of glutathione peroxidase (GPx) (18b) or guanidine (18c) were introduced into the supramolecular amphiphile by modifying CDs at its C6 position, respectively (Figure 16h−k). Nanotubes with similar morphology and size could be obtained by using these functionally modified CDs. In order to mimic the selenocysteine function, CD-based selenonic acid (6-CD-SeO3H, 18bSe) or telluronic acid (6CD-TeO3H, 18bTe) were introduced into the supramolecular systems to participate in the self-assembly. By manipulating the surfaces of the nanotubes through a molecular imprinting strategy, hybrid nanotubes possessing both active sites and recognition sites were obtained. The catalytic activities of the hybrid nanotubes were enhanced remarkably by loading the artificial GPx center on these well-defined nanotubes. The results suggested that the strategy of CD-based self-assembly of supramolecular amphiphiles might have great potential applications ranging from the construction of functional nanomaterials to more complex biologically devices. 3.9.2. Chiral Self-Assembly and Reversible Light Modulation of a Polyoxometalate Complex via Host− Guest Recognition. Polyoxometalates (POMs) are oligomeric aggregates of metal cations bridged by oxide anions that form by self-assembly processes.273−276 Taking into account various topological architectures and the presence of transition metal, such as V(V), Nb(V), Ta(V), Mo(VI), and W(VI), POMs exhibit significant potential in catalysis, optics, and nanomaterials. Increasing attention is devoted to supramolecular polyoxometalate chemistry, i.e., the self-assembly of large species from smaller fragments. A variety of organic or polymeric groups have been employed to modify POMs on the active sites through covalent or noncovalent methods, enriching the intrinsic functions in synergistic self-assemblies. Wu and co-workers elegantly constructed a novel bola-form supramolecular amphiphile based on a new hybrid polyoxometalate (POM) complex.277 An Anderson-type cluster was chemically functionalized with azobenzene groups on both sides to form a dumbbell-shaped guest molecule (Azo-POM). A β-CD cation bearing a pyridine group (β-CD-Py) acted as a host. Driven by host−guest interactions between β-CD and the azobenzene group, a supramolecular bola-amphiphile (CDAzo-POM) was obtained with the inclusion complexes as the hydrophilic parts and the Anderson-type POM as the hydrophobic center. SEM and high solution transmission electron microscopy (HRTEM) revealed that micrometer-scale right-handed twisted assemblies with clear lamellar structures formed from the [3]pseudorotaxane-type supramolecular amphiphile. The size of the aggregates could reach ∼10 μm. Under the action of electrostatic and host−guest interactions, the complex was connected to form two-dimensional self-cross-linked lamellar assemblies with a right-handed twist (Figure 17b). However, the right-handed twisted assemblies were disinte-

selected a typical host−guest pair to fabricate a supramolecular amphiphile (β-CD⊃17) based on the cyclodextrin-adamantane molecular recognition driven by hydrophobic interactions between the adamantyl moiety (17) and β-CD. Supramolecular amphiphile β-CD⊃17 self-assembled into unusual giant nanotubes due to its amphiphilic nature (Figure 16c−f).272 Nearly monodispersed tubelike aggregates 20 μm in length and ∼500 nm in diameter were observed by optical microscopy (Figure 16d). The hollow structure was confirmed by the observation of a strong contrast between the center and the periphery in a TEM image (Figure 16f). The wall thickness of the nanotubes was about 40 nm, indicating that the giant

Figure 16. (a) Structures of guest 17 and β-CD. (b) Graphitic nanotube and possible self-assembled multilayers. (c) Structures of βCD and modified hosts: L-tryptophan-modified β-CD (L-Trp-β-CD, 18a), 6-β-CD-SeO3H (18bSe) or 6-β-CD-TeO3H (18bTe), 6guanidino-β-CD (18c), glutathione-modified seleno-CD (6-β-CD-SeSG,18d). (d) Optical microscopy (light source: white), (e) SEM, and (f) TEM images of the aggregates formed by self-assembly of supramolecular amphiphile β-CD⊃17. (g) SEM image of the aggregates formed by 17 and 18b. (h−k) Preparation of the GPx catalytic center on nanotubes by the combination of molecular selfassembly and an imprinting strategy: (h) GPx active site with a GSH binding site; (i) complex of the substrate GSH and guanidino-CD; (j) fixing the conformation of the complex on nanotubes by a selfassembly process; (k) the designed active center of GPx with a specific binding site for GSH and oriented catalytic site. Reproduced with permission from ref 272. Copyright 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. T

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Figure 17. Schematic chemical structures and representations of the azobenzene-modified POM anion in its trans-state and cis-state, and βCD cation in the CD-Azo-POM complex. SEM images of CD-AzoPOM (0.24 μM) after (a) initial UV light irradiation for 2 h and (b) aging in the dark for 7 d. Reproduced with permission from ref 277. Copyright 2013 The Royal Society of Chemistry.

grated upon UV light irradiation after enough time owing to the disassociation of the inclusion complexes. This led to the appearance of irregular nanofibers which were similar to the morphology of β-CD-Py alone (Figure 17a). Due to the reversible trans−cis photoisomerization of the azobenzene group, the host−guest complexation between the POM complex and β-CD-Py could be adjusted by UV and visible light, resulting in reproducible transformations between twisted assemblies and irregular nanofibers. The reversible morphology changes were determined by the association and dissociation of the self-cross-linked structure. More interestingly, the chirality transfer and amplification of the CD-Azo-POM system were achieved during the host−guest complexation and assembly process. This work can be regarded as a new strategy to bring the supramolecular chirality into POM-based self-assemblies, endowing the hybrid materials with interesting functions. 3.9.3. Self-Assembly of Soft Hybrid Materials Directed by Light and a Magnetic Field. Ravoo and co-workers fabricated microscale linear aggregates by using a soft hybrid material composed of magnetic nanoparticles (iron oxide) and CDVs with an average diameter of around 400 nm under the influence of a magnetic field in aqueous solution (Figure 18).278 “Magnetic” CDVs were prepared by incorporating oleic acid stabilized magnetic iron oxide nanoparticles (MNP) in the bilayer of the CDVs due to their hydrophobicity (Figure 18b,c). As examined by TEM (Figure 18d), AFM, and DLS (Figure 18e), the diameter of the soft and flexible hybrid vesicles (MNP-CDV) became larger (around 500 nm) than that of the CDVs. Stained by 10% sulforhodamine B, the hybrid vesicles were monitored by fluorescence microscopy. Spherical aggregates ∼500 nm in diameter were observed, which was confirmed by TEM and DLS studies. Driven by the dipole−dipole interactions of the superparamagnetic MNP in the membrane of the CDVs, the hybrid vesicles were aligned in an external magnetic field. The length of the linear self-assemblies reached 10 μm (Figure 18g). Moreover, the orientation of the linear aggregates could be adjusted by changing the direction of the applied magnetic field. The microscale linear aggregates containing MNP were not stable in the absence of a magnetic field on account of their

Figure 18. (a) Photoresponsive azobenzene cross-linker 19. (b) Schematic representation of magnetic nanoparticle-cyclodextrin vesicle hybrids (MNP-CDV). TEM images: (c) iron oxide MNP; (d) MNPCDV hybrid. (e) DLS size distributions of MNP and MNP-CDV hybrids. Fluorescence microscopic images of sulforhodamine B labeled magnetic vesicles: (f) MNP-CDV in the absence of an external magnetic field; (g) MNP-CDV in a magnetic field; (h) linear aggregates of MNP-CDV after switching off the magnetic field; (i) linear aggregates of MNP-CDV formed in an external magnetic field and stabilized by the cross-linker trans-19; (j) deaggregation of MNPCDV and cis-19 after UV irradiation for 30 min in the absence of an external magnetic field; (k) reaggregation of MNP-CDV and trans-19 in a magnetic field after visible light irradiation for 30 min. Reproduced with permission from ref 278. Copyright 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

superparamagnetism (Figure 18h). Switching off the magnetic field led to spontaneous disassociation of the linear aggregates, indicating that magnetic field assisted self-assembly was reversible (Figure 18h). Due to the presence of free macrocyclic hosts in the walls of the vesicles, the supramolecular aggregates could be decorated by hydrophobic guest molecules (such as adamantane, tbutylbenzene, and azobenzene) through host−guest interactions, endowing the vesicles with various functions by simply introducing guest-appended biomolecules. A divalent azobenzene (19) was employed as a cross-linker to adhere to CDVs U

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section of the tubular wall in a bilayer pattern. In this nanostructure, the interior and exterior surfaces of the nanotubes contained the highly stable PMCD/porphyrinassociated units with rigid phthalocyanine spacers, whereas the middle of the tubular walls was composed of the hydrophobic alkyl chains interlaced with each other. It was noteworthy that numerous pendant carboxylic acid groups located at the periphery of the porphyrins acted as anchoring sites for various metal-based catalysts to prepare hybrid materials. Driven by the electrostatic interactions between the carboxylic acid groups and Pd2+, metal catalysts conveniently adhered onto the interior and exterior surfaces of the nanotubes without changing the tubular nanostructures (Figure 19d,e). These hybrid nanotubes (Pd@NT) were excellent catalysts for Suzuki−Miyaura coupling reactions. Pd@NT exhibited outstanding catalytic activity under environmentally benign conditions in only 1 h, ultimately leading to excellent isolated yields (93−99%). Moreover, the Pd@NT catalyst can be easily recovered and reused for many cycles without significant loss of catalytic activity. Individual 21 selfassembled into vesicles, which could also be employed to fabricate a Pd-loaded hybrid nanostructure. However, its catalytic activity was much lower than that of Pd@NT, because the catalytic reaction only occurred on the exterior surface of vesicles. For the Pd@NT, catalytic reaction actively occurred on both interior and exterior surfaces of the nanotubes, leading to significant improvement of catalytic activity (Figure 19f). This elegant system demonstrated that supramolecular tubules can not only act as supporting materials but also promote catalytic reactions.

due to its photoresponsive host−guest complexation with CD, endowing the MNP-CDV with photoresponsiveness as well. Upon addition of 19, ∼100 μm long threads of compactly clustered MNP-CDV were obtained under the assistance of a magnetic field arising from the formation of small linear aggregates (Figure 18i). These amorphous microscale clusters could persist for several hours in the absence of the external magnetic field, behavior different from those in the absence of 19. The reason was that 19 acted as a noncovalent linker to stabilize and interconnect the linear aggregates to form clusters, enhancing the stability of the superstructures in the absence of a magnetic field. However, the thread-like aggregates recovered their initial size and spherical shape under UV irradiation, caused by the disassociation of the noncovalent connections. These adhesive and nonadhesive configurations could be easily controlled by UV and visible light irradiation due to the dynamic nature of the host−guest interactions (Figure 18j,k). 3.9.4. Supramolecular Tubular Nanoreactor. Liu and co-workers constructed a supramolecular amphiphile (20⊃21) composed of a permethylated β-cyclodextrin (PMCD) dimer with a rigid silicon(IV) phthalocyanine core (20) and a carboxylated porphyrin bearing long hydrophobic tails (21).279 Followed by the self-assembly of 20/21 couples through strong host−guest interactions (Ka = 1.3 × 107 M−1), well-defined nanotubes were obtained (Figure 19b). Hollow tubular

3.10. Supramolecular Amphiphiles as Drug Delivery Vehicles

Cancer remains the second leading cause of death in the Americas and Europe after heart disease, and the third leading cause of death in the world after heart and infectious diseases. Billions of dollars and intense studies have been spent to increase our knowledge of the causes and biology of cancer, leading to the development of improved treatment strategies. Yet, an estimated 7.6 million deaths in 2008 alone were caused by cancer (accounting for about 13% of all deaths), and deaths from cancer are expected to continue to rise to over 13.1 million in 2030, signaling the pressing need for newer, even more effective therapies.280 Stimuli-responsive supramolecular micelles with sharp intelligent response to intracellular environmental stimuli, such as pH-change, redox, enzymes, temperature-change, and so on, are promising anticancer drug carriers. Among various intelligent delivery systems, pHsensitive drug delivery has received greater attention due to their site-specific targeting release of payloads, leading to aggressive anticancer activity and maximal chemotherapeutic efficacy with fewer side effects.281,282 The interstitial pH in malignant tumors is lower than that in normal tissues as a result of increased lactic acid production and reduced buffering and perfusion, which can be employed to achieve target release of the drugs in cancer cells. 3.10.1. Intracellular pH-Sensitive Supramolecular Amphiphiles Based on Host−Guest Recognition between Benzimidazole and β-CD as Potential Drug Delivery Vehicles. Dextran, a polysaccharide consisting of 1,6- and 1,3-glucosidic linkages, is a biocompatible, highly branched polysaccharide polymer. It is a natural analogue to PEG and has been incorporated into a variety of nanoparticle

Figure 19. (a) Structural illustration of compounds 20, 21, and permethyl β-cyclodextrin (PMCD). (b) Typical SEM and (c) TEM images of the tubular assembly (inset: magnified image of tubules with 100 nm scale bar). (d) Typical SEM and (e) TEM images of Pd@NT. (f) Schematic representation of the hybrid tubular self-assembly. Reproduced with permission from ref 279. Copyright 2014 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim.

structures with uniform size were observed, indicating the formation of nanotubes. As depicted in the TEM images, the average inner and outer diameters of the nanotubes were around 182 and 200 nm (Figure 19c), respectively. The wall thickness of the nanotubes was 9 nm, indicating that the supramolecular amphiphile 20⊃21 packed along the vertical V

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Dex-β-CD/BM-PCL self-assembled into micelles with an average diameter of around 90 nm at pH 7.4 (Figure 20a). These micelles were quite stable under physiological (pH 7.4) and tissular pH (pH 6.8) conditions. On the contrary, the BM group was protonated into the cationic state and exposed toward the hydrophilic surroundings when the pH was reduced below 6.0, resulting in the dissociation of the supramolecular amphiphile (Figure 20b). In contrast, the average diameter of the self-assemblies increased drastically from around 112 ± 9.8 to 259 ± 90.2 nm when the pH decreased from 7.4 to 5.5 (Figure 20c), which was attributed to the aggregation of the hydrophobic BM-PCL chain after the disassociation of the supramolecular amphiphile at low pH. The diameter determined by TEM was smaller than that obtained from DLS, because the dehydration of the micelles occurred in the process of TEM sample preparation, associated with the shrinkage of the Dex shell. These supramolecular micelles were utilized as nanocarriers to encapsulate hydrophobic anticancer drug doxorubicin (DOX). A pH-insensitive dextran-b-poly(ε-caprolactone) (Dex-PCL) copolymer linked by covalent bond was synthesized as a control. The in vitro release experiments demonstrated that the supramolecular micelles formed by Dex-β-CD/BM-PCL exhibited distinct release behaviors of DOX at pH 5.5 and 7.4 due to its pH-responsiveness. Up to 90% of DOX was released from the micelles at pH 5.5 in 24 h, whereas the DOX release was inhibited significantly at pH 7.4. On the contrary, no obvious difference in the release rate of DOX was observed at pH 5.5 and 7.4 for Dex-PCL micelles due to its pH-insensibility. A MTT assay was carried out to evaluate the in vitro cellular proliferation inhibitions of DOXloaded Dex-β-CD/BM-PCL and Dex-PCL micelles against HepG2 cells. Compared with DOX-loaded Dex-PCL, DOXloaded Dex-β-CD/BM-PCL showed dramatically higher growth inhibition efficiency to HepG2 cells, which was attributed to the enhanced intracellular DOX release induced by acid-trigged disassociation of the supermolecular micelles. These features revealed that the supramolecular micelles could efficiently load and deliver DOX into tumor cells and enhance the efficacy of the anticancer drug in vitro, demonstrating the promising application of supramolecular self-assemblies in intelligent drug delivery (Figure 20i). 3.10.2. Polymeric Core−Shell Assemblies Mediated by Host−Guest Interactions: Versatile Nanocarriers for Drug Delivery. Ma and co-workers adopted a diblock hydrophilic copolymer (PEG-b-PCD) containing a polyethylene glycol (PEG) (M w = 5000) block and a polyaspartamide block bearing β-CD units on the side chain to fabricate supramolecular amphiphiles with hydrophobic guest molecules (polymeric or low molecular weight compounds).289 Mediated by host−guest interactions between βCD on PEG-b-PCD and hydrophobic pyrene, the guests penetrated into the apolar cavity of β-CD, resulting in the formation of a pseudoamphiphilic block copolymer with localized hydrophobicity. As revealed by AFM, PEG-b-PCD containing pyrene (0.6 wt %) self-assembled into spherical aggregates with diameters in the range 20−120 nm (Figure 21a). The core−shell structural spheres displayed excellent ductility. The diameters of the aggregates were 10−17 times larger than their heights due to the tip convolution effect and the flattening of spherical particles upon adsorption onto the mica surface. Similarly, other hydrophobic compounds, such as indomethacin (IND) and coumarin 102, also induced the self-

formulations due to its biodegradability, wide availability, and nonfouling property.283−285 In contrast to PEG, dextran contains abundant functional hydroxyl groups along the chain, which can be functionalized easily via its numerous hydroxyl groups, endowing the obtained materials with various desired functions. The protonation and deprotonation processes of benzimidazole (BM) can be easily controlled by changing solution pH. At low pH, the nitrogen atom is protonated into the cationic state, making it thread out of β-CD cavity.286,287 On the contrary, the BM group in the neutral state can interact with the β-CD molecule via host−guest interactions at the physiological pH (∼7.4). Therefore, the host−guest complextion between BM and β-CD exhibits pH-sensitive property in aqueous solution. On the basis of this pH-responsive host− guest molecular recognition, Chen and co-workers masterfully designed a pH-responsive supramolecular amphiphile comprising BM functionalized poly(ε-caprolactone) (BM-PCL) and βCD modified dextran (Dex-β-CD) (Figure 20).288 Linked by host−guest complex, supramolecular amphiphile Dex-β-CD/BM-PCL was obtained under neutral pH conditions (at pH 7.4) with Dex-β-CD as the hydrophilic segment and BM-PCL as the hydrophobic part (CMC = 0.82 mg/mL).

Figure 20. Top: pH-controlled complexation between Dex-β-CD and BM-PCL. TEM micrographs of Dex-β-CD/BM-PCL at pH 7.4 (a) and pH 5.5 (b), respectively. (c) The hydrodynamic radii (Rh) of Dexβ-CD/BM-PCL micelles in PBS at pH 7.4 and pH 5.5. (d) Schematic illustration of DOX loading and intracellular microenvironment triggered release from DOX-loaded Dex-β-CD/BM-PCL micelles. Reproduced with permission from ref 288. Copyright 2013 The Royal Society of Chemistry. W

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obtained in the presence of small molecule stimulants, such as potassium iodide (Figure 21g), benzylalcohol (BA) (Figure 21h), and CTAB. The morphologies of the aggregates were distinct from the original assemblies (Figure 21e), which was attributed to the deshelling effect caused by the competitive complexation. More interestingly, polyion complex (PIC) micelles could be constructed by taking advantage of the host−guest interactions between PEG-b-PCD and guest molecules. ADCA was employed to modify the β-CD-grafted block of PEG-b-PCD through inclusion interactions, endowing PEG-b-PCD with negatively charged property. This supramolecular polyelectrolyte further interacted with positively charged polyethylenimine (PEI) through electrostatic interactions. PIC micelles with a mean diameter of 100.7 nm were obtained with PEG as the shell and the polyelectrolyte complex containing PEI and an ADCA-complexed block of PEG-b-PCD as the core (Figure 21d). On the basis of the β-CD/benzene ring molecular recognition, Ma and co-workers further developed a novel multifunctional nanocarrier for simultaneous drug delivery and gene therapy.290 By using a β-CD-conjugated positively charged host polymer PEI (PEI-CD) and a hydrophobic guest polymer (PBLA), core−shell structural nanoassemblies were fabricated effectively. Hydrophobic anti-inflammatory drug (dexamethasone) could be encapsulated into the hydrophobic cores of the micelles and released from the cores. On the other hand, the hydrophilic shell of the positive segment could act as gene delivery vehicle which was able to condense the plasmid DNA and achieve its transfection/expression in osteoblast cells. 3.10.3. Core−Shell Nanosized Assemblies Mediated by an α−β Cyclodextrin Dimer with a Tumor-Triggered Targeting Property. With regard to slight changes in temperature or pH variation between malignant cells (T > 37 °C, pH < 6.8) and normal cells (T = 37 °C, pH = 7.4), stimuliresponsive drug delivery systems with high sensitivities are urgently needed. Zhang and co-workers cleverly constructed a subtle supramolecular amphiphile which could be used as a drug vehicle with tumor targeting property (Figure 22). The hydrophilic N-isopropylacrylamide P(NIPAAm-co-NAS) (Mn = 27 000 g/mol) segment bearing a phenyl group and the hydrophobic segment poly(ε-caprolactone) (Ad-PCL, Mn 5100 g/mol) with a terminal adamantyl group were connected by a α−β cyclodextrin dimer through host−guest interactions, affording a supramolecular polymeric amphiphile.291 In accordance with the geometric compatibility, the adamantyl group in the hydrophobic Ad-PCL segment favored interacting with β-CD, whereas the phenyl group in P(NIPAAm-co-NAS) chain preferred to be accommodated in α-CD. A peptide containing the Arg-Gly-Asp (RGD) sequence was introduced to modify the self-assemblies as a tumor target ligand to improve the cell uptake efficacy. The PEG side chains were grafted to the main chains through pH-responsive benzoicimine bonds to protect the ligands in normal tissues and body fluid. The CMC value of this supramolecular polymeric amphiphile was measured to be 0.26 mg/mL. As shown in TEM images, it self-assembled into core−shell structural NCCMs with an average size of around 100 nm at different pH values (Figure 22a,b). Rhodamine B and fluorescein isothiocyanate (FITC) were further introduced to the ends of the hydrophilic and hydrophobic segments, respectively, to investigate the endocytosis behavior of the obtained micelles under different conditions (Figure 22d). At pH 7.4, very few micelles could be

Figure 21. TEM images of assemblies based on PEG-b-PCD containing (a) pyrene, (b) PBLA (PBLA/PEG-b-PCD 1:20), (c) PBLA (PBLA/PEG-b-PCD 8:20), and (d) ADCA and PEI. TEM images of assemblies based on a PEG-b-PCD/PBLA ratio of 15:6: (e) control; (f) stained with PTA; (g) in the presence of potassium iodide (0.05 M); (h) in the presence of benzyl alcohol (0.05 M). Bottom: schematic illustration of the formation of various host−guest assemblies. Reproduced with permission from ref 289. Copyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

assembly of PEG-b-PCD resulting from the formation of inclusion complexes with β-CD. The hydrophobic IND encapsulated by the core−shell aggregates was triggered to release in the presence of a competitive guest (adamantane carboxylic acid, ADCA), indicating that these supramolecular self-assemblies could be utilized as nanocarriers for drugs with poor solubility. Furthermore, a hydrophobic polymer poly(β-benzyl Laspartate) (PBLA) with Mn of 2000 was selected as a model guest polymer to construct another supramolecular amphiphile (PBLA/PEG-b-PCD). Driven by multiple host−guest interactions, spherical assemblies with diameters ranging from 50 to 200 nm were observed (PBLA/PEG-b-PCD = 1:20, w/w) (Figure 21b). The average diameter of the aggregates was calculated to be about 96.4 nm on the basis of TEM images, which agreed with the result obtained from DLS (118.7 nm). However, the mean size measured from SEM images was much larger (256.7 nm) attributed to the flattening of assemblies when they were dried on the mica surface (Figure 21c). The average thickness of shells was calculated to be about 30 nm by statistical analysis of the TEM images (Figure 21f), close to the length of the PEG chain, confirming that the shells of the assemblies were mainly composed of PEG blocks and the cores of these assemblies were mainly composed of PBLA. On account of the dynamic nature of host−guest interactions, new stimulant-sensitive assemblies could be X

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segments containing NIPAAm and N-acroyloxysuccinimide (NAS) units kept the hydrophilic state. The LCST of the nonPEGylated micelles decreased to 35.5 °C, and the segments comprising NIPAAm units became hydrophobic when the PEG segments were cleaved from the hydrophilic block due to the hydrolysis of benzoic-imine bonds, resulting in the sufficient release of the loaded drug from micelles. From in vivo investigations (Figure 22c), it could be known that the cell viability of the HeLa cells cultured with Dox-loaded micelles for 4 h at pH 7.4 was around 95% and changed slightly by increasing the concentration at 37 °C, which demonstrated that the NCCMs could not be effectively endocytosed by tumor cells. On the contrary, the cell viability decreased effectively by increasing the concentration of drug-loaded micelles when the pH was below 6.8. The cell viability further decreased rapidly, and only 26% of the cells survived when the temperature increased to 39 °C. The reason was that the RGD cell targeting was switched on in the tumor sites at pH < 6.8, and the endocytosis efficacy of the micelles was improved pronouncedly due to the deshielding of the PEG segment. However, most of the loaded drugs were still trapped in the micelles at 37 °C. When the temperature was adjusted to 39 °C, the loaded drugs were released quickly from the micelles because the micelles were destroyed, enhancing the efficacy of the anticancer chemotherapy. The tumor-triggered targeting NCCMs arising from the supramolecular amphiphile that switched off before reaching the tumor sites and switched on in the tumor sites could optimize the cure efficiency and minimize the side effect to normal tissues in tumor treatment.

4. CALIXARENE-BASED SUPRAMOLECULAR AMPHIPHILES Calix[n]arenes are versatile macrocyclic hosts that can be traced back to Bayer’s 19th-century investigations of phenol/formaldehyde reactions.292−294 Their macrocyclic structure was ascertained in 1944 by Zinke and Ziegler. Calix[n]arenes are cyclic oligomers composed of phenolic units linked through methylene groups, possessing well-defined conformational properties and cavities that are able to encapsulate neutral and ionic species.295−298 By modulating their conformation or by modifying the nature and number of ligating sites, functional calix[n]arene derivatives can serve as efficient supramolecular hosts and sensor substances for different guests.299−302 Different families of calix[n]arenes are known depending on the number of phenol residues. One of the well-known characteristics in calixarene chemistry, especially for calix[4]arene derivatives, is the formation of several stable conformers, described by the geometrical arrangement of the benzene subunits as cone, partial cone, 1,2-alternate, and 1,3-alternate conformations.303−305 Apart from normal calix[n]arenes, there also exist analogous macrocycles, such as oxacalixarenes, thiacalixarenes, and azacalixarenes, where the methylene groups are replaced by other units. Selective modifications of the calix[n]arene scaffolds have been utilized to enhance their receptor ability and selectivity toward target guests or to develop sophisticated functional applications ranging from supramolecular polymers, sensors, drug/gene delivery systems, to nanodevices.306−311 Therefore, calixarenes are considered as the third generation of host molecules next to crown ethers and cyclodextrins. Recently, calix[n]arene-based derivatives have received certain attention in the fabrication of supramolecular amphiphiles because their relatively rigid framework can

Figure 22. Top: formation of shell−core micelles with switchable tumor cell triggered targeting. TEM images of micelles (a) with and (b) without PEG segments at different pH values. (c) Viability of HeLa cells after being incubated with blank micelles and Dox-loaded micelles for 4 h: I, micelle, 37 °C, pH 7.4; II, Dox-loaded micelle, 37 °C, pH 7.4; III, Dox-loaded micelle, 37 °C, pH 6.8; IV, Dox-loaded micelle, 39 °C, pH 6.8. (d) Confocal microscopy images of HeLa cells treated by rhodamine B loaded (A2, B2, C2, D2) and FITC labeled (A1, B1, C1, D1) micelles for 4 h under different conditions. Reproduced with permission from ref 291. Copyright 2010 American Chemical Society.

endocytosed by tumor cells. However, the endocytosis of nanoparticles was greatly improved at pH 6.8, because the benzoic-imine bonds were stable in human physiological pH and the target ligands were shielded by the PEG corona. The benzoic-imine bonds were hydrolyzed when the pH value was below 6.8, resulting in the exposure of target ligands. Therefore, the micelles could be easily endocytosed by tumor cells, exhibiting a switchable targeting property for solid tumor. Another sophisticated point of this system was that this supramolecular modification endowed the micelles with high thermoresponsibility by adjusting the transition temperature after a pH-induced structural change. In normal tissues, the PEGylated micelles have a relatively lower critical solution temperature (LCST) of about 38 °C. Under this condition, the Y

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enhance the stability of amphiphilic aggregation. On the other hand, the intrinsic cone structure of this macrocyclic host is the prerequisite for high-curvature aggregations of amphiphiles. With the current emphasis on “sustainability”, the search for a water-soluble host that could accommodate water-insoluble guest molecules within its confined hydrophobic cavity has gained momentum. On the other hand, the binding affinity of the supramolecular systems should be enhanced to ensure the stability of the self-assemblies in aqueous solution. Therefore, suitable chemical modification on the calix[n]arene scaffolds should be performed to obtain modified hosts. A calixarene platform with appropriate functionalization (sulfonate, phosphate, ammonium, peptide, carbohydrate, etc.) on the upper rim renders this class of macrocycles as templates for the design and fabrication of special receptors, which can form large molecular assemblies with various guest molecules (cations, anions, and neutral species), leading to supramolecular architectures of high complexity mimicking biological processes.312−316 Among various functional calix[n]arenes, water-soluble psulfonatocalix[n]arenes (n = 4, 5, 6, 8) possessing threedimensional, flexible, π-election rich cavities have attracted considerable interest over the past three decades since the first report in 1984 by Shinkai.317 p-Sulfonatocalix[n]arenes as versatile macrocyclic receptors are made of 4-hydroxybenzenesulfonate units linked by methylene bridges (Figure 23). Their

Figure 24. Top: chemical structures of SC4, SC6HM, C12TAB, and C14TAB. (a) Schematic illustration of supramolecular amphiphilic assemblies. (b) Critical micelle concentration investigations of C12TAB in the absence (black circles) and presence (red circles) of SC6HM (5 mM) by 1H NMR spectroscopy. (c) Two possible inclusion modes of C14TAB in SC4. Panels a and b reproduced with permission from ref 326. Copyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Panel c reproduced with permission from ref 327. Copyright 2010 The Royal Society of Chemistry.

first critical micelle concentration (CMC1 = 0.2 mM) and the second critical micelle concentration (CMC2 = 30 mM), indicating that SC6HM⊃C12TAB self-assembled at lower concentration by a factor of 70 than that of the guest alone upon formation of host−guest complexes. The complexed SC6HM acted as the hydrophilic part of the supramolecular amphiphile and promoted micelle formation (Figure 24b). On the other hand, the CMC2 value was exactly at the point where all of the calixarene negative charges were neutralized by surfactant positive charges. The mean hydrodynamic radius of the self-assemblies exhibited a concentration-dependent characteristic in the presence of SC6HM (5 mM), of which the micelles varied between 1.8 nm for C12TAB alone and 12.2 nm for C12TAB (50 mM) in the presence of SC6HM. At low concentrations (0.2 mM < [C12TAB] < 10 mM), the micelles were rich in SC6HM and possessed a negative charged surface, because the amount of positively charged C12TAB was not sufficient to neutralize anionic SC6HM. By increasing the concentration of C12TAB (10 mM < [C12TAB] < 30 mM), the aggregate charge density decreased effectively as a consequence of charge neutralization. For an excess of C12TAB (>CMC2), the aggregates became richer in C12TAB and exhibited a positively charged surface, preventing the growth of the micelles (Figure 24a). ́ ó and co-workers further constructed an Afterward, Garcia-Ri supramolecular amphiphile based on the most common psulfonatocalix[4]arene (SC4) with tetradecyltrimethylammonium bromide (C14TAB).327 A white dispersion was obtained with the C14TAB concentration ranging from 0.1 to 50 mM in the presence of SC4 (2 mM) (Figure 24c). Giant vesicles (0.5− 5 μm) were observed under Nomarski light microscopy for a milky dispersion of 50 mM SC4/C14TAB with molar ratio 1:2.5. After sonication of a dispersion containing 2 mM SC4

Figure 23. Three synthetic routes to para-sulfonatocalix[n]arenes. Reproduced with permission from ref 319. Copyright 2006 The Royal Society of Chemistry.

high water solubility, apparent biological compatibility, catalytic properties, and excellent inclusion properties have enabled them to emerge as one of the most important families of supramolecular hosts in supramolecular chemistry.318−325 Furthermore, the recognition abilities of p-sulfonatocalixarenes to form supramolecular complexes with amphiphilic properties enable them to be applied as building blocks in the construction of supramolecular amphiphiles. 4.1. Supramolecular Amphiphiles from Sulfonated Calixarenes and Single-Chain Surfactants

́ Garci a-Ri ó and co-workers used a hexamethylated psulfonatocalix[6]arene (SC6HM) and a cationic surfactant dodecyltrimethylammonium bromide (C12TAB) as building blocks to construct a supramolecular amphiphile (Figure 24).326 The cooperation of π−π stacking, CH−π, and cation−π interactions inside the cavity of the host and additional Coulombic interactions provided by the presence of the sulfonate groups at the portal of the macrocycle were responsible for the formation of supramolecular amphiphile (Ka = 1553 M−1). For the surfactant alone, the CMC value was 14 mM. However, there existed two CAC values for the supramolecular system in the presence of 5 mM SC6HM: the Z

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state) with an average diameter of 13−20 nm above the critical micelle concentration (CMC = 0.54 mM) (Figure 25a). Compared with the size of 22, the diameter of the micelles was quite large, which suggested that the micelles were loose due to the electrostatic repulsion arising from the hydrophilic cationic viologen moieties. Upon addition of 0.1 equiv of bissulfonatocalix[4]arene (BSC4), the morphology of the selfassemblies transformed from micelles to an amorphous wormlike network (N-state) (Figure 25b). BSC4 acted as a crosslinker to connect the micelles to form larger aggregates through host−guest interactions with the hydrophilic methyl viologens exposed to the aqueous solution in the micelle state. Compound 22 formed a stable 2:1 complex with BSC4 by increasing the fraction of BSC4 up to 0.5 equiv, resulting in the destruction of the original spherical micelles. Moreover, a linear supramolecular polymer formed for the ternary system containing 1 equiv of 22, 0.5 equiv of BSC4, and 0.5 equiv of γ-CD, because the alkoxyl coumarin can form a 2:1 complex with γ-CD through the hydrophobic interactions. Thin fibers with a length of several hundred nanometers were monitored, confirming the formation of 1D ternary supramolecular polymer (L-state) through selective host−guest interactions. As determined by DLS (Figure 25d), the mean diameter of the micelles was 16 nm, and the hydrodynamic radius of the worm-like network was around 1000 nm. For the linear supramolecular polymer, the size distribution was relatively wide ranging from 100 to 600 nm. This work may assist researchers to enrich strategies to construct shape and size controllable supramolecular materials with potential applications in biological and sewage purification systems.

and 5 mM C14TAB, the supramolecular amphiphile selfassembled into unilamellar vesicles with an average hydrodynamic radius of ca. 57.2 ± 0.7 nm. The vesicles were coalescing and growing to form larger structures after 7 days from preparation due to their high curvature. Freeze-drying technique was utilized to remove water to allow for long-term storage of the vesicles that could reform vesicles in water with a similar size, suggesting that the inclusion complex SC4⊃C14TAB had little influence on the transport of water across the vesicle bilayer. 4.2. Multistate Self-Assembled Micromorphology Transitions Controlled by Host−Guest Interactions

Ma and co-workers employed the selective host−guest interactions to fabricate dynamic supramolecular amphiphiles with variable self-assemblies in solution.328 An amphiphilic ditopic monomer 22 bearing a hydrophilic dication viologen moiety and another hydrophobic coumarin moiety connected by an alkyl chain was chosen as the guest (Figure 25). For the guest alone, it self-assembled into spherical micelles in water (S-

4.3. Hybrid Systems Constructed from Calixarene-Based Supramolecular Amphiphiles

4.3.1. Architecture-Controlled “SMART” Calix[6]arene Self-Assemblies in Aqueous Solution. Rémita and coworkers designed a calix[6]arene (23) modified by three imidazolyl arms at the small rim and three hydrophilic sulfonato groups at the large rim (Figure 26).329 In the aqueous solution, this calix[6]arene-based macrocyclic amphiphile self-assembled into multilamellar vesicles at pH 7.8 with a high size polydispersity ranging from 50 to 250 nm (CAC ∼ 10−4 M) (Figure 26c). The morphology and size of the aggregates changed obviously over time. The thickness of the membrane shells was increased by culturing the aqueous solution for 1 day, and the vesicles fused to form giant vesicles after 1 week. Moreover, unilamellar vesicles with much lower polydispersity and smaller size (≤50 nm) formed after sonication (Figure 26a,b). The size and shape of the self-assemblies exhibited pHresponsive capability, because 23 bore acid−base functions. The ratio of hydrophilic and hydrophobic regions was closely related to the protonation state of the imidazole rings (pKa = 6.2 ± 0.2), which determined the self-assembly of the macrocyclic amphiphile. When the solution pH was adjusted to 6.5, small vesicles with an average diameter of about 50 nm were obtained (Figure 26f). Further acidification of the solution pH lower than 5.3 led to the formation of precipitate as a zwitterionic compound. However, 23 self-assembled into large vesicles 450 nm in diameter at pH 8.5 (Figure 26g). Owing to the existence of three imidazole arms, 23 was able to coordinate Ag+ at the small rim to form a hybrid supramolecular amphiphile. Contrary to the vesicles formed by 23, monodisperse spherical particles 2.5 nm in diameter formed by this hybrid system (Figure 26h). The diameter of the

Figure 25. Top: schematic representation of the morphology transition from spherical micelles (S-state) to the amorphous wormlike network (N-state) and the linear polymer (L-state) controlled by host−guest interactions. Negative-staining TEM images: (a) 22 spherical micelles (S-state), prepared in aqueous solution, [22] = 1 mM; (b) the amorphous worm-like network (N-state) formed by adding 0.1 equiv of BSC4 to the 22 micelle solution; (c) the linear supramolecular polymer (L-state) formed by 22, BSC4, and γ-CD ternary complex. (d) Size distribution of the three morphology states. Reproduced with permission from ref 328. Copyright 2014 The Royal Society of Chemistry. AA

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Figure 27. Molecular models of CCaL3, CCaL3/AuCl4−, and CCaL3/Au and the corresponding morphologies of the selfassemblies. Reproduced with permission from ref 336. Copyright 2013 American Chemical Society.

formed on the surfaces of the aggregates, associated with the disappearance of twisted structures (Figure 27c). The spatial confinement of the four cysteine groups on the upper rim of CCaL3 played an important role in the formation of such nanoparticles. The AuCl4− ion complexed by CCaL3 could also be moderately reduced by the amine groups on the host, because the lone electron pair of the amine group could reduce Au ions without the addition of any reducing agent. More importantly, the self-assembly structure formed by CCaL3⊃AuCl4− was retained after reduction of AuCl4− and was covered with small Au nanoparticles. The sizes of these particles were more uniform than those obtained from the former reduction method. CCaL3 functionalized with cysteine groups acted as a supramolecular template to capture AuNPs and to prevent further aggregation of the particles by the host− guest interactions between the cysteines and Au.

Figure 26. Schematic representation of the modification of the architecture of 23 self-assemblies in the presence of silver ions. AFM images of vesicles adsorbed on a silicon wafer at two different scales: (a) 5 μm; (b) 500 nm. (d) Section analysis of two vesicles along the line marked by the arrow. TEM images: (c) 23 at pH 7.8; (e) 23 at neutral pH; (f) 23 at pH 6.5; (g) 23 at pH 8.5; (h) 23 in the presence of 10−3 M silver perchlorate. Reproduced with permission from ref 329. Copyright 2007 American Chemical Society.

aggregates was almost equal to the length of two molecules, confirming that the aggregates in the presence of silver ions were micelles. Upon complexation with Ag+, the geometry of the macrocyclic amphiphile 23 changed from uasi-cylindrical shape into a more conic structure with a higher curvature and a reduced cross sectional area of the hydrophobic head group, resulting in the collapse of the vesicles into micelles. 4.3.2. Hybrid Self-Assemblies Constructed from an Amphiphilic Calix[4]arene and Au Nanoparticles. Golden nanoparticles (AuNPs) are of great interest due to their fascinating optical properties and their promising applications, ranging from chemical sensing, imaging, cancer treatment, to drug delivery.330−335 The physical and chemical properties of golden nanoparticles are closely related to their morphology and size. However, it is still a challenge to prepare AuNPs with the size smaller than 4.0 nm. Sakurai and co-workers designed and synthesized a novel amphiphilic calix[4]arene bearing cysteine groups at the upper rim of the platform (CCaL3).336 This macrocyclic amphiphile self-assembled into a spherical micelle consisting of 12 molecules at low pH in aqueous solution (Figure 27a). CCaL3 was used as a supramolecular cage to wrap AuCl4− through multiple electrostatic interactions between the protonated amine groups and the anionic AuCl4− ion, resulting in the formation a novel hybrid supramolecular amphiphile (CCaL3⊃AuCl4−). Upon addition of AuCl4−, the conformation of CCaL3 changed from the open-head to the closed-head state due to the reduction of electrostatic repulsion between the amine heads. The closed-head conformation of the hybrid supramolecular amphiphile CCaL3⊃AuCl4− was more favorable for a plate than for a sphere, resulting in the formation of helically coiled bilayer sheets (Figure 27b). Reduced by NaBH4, small Au particles more or less 2.0 nm in diameter

4.4. Photomodulated Fluorescence of Supramolecular Assemblies of Sulfonatocalixarenes and Tetraphenylethene

Calixarene-induced aggregation (CIA) phenomenon was observed for p-sulfonatocalix[n]arenes, which promoted the aggregation of amphiphilic guests by lowering their critical aggregation concentrations and enhancing the aggregate stability. Combining the advantages of aggregation-induced emission (AIE) and CIA, Liu and co-workers prepared unique water-soluble fluorescent organic nanoparticles via selfassembly of quaternary ammonium-modified teraphenylethene (QA-TPE) and SC4 (Figure 28).337 QA-TPE is a typical bolaform amphiphile, and it aggregated to form spherical nanoparticles with a CAC value of 1.4 × 10−4 M (Figure 28c). Notably, the fluorescence of the free QA-TPE aggregates was low, because the aggregates were so loose that the intramolecular rotation of the phenyl rings could be easily realized due to the unfavorable electrostatic repulsion between the terminal QA groups. Upon addition of SC4, the AIE fluorescence appeared apparently as a result of complexation-induced decrease in the CAC (7.0 × 10−6 M). The host−guest inclusion interactions and the electrostatic interactions between QA-TPE and SC4 were contributed to the AIE phenomenon. After the formation of host−guest complexes, the bola-type supramolecular amphiphile (SC4)2⊃QA-TPE self-assembled into multilamellar nanoparticles with an average hydrodynamic diameter of about AB

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Figure 28. (a) Chemical structures and cartoon representations of MQA-TPE, QA-TPE, SC4, and BSC4. (b) Schematic illustration of the selfassembly process and photocyclizations of free QA-TPE and the SC4 + QA-TPE nanoparticles. TEM and AFM images: (c) QA-TPE; (d, f) SC4 + QA-TPE; (e,g) BSC4 + QA-TPE. Reproduced with permission from ref 337. Copyright 2014 American Chemical Society.

to the formation of nanoparticles in the presence of SC4. The photocyclization rate of QA-TPE was 6.8 times as fast as that of free QA-TPE by complexation with SC4, because the intramolecular rotations of the phenyl groups for the complexed QA-TPE were effectively restricted by π−π stacking of the neighboring TPE units in compact aggregates (Figure 28b).

60 nm (Figure 28d,f). These compact aggregates exhibited desired AIE fluorescence, because the electrostatic repulsion between the QA groups which inhibited the occurrence of the AIE effect was replaced by the cooperativity of host−guest, electrostatic, π-stacking, and hydrophobic interactions. For the dimeric host BSC4, the host−guest molar ratio was measured to be 1:4. As shown in a TEM image (Figure 28e), the morphology of the self-assemblies was also spherical nanoparticles with an average diameter of about 90 nm. However, regular linear arrays extending away from the spherical nanoparticles were observed in an AFM image (Figure 28g). Due to the existence of two cavities, the linear arrays rolled into a random coil stabilized by π-stacking interactions among the TPE groups and BSC4. TPE derivatives can cyclizate into diphenylphenanthrene (DPP), thus exhibiting aggregation caused quenching (ACQ) upon UV irradiation.338−340 The nonfluorescent QA-TPE switched to fluorescent QA-DPP (λem = 385 nm, Φ = 9.3%), and the fluorescence was quenched by the formation of host− guest complexes with SC4. However, for the supramolecular amphiphile (SC4)2⊃QA-TPE, the nanoparticles switched from fluorescent (λem = 480 nm, Φ = 14%) to nonfluorescent. By restricting intramolecular rotation of the aromatic rings, the photoreaction product QA-DPP showed the typical fluorescence by the formation of a C−C bond between the neighboring phenyl rings. However, the fluorophore was prone to decay in condensed phase by means of ACQ owing

4.5. Photodynamic Therapy System Fabricated from a Calixarene-Based Supramolecular Amphiphile

Photodynamic therapy (PDT) currently represents an alternative or complementary therapeutic approach in the treatment for various cancers, including bladder, cervical, lung, head, neck, esophageal, and gastric cancers.341−344 In PDT, three individually nontoxic components (photosensitizer, light, and molecular oxygen) are combined to produce a reactive oxygen species (ROS), especially singlet oxygen which can then oxidize cell compartment components and cause irreversible damage to tumor cells.345−348 To date, cyclic tetrapyrroles (e.g., porphyrins, chlorins, and bacteriochlorins) with absorbance in the red region of the spectrum have been widely utilized as PDT agents in clinical PDT due to their good cytotoxic oxygen species generation and exhibition of no dark toxicity.349−353 However, the aggregation propensity of most of hydrophobic photosensitizers in the physiological environment decreases the photosensitization efficiency and limits their applications. To overcome these limitations, considerable efforts have been focused on the development of certain nanocarriers for use as AC

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DC4-PEG, and DC4-PEG/Ce6 micelles was low even when the corresponding concentrations were up to 90 μmol L−1. On the other hand, long-circulation of the micelles was achieved due to the existence of PEG chains, preventing the cell−protein interaction. DC4-PEG acted as supramolecular carriers to encapsulate the Ce6 molecules, and shielded their negative charges, thereby resulting in the significant enhancement of the cellular uptake. Moreover, PDT efficiency improved effectively by the formation of supramolecular micelles. The IC50 value (50% cellular growth inhibition) of the micelles was determinded to be 1.6 μmol/L, much lower than that of Ce6. This supramolecular amphiphile composed of calixarene derivatives and hydrophobic PSs opened a promising pathway for future PDT applications.

photosensitizer drug delivery vehicles, such as mesoporous silica nanoparticles, liposomes, and polymeric micelles, etc.354−357 By employment of supramolecular self-assemblies, photosensitizers can be homogeneously dispersed, and selfaggregation can be suppressed so that the photosensitizing efficiency can be retained. More importantly, targeting moieties can be introduced into the delivery systems easily, enhancing the tumor-targeting selectivity. Zhu and co-workers designed a novel water-soluble PEGylated star-like calix[4]arene derivative modified by long hydrophilic PEG chains at the lower rim (Figure 29).358 Due to

4.6. Multi-Stimuli-Responsive Supramolecular Amphiphile as a Drug Delivery System

Liu and co-workers constructed a multi-stimuli-responsive supramolecular amphiphile (SC4⊃MVC12) on the basis of a water-soluble p-sulfonatocalix[4]arene (SC4) and asymmetric viologen (MVC12) (Figure 30).359 Compared with the free MVC12 (CAC ∼ 2 × 10−2 M), the corresponding CAC values decreased dramatically (0.02 mM at 0.02 mM SC4, 0.04 mM at 0.05 mM SC4, and 0.07 mM at 0.08 mM SC4) caused by CIA. The supramolecular amphiphile SC4⊃MVC12 self-assembled into bilayered structural vesicles with an average diameter of 362 nm (Figure 30c−f). The host−guest complexation was the decisive factor for the formation of binary vesicles, where the electrostatic interaction between negative sulfonate groups and positive viologen groups reinforced the stability of the vesicles. The hydrophobic alkyl chains in MVC12 packed together through van der Waals interactions, and the hydrophilic complexed SC4 located on the inner- and outer-layer surfaces. The host−guest complexation was enthalpy-driven, and the interactions were weakened upon warming. On the other hand, the amphiphilicity of the guest was affected by either redox or inclusion of cyclodextrins (CDs). Therefore, the obtained supramolecular binary vesicles exhibited multi-stimuli-responsivenesses, including temperature, host−guest inclusion, and redox. The assembly/disassembly process of the supramolecular amphiphile SC4⊃MVC12 could be reversibly regulated by changing the temperature. The average diameters of aggregates decreased from 359, to 362, and to 319 nm by increasing the temperature from 15, to 25, and to 45 °C, respectively. When the temperature reached 70 °C, the selfassemblies were completely disintegrated. The amphiphilicity of SC4⊃MVC12 was disrupted by the addition of α-CD (ca. 2 equiv), because the alkyl chain moiety of the guest threaded into the cavity of α-CD to form an inclusion complex. As a result, the vesicles collapsed completely to form water-soluble [3]pseudorotaxane-type complexes (Figure 30k). Due to the discrepancy in the binding abilities between the alkyl chain and cyclodextrins with different cavity sizes, more β-CD (or γ-CD) was required to disrupt the vesicles (ca. 3 equiv). The viologen group in MVC12 is redox-active, which can be chemically or electrochemically (Figure 30l) reduced into the corresponding radical cation and neutral state. Therefore, the self-assembly of the supramolecular amphiphile could be modulated by one- or two-step reduction of MVC12, because the binding affinities between SC4 and the viologen dication, the radical cation, or the neutral form were distinct. After reduction by hydrazine, the radical cationic head interacted

Figure 29. Top: cartoon representations of the structures of DC4PEG and Ce6 and the formation of the supramolecular polymeric micelles based on host−guest interactions. Bottom: (a) DLS plot and (b) representative TEM image of DC4-PEG/Ce6 (1:1) micelles. Reproduced with permission from ref 358. Copyright 2011 The Royal Society of Chemistry.

the existence of large π-conjugation domains, DC4-PEG could incorporate with hydrophobic photosensitizers (chlorin e6, Ce6) to form a supramolecular amphiphile (DC4-PEG⊃Ce6) through host−guest interactions. This supramolecular amphiphile self-assembled into supramolecular micelles in aqueous solution (Figure 29b), avoiding the aggregation of Ce6. The average diameter of the core−shell micelles was 139 nm with a polydispersity index of 0.23 (DC4-PEG/Ce6 = 1:1) (Figure 29a), which was preferentially delivered to tumors owing to the enhanced permeability and retention (EPR) effect. Improvement of the Ce6 fraction resulted in the formation of large micelles or precipitation, because there were not enough binding sites for hydrophobic Ce6. The loading content of Ce6 in the supramolecular micelles was about 12% (w/w). MTT assay on HeLa cells demonstrated that the toxicity of Ce6, AD

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Figure 30. (a) Chemical structures and cartoon representations of SC4, MVC12, and CDs. (b) Schematic representation of the multistimuli responsiveness of supramolecular binary vesicles. TEM images: (c, d, e, f) SC4 + MVC12 aggregates; (g, h, i, j) the aggregates after reduction by excess hydrazine; (k) the aggregates in the presence of excess α-CD; (l) the aggregates after application of a reduction potential (−1.6 V vs Ag/ AgCl) for 30 min. Reproduced with permission from ref 359. Copyright 2011 American Chemical Society.

with SC4 as well to form a supramolecular amphiphile, which self-assembled into vesicles with smaller diameter (153 nm) (Figure 30g−j). The reason was that the membrane curvature became higher as the electrostatic repulsion on the surface of the aggregates was weakened with the reduction of MVC12 from the dication to the radical cation state, resulting in the decrease of the vesicle size. Interestingly, the vesicles recovered to the initial vesicles (average diameter of 308 nm) after reoxidation of MVC12 from the radical cation state to its dication state, indicating the reversible conversion between these two different vesicles. These multi-stimuli-responsive vesicles were utilized as drug nanocarriers. An anticancer drug (DOX) could be successfully encapsulated in the vesicles with the loading efficiency of 86%. The loaded anticancer drug was released from the vesicles upon warming or addition of a competitive supramolecular host (αCD) accompanied by the disassembly of the vesicles. In vitro investigations confirmed that the toxicity of DOX for the normal cells was reduced upon loading by the vesicles while the therapeutic effect of DOX for cancer cells was maintained. The present multi-stimuli-responsive binary vesicles formed by the

calix[4]arene-based supramolecular amphiphile exhibited enormous substantial applications in the fields of controlled release and drug delivery. 4.7. Cholinesterase-Responsive Supramolecular Vesicles as Drug Delivery Carriers

Among numerous external stimuli, enzyme-responsive selfassembly is especially attractive on account of its good biocompatibility and sensitivity, and therefore displays potential applications in biological materials and drug delivery systems.360−365 Liu and co-workers constructed an enzymeresponsive supramolecular amphiphile by using psulfonatocalix[4]arene as the macrocyclic host and natural enzyme-cleavable myristoylcholine as the guest molecule (Figure 31).366 The CAC values of myristoylcholine and its hydrolysis product myristic acid were 2.5 and 4.5 mM, respectively. Both of them self-assembled into micelles in aqueous solution, so it was defective in fabricating enzymeresponsive self-assemblies. The CAC value of myristoylcholine decreased effectively by a factor of ca. 100 (0.02−0.03 mM) in the presence of SC4 due to CIA. The average diameter of the self-assemblies formed by AE

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disassembly of the vesicles and release of drugs sequestered within the vesicular interior. It should be noted that the tacrineloaded vesicles underwent only partial disassembly by culturing with BChE, which was different from the free vesicles that disassembled completely under the same condition. This sustained-release phenomenon will not only enhance the drug efficacy but also minimize the undesired side effects caused by excessive tacrine release. More importantly, the supramolecular amphiphile exhibited excellent biocompatibility and low toxicity, suggesting that this supramolecular system can be utilized as an ideal carrier for drug delivery. 4.8. Supramolecular Amphiphiles Constructed from Calixarene Analogues

4.8.1. Supramolecular Amphiphile Based on Calix[4]resorcinarene and a Cationic Surfactant for Controllable Self-Assembly. A resorcinarene (also called resorcinolarene, resorcarene, or calixresorcinarene) is a macrocycle mainly in the form of their rccc isomer, which is commonly produced by the Brønsted acid-catalyzed reaction of resorcinol and an aromatic or aliphatic aldehyde in the absence of template.367−371 As the analogues of calixarenes, resorcinarenes have aroused great interest in the host−guest chemistry as molecular receptors for many useful guests. The most fascinating advantage of resorcinarenes is that they can be modified either via nucleophilic aromatic substitutions at position 2 on the aromatic rings or the phenol hydroxyl groups at the lower rim, giving the possibility to access more straightforwardly the molecules with multifunctional groups. Kharlamov et al. fabricated a novel supramolecular amphiphile based on a calix[4]resorcinarene (24) sulfonatoalkylated at the lower rim and piperidine-methylated at the upper rim and a cationic surfactant hexadecyl-1-azonia-4azobicyclo[2.2.2]octane bromide (DABCO) (Figure 32).372

Figure 31. Top: schematic illustration of amphiphilic assemblies of myristoylcholine in the absence and presence of SC4. (a) SEM, (b) high resolution TEM, and (c, d) TEM images of the SC4 + myristoylcholine assembly. (e) TEM, (f) high-resolution TEM, and (g, h) SEM images of the SC4 + myristoylcholine assembly after addition of BChE for 3 h. Reproduced with permission from ref 366. Copyright 2012 American Chemical Society.

the supramolecular amphiphile (SC4⊃myristoylcholine) was monitored to be 194 nm with a narrow size distribution. Spherical morphology with a diameter range from 90 to 200 nm was verified by TEM (Figure 31c,d) and SEM (Figure 31a). Moreover, the hollow spherical morphology with distinguishably dark periphery and light central parts was revealed by highresolution TEM (Figure 31b) and cryo-TEM, confirming the formation of vesicles. The wall thickness of the vesicles was calculated to be about 4 nm, which is equal to the length of two supramolecular amphiphiles, indicating that the membrane was bilayer structure. The alkyl chains of SC4⊃myristoylcholine packed together to form the hydrophobic layer, and the hydrophilic heads of the supramolecular amphiphiles located on the inner- and outer-layer surfaces. Due to enzyme-responsiveness of myristoylcholine which was cleaved by butyrylcholinesterase (BChE), the vesicular morphology formed by the supramolecular amphiphile collapsed completely in the presence of BChE (0.5 U/mL) for 3 h. The specificity of the cholinesterase-responsive disassembly brought significant changes in DLS, TEM (Figure 31e), high-resolution TEM (Figure 31f), and SEM (Figure 31g,h) results. The enzyme-responsive binary vesicles were utilized as nanocarriers to encapsulate a typical water-soluble cholinesterase inhibitor (tacrine). The release rate of the entrapped drug was quite low in the presence of denatured BChE, because the vesicles were stable. An enzyme-induced cleavage of myristoylcholine broke the hydrophilic−hydrophobic balance of the binary supramolecular amphiphile, resulting in the

Figure 32. Structural formulas of calix[4]resorcinarene 24 and DABCO and cartoon representation of the changes in the supramolecular architecture with the variation in the ratio between 24 and DABCO. Reproduced with permission from ref 372. Copyright 2013 American Chemical Society.

Due to its multicharged nature, 24 self-associated with a supramolecular polymer form in water in a “head-to-tail” packing mode through electrostatic interactions. As confirmed by various methods, including diffusion NMR measurements, surface tension measurements, and specific conductivity measurements, there existed two critical points: the first critical association concentration (CAC1) and the second critical AF

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concentration (CAC2) related to the changes in the shape of aggregates. DABCO itself self-assembled into micelles when the concentration was higher than its critical micelle concentration (ca. 0.8 mM). For the binary system, the CMC value of DABCO decreased to ca. 0.1 mM in the presence of 24, which was ascribed to the low diffusion coefficients of DABCO in a mixed system. When the surfactant concentration was lower than 2 mM, most of 24 was in the disassociated form, while DABCO was in the associated state, indicating that the host assisted the surfactant self-assembly. Owing to the electrostatic repulsion between the protonated piperidine groups and the cationic head of DABCO, inclusion complexes could not form. The surfactant interacted with the anionic sulfonato groups at the low rim of the calix[4]resorcinarene through electrostatic interactions to form a supramolecular amphiphile (Figure 32), of which 24 acted as the hydrophilic “head”, while the alkyl chain of DABCO acted as the hydrophobic “tail”. The supramolecular amphiphile self-assembled into spherical micelle-like aggregates with a hydrodynamic radius (Rh) of ca. 4 nm. On the contrary, the vast majority of 24 was in the bound state, and the fraction of free DABCO rose when the concentration of DABCO was higher than 2 mM. It should be pointed out that free DABCO aggregated to form micelles when the concentration of DABCO exceeded a critical point (3 mM). The morphologies of the binary aggregates were closely related to the relative molar ratio of the building blocks, because 24 acted as “electrostatic forceps” to nip off positively charged surfactant molecules from their own micelles. As demonstrated by DLS investigations, 95% of the aggregates were micelles (Dh ∼ 18 nm) corresponding to the system with excess DABCO (1 mM of 24 vs 10 mM of DABCO), while the rest of the aggregates formed by the supramolecular amphiphile showed much larger diameter (Dh ∼ 130 nm). On the opposite, the amount of the supramolecular amphiphile-based aggregates (Dh ∼ 94 nm) reached 90% for the binary system in the presence of excess 24 (10 mM of 24 vs 5 mM of DABCO). This calix[4]resorcinarene-based supramolecular system could potentially perform as an excellent candidate to fabricate molecular transporters with controllable morphology and size. 4.8.2. Fabrication of Well-Defined Crystalline Azacalixarene Nanosheets Assisted by Se···N Noncovalent Interactions. Selenium (Se) is an essential trace element and micronutrient for the human body, which participates in the incorporation of selenoproteins preventing cellular damage from free radicals. Compared with its homologues (sulfur), Se possesses unique chemical properties arising from its relatively weaker electronegativity and larger atomic radius. As a consequence, the bond energies of C−Se and Se−Se were lower than those of C−S and S−S (C−S 272 kJ mol−1; S−S 240 kJ mol−1; C−Se 244 kJ mol−1; Se−Se 172 kJ mol−1), making it easier to be oxidized. Therefore, selenium-containing polymers exhibited enormous potential applications as physiological condition-responsive drug delivery vehicles and artificial enzymes.373−380 Xu and co-workers employed a Se-containing amphiphile (SeG) containing three hydrophilic branches with a Se atom in each branch as the guest and an azacalix[6]pyridine (APy6) bearing 12 nitrogen atoms as the host (Figure 33) to construct a supramolecular amphiphile (APy6⊃SeG).381 SeG aggregated to form micelles with a diameter of 140 nm when the concentration was higher than its CMC (Figure 33c). For APy6

Figure 33. Fabrication of well-defined azacalix[6]pyridine nanosheets assisted by Se···N noncovalent interactions. TEM (a) and AFM (b) images of the nanosheets. TEM images: (c) the micelles of SeG in water; (d) the irregular aggregates of the insoluble APy6 molecules in aqueous solution. Reproduced with permission from ref 381. Copyright 2012 The Royal Society of Chemistry.

alone, it just formed irregular precipitations in aqueous solution because of its poor solubility (Figure 33d). However, APy6⊃SeG self-assembled into well-defined nanosheets in aqueous solution under the same preparation conditions (Figure 33a,b), which was driven by both intermolecular Se··· N noncovalent interactions as well as hydrophobic interactions between APy6 and SeG. TEM electron diffraction and X-ray diffraction (XRD) measurements confirmed that the nanosheets were a triclinic single crystal structure, and the layer distance of the nanosheets was measured to be 0.93 nm. On the other hand, the thickness of the nanosheets was determined to be 24−35 nm by AFM, which indicated that they were composed of multilayers. The self-assembly mechanism of the supramolecular amphiphile list is as follows: First, SeG acting as a surfactant assisted to enhance the solubility of APy6 and facilitated the crystal growth. Then, SeG complexed with APy6 to afford a stable host−guest complex, and the complex was attached to the surface of the nanocrystal to prevent growth of the face packing dimension, assisting to form 2D nanosheets. Moreover, the adsorption of SeG further prevented the growth of the crystals, resulting in the formation of well-defined nanosheets. Upon replacement of SeG by 1,3,5-tri(2,5,8,11tetraoxadodecyl)benzene, the supramolecular amphiphile could not form, and only irregular aggregates self-assembled AG

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Table 2. Some Structural Parameters of CB[n] (n = 5−8)a

by APy6 were observed, emphasizing that the intermolecular Se···N noncovalent interactions played a significant role in the formation of the supramolecular amphiphile APy6⊃SeG. Furthermore, the supramolecular amphiphile displayed pH and oxidation dual responsivenesses. The nitrogen atoms in APy6 were protonated by HCl, which caused the failure of the host−guest interactions between APy6 and SeG. Consequently, the nanosheets completely decomposed when cultured in the solution at pH 2 for 12 h. On the other hand, the surfaces of the nanosheets were partly destroyed by treating with 1% H2O2 for 12 h due to the oxidation of the Se atoms.

5. CUCURBITURIL-BASED SUPRAMOLECULAR AMPHIPHILES The first report about cucurbiturils obtained from the acidinduced condensation reaction of urea, glyoxal, and formaldehyde appeared in 1905 by Behrend and co-workers.382 The chemical nature and structure of the obtained cucurbituril had been unknown until 1981, when full characterization was reported by Mock and Freeman et al.383,384 From the X-ray structure of the calcium bisulfate complexed cucurbituril which precipitated from a sulfuric acid solution, it turned out to be a cyclic hexamer of glycoluril units linked by methylene bridges. Afterward, the pioneering work of Kim and Day enabled chemists to synthesize and isolate cucurbit[n]uril (CB[n], n = 5, 7, 8, 10) homologues containing different numbers of glycol units in the early 2000s (Figure 34).385−389

outer diameter (Å) cavity (Å) height (Å) cavity volume (Å3)

a b c d

CB[5]

CB[6]

CB[7]

CB[8]

13.1 4.4 2.4 9.1 82

14.4 5.8 3.9 9.1 164

16.0 7.3 5.4 9.1 279

17.5 8.8 6.9 9.1 479

a

Reproduced with permission from ref 390. Copyright 2003 American Chemical Society.

cavities of CB[n]s, they form very stable host−guest complexes with organic and inorganic cations, and neutral organic guests in aqueous media.392 Although CB homologues possess similar characteristic features, hydrophobic cavity, and polar carbonyl groups surrounding the portals, specfic host−guest molecular recognitions have been established between the CB homologues and guests with different sizes owing to their discrimination in cavity and portal sizes (Figure 35).393,394 CB[5] with the

Figure 34. X-ray crystal structures of CB[n] (n = 5−8). Color codes: carbon, gray; nitrogen, blue; oxygen, red. Reproduced with permission from ref 390. Copyright 2003 American Chemical Society.

Figure 35. Typical guests for CB[n] (n = 5−8). Reproduced with permission from ref 390. Copyright 2003 American Chemical Society.

Some structural parameters of CB[n]s are listed in Table 2, which are obtained from their single crystal structures. The heights of CB[n]s (n = 5, 6, 7, 8, 10) stay 9.1 Å, while their equatorial widths, annular widths, and cavity volumes vary systematically with the ring size.390,391 On going from CB[5] to CB[8], the mean diameter of the internal cavity increases gradually from ∼4.4 to ∼8.8 Å associated with the improvement of their mean portal diameter from ∼2.4 to ∼6.9 Å. It should be emphasized that the cavity sizes of CB[6], CB[7], and CB[8] are analogous to α-, β-, and γ-CD, respectively. However, the highly symmetrical pumpkin-like structure with two identical openings distinguishes them from CDs. Electrostatic potential surface calculations indicate that the regions around the portal carbonyl groups on CB[n]s are significantly negatively charged, which are favored to complex positively charged groups. Because of the strong charge-dipole and hydrogen bonding interactions, as well as the hydrophobic/ hydrophilic effect derived from the negative portals and rigid

smallest cavity size is able to complex with cations such as NH4+ and Pb2+.395−397 These cations are too large to enter into the cavity and just suspend on the portals. In a similar way to CDs, the hydrophobic cavity of CB[6] provides a potential binding site for inclusion of hydrophobic guest molecules, such as tetrahydrofuran and benzene. In sharp contrast, CB[6] forms stable inclusion complexes with protonated diaminoalkanes (+NH3(CH2)nNH3+, n = 4−7, Ka >105 M−1) and moderately stable complexes with protonated aromatic amines, such as pmethylbenzylamine (Ka ∼3 × 102 M−1), which is dramatically different from that of CDs.398−400 For CB[7], 2,6-bis(4,5dihydro-1H-imidazol-2-yl) naphthalene, protonated adamantanamine, and methylviologen dication are ideal guests, which form 1:1 host−guest complexes with CB[7] in aqueous solution.401−403 Moreover, hydrophobic ferrocene derivatives and carborane guest can easily penetrate into the CB[7] cavity mainly driven by hydrophobic interactions. AH

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For CB[8], its cavity is large enough to encapsulate relatively large guests, such as cyclen, cyclam, and the corresponding transition metal complexes. More interestingly, CB[8] can be used as a “molecular handcuff” to join two molecules together in a noncovalent fashion due to its large cavity volume (479 Å3).404−408 It is able to simultaneously encapsulate two guests inside its cavity, forming a dynamic 1:1:1 ternary complex in water with an association constant up to 1015 M−2 through multiple noncovalent interactions with an electron-deficient guest such as methylviologen (MV2+) and an electron-rich guest, such as 2,6-dihydroxynaphthalene. Given its unique host−guest binding properties, CB[8] has recently been widely utilized as a linkage to construct various aqueous-based materials via a noncovalent route, including supramolecular polymers, micelles, vesicles, microcapsules, supramolecular glycolipid, and dynamic hydrogels.404−408 These selective host−guest molecular recognitions have been extended generally to construct supramolecular amphiphiles. 5.1. Supramolecular Vesicles Formed by Amphiphilc Cucurbit[6]uril and Multivalent Binding of Sugar-Decorated Vesicles to Lectin

CB[6] and its derivatives with the cavity diameter of 5.8 Å form stable host−guest complexes with polyamines in aqueous solution, and the association constant can reach >105 M−1. By taking advantage of the molecular recognition between CB[6] and polyamine, Kim and co-workers designed a novel amphiphilic CB[6] (25) modified by 2-[2-(2-methoxyethoxy)-ethoxy]ethanethiol and constructed various supramolecular amphiphiles in water with spermine-based guest molecules 26−28 (Figure 36).409 Spherical aggregates with the diameters ranging from 30 to 1000 nm formed by simply adding water to a film of 25 and sonicating the mixture for 30 min (Figure 36a). Light scattering studies revealed that the radius of gyration (Rg) was 54.7 nm and hydrodynamic radius (Rh) was 50.9 nm related to the monodisperse self-assemblies (ρ(Rg/Rh) = 1.06), confirming the formation of vesicles. The wall thickness of the vesicles was 6 ± 1 nm, which indicated the bilayered packing mode of the macrocyclic amphiphile. The membrane of the vesicles was composed of the amphiphilic CB[6], so the vesicles were easily modified by the guests via noncovalent host−guest interactions. FITC (fluorescein isothiocyanate)-spermine conjugate ligand 26 was attached onto the vesicle surface where spermine served as a binding motif to CB[6] and FITC as a fluorescent tag, resulting in the formation of green fluorescent spheres (Figure 36b). By introducing functional tag moieties, the surfaces of the vesicles were decorated with the specific groups, endowing the vesicles with interesting functions (Figure 36c). Upon incorporation of the vesicle surfaces with thiourea-linked α-mannose-spermidine conjugate 27, the binary vesicles exhibited specific interactions with concanavalin A (ConA), a lectin with specificity toward αmannose. The binding constant of the vesicles decorated with 27 to ConA (3 × 104 M−1) was enhanced 3 orders of magnitude higher than that of monomeric ligand 27 to ConA (∼50 M−1), indicating multivalent interactions between the mannose-decorated vesicle and ConA. In sharp contrast, no aggregates formed with ConA for the vesicles decorated with a galactose-spermidine conjugate 28, demonstrating the achievement of specific carbohydrate−protein interaction. These results provided a new noncovalent, modular approach to the modification of vesicle surfaces.

Figure 36. Top: chemical structures of 25−28. (a) High-resolution TEM image of vesicle 25 (0.4 mM) with an inset showing the membrane thickness. (b) Confocal microscope image of vesicle 25 (0.4 mM), the surface of which is decorated with 26 (scale bar = 2 μm). (c) Pictorial illustration of the facile surface modification of the vesicle through host−guest chemistry. Reproduced with permission from ref 409. Copyright 2005 American Chemical Society.

5.2. Supramolecular Photosensitizers with Enhanced Antibacterial Efficiency

Zhang and co-workers created a sophisticated four-armed supramolecular amphiphile by employing CB[7] as a bulky noncovalent building block to weaken the close stacking of porphyrins modified with four positive charges (TPOR) through host−guest interactions (Figure 37).410 This novel supramolecular system was utilized as a supramolecular photosensitizer to enhance antibacterial efficiency. Because of the amphiphilic nature of TPOR, it self-assembled into spherical-like aggregates with the hydrodynamic diameter of around 100 nm (Figure 37c). No clear contrast between the rim and the center of the spheres was observed, suggesting that these aggregates were micelle-like structures rather than hollow vesicles. Driven by strong host−guest interactions between CB[7] and naphthalene-methylpyridinium moiety on TPOR, a four-armed supramolecular amphiphile (CB[7])4⊃TPOR was prepared with the porphyrin platform as the hydrophobic part and the complexed CB[7] heads as the hydrophilic part (Figure 37b). (CB[7])4⊃TPOR self-assembled into well-defined nanosheets with a larger hydrodynamic diameter of about 600 nm (Figure 37d,e), which was different from the morphology formed by TPOR alone. Upon formation of stable host−guest complexes, the bulky and space-demanding CB[7] molecules were noncovalently attached to the porphyrin aromatic rings. Hydrophobic π−π interactions between the porphyrins were inhibited effectively AI

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photovoltaics. 411−415 PDI is both photochemically and thermally stable with high fluorescence quantum yields in organic solvents and can be easily modified at its imide nitrogens and its 1, 6, 7, and 12 positions. However, PDI easily self-assembles to form large aggregates in aqueous solution via hydrophobic/hydrophilic interactions as well as by π−π stacking, which hinder the exploitation of their properties and further applications to some extent. Perhaps the largest challenge with PDI chromophores is developing water-soluble, nonaggregating analogues that retain their exceptional properties.416−419 Recently, significant progress in the development and implementation of various covalent and noncovalent modifications and solubilization of PDI chromophores has been made. Compared with covalent functionalization involving difficult organic synthesis with multiple steps, supramolecular functionalization approaches are especially important to the biocompatibilization and bioapplications of PDI, because the unique properties of PDI can be effectively preserved.420,421 Zhang and co-workers employed CB[7] as a bulky “noncovalent building block” to suppress the π−π stacking interactions of a PDI chromophore (BPDI) in water to obtain a supramolecular material with high fluorescence (Figure 38).422

Figure 37. (a) Chemical structures of TPOR (photosensitizer) and CB[7]. (b) The construction of (CB[7])4⊃TPOR supramolecular photosensitizer. TEM images of (c) TPOR and (d) (CB[7])4⊃TPOR assemblies. (e) DLS measurements of the TPOR and (CB[7])4⊃TPOR aqueous solutions. (f) The mechanism for the enhanced antibacterial efficiency of (CB[7])4⊃TPOR compared with that of TPOR. Reproduced with permission from ref 410. Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

in aqueous medium, associated with the suppression of the aggregation-induced fluorescence self-quenching of porphyrins. Excitingly, the efficiency for the 1O2 generation of the porphyrins was enhanced significantly and the generation rate for the supramolecular photosensitizers (CB[7])4⊃TPOR was 7.5 times faster than that of TPOR (Figure 37f). Compared with free TPOR, an appreciable improvement of the photocytotoxicity was achieved by the formation of the supramolecular amphiphile, which was attributed to the suppressed self-quenching of the excited states of porphyrins. Furthermore, this supramolecular modification was highly reversible and adaptive. The host−guest complex disassembled completely upon addition of a competitive guest (1-adamantanamine hydrochloride), which showed a much higher binding constant (4.2 × 1012 M−1) with CB[7]. It is anticipated that this supramolecular amphiphile might be effective for improving the anticancer properties of porphyrins or other photosensitizers in photodynamic therapy systems.

Figure 38. Top: schematic illustration of the fabrication of the adaptive “dumbbell-shape” supramolecular amphiphiles. (a) SEM and (b) cryo-TEM images of (CB[7])2⊃BPDI self-assemblies. Fluorescence microscopic images of BPDI (c) and (CB[7])2⊃BPDI (d) solid-state thin films upon irradiation with a 550 nm light source. (e) Fluorescence spectra of the BPDI-CB[7] complexes with different molar ratios. Inset: photographs of the BPDI (left) and (CB[7])2⊃BPDI (right) aqueous solutions upon irradiation with a 354 nm light source. Reproduced with permission from ref 422. Copyright 2013 Nature Publishing Group.

For the BPDI assemblies, the fluorescence of the PDI chromophores was quenched severely due to their “Haggregated” nature. Driven by the host−guest interactions between CB[7] and naphthalene-methanaminium moiety on BPDI (Ka = 4.4 × 105 M−1), a bola-form supramolecular amphiphile was obtained with the PDI group as the hydrophobic core and complexed CB[7] as the bulky hydrophilic heads. CB[7] and BPDI were mixed in water at a 2:1 molar ratio in order to form a “dumbbell-shape” supramolecular amphiphile. As studied by SEM (Figure 38a),

5.3. Supramolecular Approach To Fabricate Highly Emissive Smart Materials

Perylenediimide (PDI) and its derivatives have attracted significant interest as active materials for light harvesting AJ

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TEM (Figure 38b), and cryo-TEM, the “dumbbell-shape” supramolecular amphiphile ((CB[7])2⊃BPDI) self-assembled into nanodiscs around 400 nm in diameter and several tens of nanometers in thickness in aqueous solution. Upon addition of CB[7], significant color changes were observed for the BPDI solution from orange to deep red (Figure 38e). A dramatic increase of the fluorescence intensity by a factor of ca. 100 was observed as compared to that of BPDI, because the close π−π stacking of the core-located PDI chromophores was inhibited effectively due to the influence of two bulky heads on the [3]pseudorotaxane-type supramolecular amphiphiles. The electronic coupling of the PDI aromatic rings in the “Haggregates” was suppressed in the nanodiscs, resulting in the enhancement of the fluorescence (Figure 38c,d). 1-Adamantanamine hydrochloride (AD), a competitive guest exhibiting stronger binding affinity with CB[7], induced the dissociation of (CB[7])2⊃BPDI. With the recovery from (CB[7])2⊃BPDI to BPDI, the morphology of the assemblies changed to the initial state. In the meantime, the fluorescence of the solution recovered to a highly quenched state, indicating that this supramolecular system was highly reversible and adaptive. The Ka value between CB[7] and spermine reached 2.6 × 107 M−1. This bola-form supramolecular amphiphile (CB[7])2⊃BPDI was further used as a supramolecular sensor for the fast and ultrasensitive detection of spermine. This supramolecular sensor (CB[7])2⊃BPDI displayed excellent selectivity for spermine, and the detection limit reached the range of tens of nanomoles, which was one of the most sensitive sensors for spermine. Figure 39. Top: formation of stable ternary complexes. TEM images of (a) ternary complex CB[8]/DHNp/MVC12 and (b) ternary complex CB[8]/DHNp/MVC16. (c) SEM image of ternary complex CB[8]/DHNp/MVC16. Reproduced with permission from ref 425. Copyright 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

5.4. Cucurbit[8]uril-Based Ternary Supramolecular Amphiphiles

CB[8] with a cavity comparable to that of γ-cyclodextrin can form a stable 1:1:1 ternary complex with electron-deficient methyl viologen and electron-rich 2,6-dihydroxynaphthalene inside the hydrophobic cavity driven by charge-transfer interaction.423,424 By employment of this host−guest molecular recognition, various ternary supramolecular amphiphiles were constructed possessing interesting properties. 5.4.1. Spontaneous Formation of Vesicles Triggered by Formation of a Charge-Transfer Complex in a Host. Kim and co-workers presented an early example by combining the host−guest chemistry with charge-transfer interactions to fabricate a supramolecular amphiphile by mixing an equimolar of CB[8], a viologen with a C12 or C16 alkyl chain (MVC12 or MVC16, respectively), and DHNp in aqueous solution (Figure 39).425 In the absence of CB[8], the guests MVC12 (or MVC16) self-assembled into micelles with the CMC of ca. 1 × 10−4 M, The supramolecular amphiphile CB[8]/DHNp/MVC12 (or CB[8]/DHNp/MVC16) with a large polar head group and a hydrophobic tail self-assembled to form unilamellar vesicles, which were verified by a series of methods, including microscopy, TEM, and SEM investigations. As shown in Figure 39a, monodispersed vesicles with an average diameter of 20 nm formed for CB[8]/DHNp/MVC12. However, CB[8]/DHNp/ MVC16 containing a longer hydrophobic tail formed vesicles with diameters ranging from 20 nm to 1.2 μm (Figure 39b), in good agreement with the result obtained from SEM measurements. The mean diameter of these supramolecular aggregates formed by CB[8]/DHNp/MVC16 was determined to be 870 nm by DLS. By encapsulation of a fluorescent dye (sulforhodamine G) within the interior of the vesicles, the ternary supramolecular

self-assemblies were observed by fluorescence microscopy. The stability of the vesicles was quite high, and the release rate of the fluorescent dye trapped inside the vesicles was slow. However, a sharp increase in the release rate of the dye was monitored by the addition of Triton X-100 that solublized the vesicles effectively. Moreover, the self-assembly of the ternary supramolecular amphiphiles could be regulated by reduction of MVC12 (or MVC16) or oxidation of DHNp due to their redox activity. The vesicles collapsed completely by culturing CB[8]/ DHNp/MVC12 or CB[8]/DHNp/MVC16 with cerium(IV) ammonium nitrate, which caused the destruction of the chargetransfer interactions. 5.4.2. Supramolecular Glycolipid Based on HostEnhanced Charge-Transfer Interaction. Zhang and coworkers fabricated a supramolecular glycolipid based on a ternary complex system, which was composed of naphthyl glucosamine (GlcNap), alkyl viologen (RV8), and CB[8] (Figure 40).426 Driven by host-enhanced charge transfer (CT) interactions between electron-donor GlcNap and the electronacceptor RV8 inside the cavity of CB[8], a stable 1:1:1 ternary supramolecular amphiphile (GlcNap-CB-RV8) formed. GlcNap-CB-RV8 self-assembled into vesicles from 200 to 400 nm in diameter (Figure 40a,b), and the self-assemblies of the supramolecular glycolipids were preserved when the temperature was lower than 60 °C. Considering the existence of carbohydrates on the surfaces of the vesicles, the vesicles could interact with ConA containing four glucose binding sites through multivalent carbohydrate−protein interactions. The AK

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Figure 40. Top: chemical structures of GlcNap and RV8 and schematic illustration of the formation of supramolecular glycolipid GlcNap-CB-RV8. (a) Spherical aggregates formed by self-assembly of supramolecular glycolipids GlcNap-CB-RV8, as indicated by TEM; (b) spherical aggregates of vesicles-like structures. Reproduced with permission from ref 426. Copyright 2013 American Chemical Society.

vesicles of supramolecular glycolipids linked by ConA further formed large irregular aggregations. The diameter recorded by DLS increased several times from about 200 nm to nearly 1 μm by mixing the supramolecular glycolipids with ConA within 5 min. Moreover, the supramolecular glycolipids displayed redox responsiveness, and they decomposed completely by the reduction of RV8 into the radical cation state. After oxidation of RV8•+ to RV82+, host-enhanced charge transfer interaction between RV8 and GlcNap formed again, resulting in the regeneration of supramolecular glycolipids. 5.4.3. Supramolecular Peptide Amphiphile Vesicles through Host−Guest Complexation. A typical peptide amphiphile molecule contains a hydrophilic peptide sequence and a hydrophobic lipid of variable length connected by covalent amide bond. Compared with conventional peptide amphiphiles, supramolecular peptide amphiphiles linked by noncovalent bond represent a major advance, especially in designing stimuli-responsive supramolecular systems capable of being targeted by specific triggers. Scherman and co-workers elegantly constructed a supramolecular amphiphile 31 by utilizing a functional pyrene bearing an imidazolium group and a simple peptide sequence (29) (Figure 41a).427 Pyrenefunctionalized peptide 29 could interact with viologen lipid 30 through CB[8] conjugation to form a 1:1:1 ternary complex. The association constant for the ternary complex reached as high as 1011 M−2. Upon formation of a noncovalent peptide supramolecular amphiphile, bilayered vesicles (100−200 nm) formed associated with a significant fluorescence quenching of the pyrene residue arising from charge-transfer interactions between the pyrene and viologen moieties in the cavity of CB[8] (Figure 41b,c,h). 2,6-Dihydroxynaphthalene (DHNp, 32) and 1-adamantylamine (33) were used as competitive guests to induce the disassembly of the ternary complex, leading to the removal of peptide 29 from the vesicles and simultaneously a “switch on” of the fluorescence. The peptide amphiphile vesicles acted as delivery vehicles and were uptaken by HeLa cells. The fluorescence of the cell nuclei remained weak as a result of the charge-transfer interactions between the pyrene and

Figure 41. (a) Chemical structures of pyrene imidazolium-labeled peptide 29 and viologen-functionalized lipid 30, and their formation of ternary complex with CB[8]. (b) Supramolecular peptide amphiphile vesicle with “switching off” of the fluorescence by the formation of ternary complexes. TEM images: (c) the formation of peptide amphiphile vesicles; (d) decomplexation of the peptide amphiphile structure with 12 equiv of trigger 32. CLSM images of HeLa cells with addition of (e) 31, (f) 31 + 32, and (g) 31 + 33. (h) Emission spectra of 29 (0.05 mM, excited at 303 nm) with addition of CB[8] and 30 in different molecular ratios. (i) Peptide release with the “switching on” of the fluorescence through dissociation of host−guest complexes with external trigger 32 or 33. Reproduced with permission from ref 427. Copyright 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

viologen moieties (Figure 41e). By the addition of either competitive guest 32 or 33, the fluorescence in cytoplasm was turned on due to the disassociation of the ternary complex (Figure 41f,g). The toxicity of the supramolecular system was modulated by controlled release of peptide 29 alone or both AL

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transfer interaction between indole and methyl viologen was highly enhanced upon formation of a 1:1:1 ternary complex that resulted from their tight contact within the cavity of CB[8]. A ternary supramolecular amphiphile PEO-MV/CB[8]/PLA-IPA fabricated by CB[8]-based host−guest molecular recognition was obtained with the PEO chain as the hydrophilic part and the PLA chain as the hydrophobic part. PEO-MV/CB[8]/PLA-IPA self-assembled into solid nanoparticles with a number-average hydrodynamic diameter of 176.8 nm and a polydispersity of 0.115 (CAC = 0.05 mg/mL) (Figure 42a). This ternary supramolecular system exhibited redox-responsive properties due to the existence of redox-active MV group. The host−guest complexation between PEO-MV and PLA-IPA by CB[8] was destroyed after being exposed to a reducing agent (Na2S2O4). The hydrophobic PLA dethreaded from the amphiphilic ternary complex and precipitated, inducing dramatic morphology changes of the self-assemblies. The average diameter of the aggregates gradually increased from 176.8 nm to 256.6 nm, 495.7 nm, and about 1 μm after adding different concentrations of the reducing agent (Figure 42b). The hydrophobic core of the nanoparticles could be used as nanocarriers to encapsulate hydrophobic anticancer drug doxorubicin (DOX). The drug loading content and efficiency reached 5.44% and 28.76%, respectively. The release rate of DOX was accelerated effectively by exposing the drug-loaded nanoparticles to Na2S2O4 arising from the collapse of the selfassemblies (Figure 42c). However, negligible release of the drug was monitored for PEO-b-PLA micelles linked by covalent bonds, which were utilized as a control sample, demonstrating that the enhancement of the release rate resulted from the breaking effect of the host−guest interactions by the reducing agent. More specifically, the release rate with higher concentrations of the reducing agent was faster in the first 2 h, because the nanoparticles disassembled faster when more reducing agent was added. However, the release speed for the systems with higher concentrations of Na2S2O4 became slower than that of the sample with 0.1 mg/mL Na2S2O4. The reason was that the hydrophobic PLA dethreaded from the cavity of CB[8] and wrapped DOX to form precipitations, making the drug stranded inside the nanocarriers. On the basis of the 1:1:1 molecular recognition between methyl viologen, 2,6-dihydroxynaphthalene, and CB[8], Jin, Ji, and co-workers further constructed a pH-responsive ternary supramolecular amphiphile MV-DOX/CB[8]/PEO-Np by using naphthalene-terminated poly(ethylene glycol) (PEONp) and methyl viologen functionalized doxorubicin (MVDOX) as the building blocks.429 MV-DOX/CB[8]/PEO-Np self-assembled into core−shell structural micelles with an average diameter of 170 nm in water. Since the hydrophobic DOX unit was conjugated to the MV group through an acidlabile hydrazone bond, the formed micelles exhibited endo/ lysosomal pH-sensitivity. In sharp comparison to the micelles under physiological conditions (pH 7.4), the release rate of DOX was improved effectively when pH was decreased to 5.0. The reason was that DOX diffused out from the core of micelles due to the cleavage of hydrazone bonds at pH 5.0. With the cleavage of the pH-responsive hydrazone bonds, the amphiphilicity of the supramolecular amphiphile was disturbed, making the micelles more loose, which further assisted the diffusion of DOX. According to fluorescence microscopy, flow cytometry, and MTT experiments, the obtained prodrug micelles formed from the supramolecular amphiphile were

peptide 29 and viologen lipid 30 upon addition of different competitive guests. Electron-rich competitive guest 32 supplanted peptide 29 outside the cavity of CB[8], and formed another 1:1:1 ternary complex with 30 and CB[8], leading to a similar cytotoxic effect as the original ternary complex. On account of the relatively large size of 33, a 1:1 complex formed upon addition of this competitive guest, and 29 and 30 were both disassembled from the cavity of CB[8]. Therefore, the cytotoxicity of this system was enhanced significantly owing to the release of toxic viologen derivative 30 in intracellular environment. This supramolecular peptide amphiphiles exhibiting fluorescence switching to multiple triggers could be employed as a novel generation of hierarchical, stimuli responsive vehicles for various applications, such as drugdelivery, peptide therapeutics, and supramolecular biomaterial conjugation. 5.4.4. Biocompatible and Biodegradable Supramolecular Assemblies for Reduction-Triggered Release of Doxorubicin. As the redox potentials are significantly different between the mildly oxidizing extracellular milieu and the reducing intracellular fluids, intracellular drug deliveries with redox-responsiveness have attracted a large amount of attention over the past decades. Jin, Ji, and co-workers employed two commercially available polymers, poly(ethylene oxide) (PEO) and poly(lacticacid) (PLA), to fabricate a smart drug delivery system for reduction-triggered release of anticancer drugs (Figure 42).428 Indole as an electron-rich group and MV as an electron-deficient group were introduced to the ends of PLA and PEO, respectively, to afford indole-terminated PLA (PLAIPA) and MV-terminated PEO (PEO-MV). The charge-

Figure 42. Top: chemical structures of PEO-MV and PLA-IPA and schematic illustration of the formation, drug loading, and reductiontriggered drug release of CB[8]-based supramolecular assemblies. (a) TEM image of CB[8]-based supramolecular assemblies (PEO-MV/ CB[8]/PLA-IPA). (b) DLS size distributions of blank assemblies before and after adding different concentrations of Na2S2O4 as well as DOX-loaded assemblies. (c) Drug release profiles of DOX-loaded assemblies with or without different concentrations of the reducing agent. Reproduced with permission from ref 428. Copyright 2014 The Royal Society of Chemistry. AM

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demonstrated to be able to effectively inhibit cancer cell proliferation.

6. PILLAR[N]ARENES-BASED SUPRAMOLECULAR AMPHIPHILES Pillararenes, a new class of macrocyclic hosts discovered in 2008, are a rising star in host−guest chemistry.430−436 Compared with the basket-shaped structure of meta-bridged calixarenes, pillar[n]arenes are linked by methylene (−CH2−) bridges at para-positions of 2,5-dialkoxybenzene rings, forming a unique rigid pillar architecture. Different from other traditional hosts, including crown ethers, cyclodextrins, calixarenes, and cucurbiturils, pillar[n]arenes show some unique advantages.437−443 First, they are highly symmetrical and rigid compared with crown ethers and calixarenes, which endow them with selective binding ability to guests. Second, they are easier to be functionalized by different substituents on all of the benzene rings or selectively on one or two positions than cucurbiturils, which enable tuning their host−guest binding properties easily. Third, pillar[n]arenes exhibit excellent solubility in organic solvents, which makes them good and necessary supplements to water-soluble cucurbiturils and cyclodextrins with similar cavity sizes. The inner surfaces of the cavities related to peralkylated pillar[n]arenes are relatively negative charged, and the outer surfaces of the cavities and rims are almost neutral.444−448 For example, the π-electron density of the pillar-structural cavities corresponding to pillar[5]arenes and pillar[6]arenes is higher than that of the open-ended calix-shaped cavities. Their electron-rich cavities endow them with good binding ability to various electron-withdrawing or neutral molecules, such as alkyl chains, pyridiniums, viologen cations, imidazoliums, alkanediamines, ammonium salts, and neutral bis(imidazole) derivatives.449−462 The unique symmetrical structures and easy functionalization of pillar[n]arenes have afforded them superior properties in host−guest recognition. Pillar[n]arenes act as useful platforms for the construction of various interesting supramolecular systems, including liquid crystals, rotaxanes, supramolecular gels, cyclic dimers, chemosensors, hybrid materials, supramolecular polymers, drug delivery systems, cell imaging agents, transmembrane channels, and cell glue.463−485 Pillar[n]arene homologues (n = 5−15) have already been synthesized.486−491 More interestingly, large pillar[n]arenes (n = 8, 9, 10) possess two pseudocavities with well-arranged columnar structures: two pentagons, one pentagon and one hexagon, and two hexagons for pillar[8]arenes, pillar[9]arenes, and pillar[10]arenes, respectively (Figure 43). However, pillar[5]arenes and pillar[6]arenes with five and six repeating units, respectively, have been most widely investigated, because they can be obtained in relatively high yields. From their single crystal structures, pillar[5]arenes appear as an equilateral pentagon and pillar[6]arenes as an equilateral hexagon arising from the methylene bridge linkages at the 2 and 5 positions of the benzene rings. By the ignorance of the substituents on the oxygen atoms of the repeating units, and treatment of pillar[5]arenes and pillar[6]arenes as a regular pentagonal and a regular hexagonal structures, respectively, the internal cavity diameters of pillar[5]arenes and pillar[6]arenes are calculated to be 4.7 and 6.7 Å (based on van der Waals radii of the atoms), respectively (Figure 43). Compared with pillar[5]arenes, pillar[6]arenes can complex with relatively larger guest molecules to form inclusion complexes due to the discrepancy

Figure 43. Cartoon representations of the structures corresponding to typical pillar[n]arenes (n = 5−10).

in the cavity size, such as azobenzene, 1,4-diazabicyclo[2.2.2]octane, tropylium tetrafluoroborate, adamantaneammonium, and so on.492−501 In order to enhance the association constants of the pillar[n]arene-based host−guest complexes in water and apply the corresponding supramolecular systems in the construction of supramolecular amphiphiles, anionic or cationic groups were introduced into the platform. Water-soluble pillar[5]arenes and pillar[6]arenes bearing carboxylate, trimethylammonium, or imidazolium units were designed and prepared,502−507 which provided binding sites for various guests, resulting in the achievement of electrostatic interactions. On the basis of pillar[n]arene-based host−guest recognitions, stimuli-responsive supramolecular amphiphiles can be obtained upon introduction of stimuli-active groups into the hosts or the guests, endowing the materials with interesting functions. 6.1. Pillar[n]arene-Based Enzyme-Responsive Supramolecular Amphiphiles

Enzymes play pivotal roles in various biochemical processes, and aberrations in the enzyme expression level always result in many diseases. For example, damage to the cholinergic (acetylcholine-producing) system in the brain is plausibly associated with Alzheimer’s disease. Therefore, the construction of a supramolecular amphiphile responsive to cholinesterases, such as acetylcholinesterase (AChE), is of particular interest and importance both in fundamental research and in practical application to biotechnology and medicine. On the basis of the pillar[5]arene/acetylcholine recognition motif in water, Yu et al. designed and fabricated an enzymeresponsive supramolecular amphiphile composed of a watersoluble pillar[5]arene (WP5S) and an amphiphilic guest (PyCh).508 Driven by π−π stacking interactions between the pyrenyl groups, PyCh itself self-assembled in water to form nanosheets (Figure 44a). Due to the existence of electrostatic repulsion generated from trimethylammonium groups on the surfaces of the nanosheets, the nanosheets favored to form a bilayered structure (Figure 44b). Notably, the thickness of the AN

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groups on the surfaces of the self-assemblies formed interlayer multiple hydrogen bonds to link the aggregates, resulting in the formation of multilayered nanoribbons. Considering the existence of trimethylammonium groups on the surfaces of nanosheets and negative carboxylate anions on the surfaces of nanoparticles, hybrid supramolecular materials were prepared by fabrication with gold nanoparticles (AuNPs). The sizes of AuNPs in these supramolecular hybrids underwent significant changes after hydrolysis, affecting their catalytic activity for the borohydride reduction of 4-nitroaniline. Compared with the hybrid supramolecular materials (AuNPs@nanosheets and AuNPs@nanoparticles), the sizes of AuNPs became larger after hydrolysis of PyCh by AChE. Correspondingly, the catalytic rate decreased effectively due to the reduction of the surface area of AuNPs. Recently, Zhou and co-workers constructed a triply responsive supramolecular amphiphile WP6S⊃AzoCh on the basis of WP6S/butyrylcholine recognition.509 Due to the existence of pH-responsive carboxylic groups on both rims of the macrocyclic host, the morphology of the self-assembled system could be reversibly transformed between vesicles and micelles by changing the solution pH arising from the complexation and decomplexation between WP6S and AzoCh. On the other hand, the amphiphilicity of the supramolecular amphiphile could be regulated by UV and visible light irradiation in the presence of α-cyclodextrin (αCD), which was caused by the association and disassociation between α-CD and the azobenzene group. In comparison to the reversible pH- and photoresponsivenesses of the supramolecular amphiphile, WP6S⊃AzoCh also exhibited irreversible enzyme-responsiveness. Interestingly, the vesicles formed from WP6S⊃AzoCh could be used as nanocarriers to encapsulate a water-soluble dye (calcein). Triggered by external stimuli (decrease of the solution pH, addition of α-CD, and treatment with enzyme), the loaded dye molecules were released from the vesicles associated with the collapse of vesicles. Compared with the cases triggered by adding α-CD or acidifying the solution pH to 6.0, the release rate of calcein from the vesicles was much slower in the presence of AChE, because the hydrolysis of AzoCh was slow upon formation of the host−guest complex, preventing the vesicles from being disrupted rapidly.

Figure 44. Top: schematic representation of enzyme-responsive selfassembly based on WP5S and PyCh. SEM images: (a) PyCh; (b) enlarged image of part a; (c) WP5S⊃PyCh; (d) WP5S⊃PyCh treated with AChE; (e) enlarged image of part d; (f) enlarged image of a broken nanoribbon. Reproduced with permission from ref 508. Copyright 2014 The Royal Society of Chemistry.

6.2. Bola-Type Supramolecular Amphiphile Constructed from a Water-Soluble Pillar[5]arene and a Rod−Coil Molecule for Dual Fluorescent Sensing

nanosheets was calculated to be about 5 nm, close to two extended lengths of PyCh (∼2.3 nm), indicating that the adjacent pyrene aromatic rings underwent considerable overlap through π−π stacking interactions. Upon addition of WP5S, the critical aggregation concentration increased from 1.25 × 10−6 M for PyCh to 1.52 × 10−4 M by a factor of ca. 122 due to the host−guest complexation. Interestingly, the resultant self-assemblies changed from nanosheets to nanoparticles with an average diameter of about 250 nm caused by the enhancement of the membrane curvature upon formation of the supramolecular amphiphile WP5S⊃PyCh (Figure 44c). The nanosheets or the nanoparticles disappeared completely in the presence of AChE at 37 °C due to the hydrolysis of PyCh into the corresponding acid (PyH). Multilayered nanoribbons in plane-to-plane packing mode formed several micrometers in length and 200−300 nm in width (Figure 44d−f). The reason was that PyH selfassembled into 2D aggregates first due to π−π stacking interactions between the pyrenyl groups. The carboxylic acid

On the basis of the WP5A/imidazolium host−guest recognition driven by the cooperativity of electrostatic interactions and hydrophobic interactions, Huang and co-workers fabricated a novel bola-type supramolecular amphiphile from a watersoluble pillar[5]arene (WP5A) and a rod−coil molecule (35) with the rigid rod as the hydrophobic part and the flexible coil segments as the hydrophilic heads (Figure 45).510 In the absence of WP5A, the amphiphilic guest 35 self-assembled into monolayered sheet-like aggregates in water, which was attributed to the π−π stacking interactions between the rigid rods (CAC = 1.62 × 10−5 M) (Figure 45a). For the bola-form supramolecular amphiphile (WP5A)2⊃35, it self-assembled into bilayered vesicles about 200 nm in diameter with the hydrophobic parts inside the bilayers and the hydrophilic complexed WP5A facing the inner and outer aqueous solution. The host−guest complexation triggered the transition from nanosheets to vesicles by the introduction of a water-soluble AO

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uncomplexed 1 aggregated into nanosheets again, along with quenching of the solution fluorescence (Figure 45f). 6.3. Cationic Water-Soluble Pillar[6]arene-Based Supramolecular Amphiphile. Xue and co-workers reported a new molecular recognition motif between a water-soluble ionic liquid pillar[6]arene (WP6I) bearing 12 cationic imidazolium groups and sodium p-hydroxybenzoate (36) in water (Figure 46).511 Such water-soluble recognition motif

Figure 45. (a) Chemical structures of WP5A and 35 and cartoon representation of a dual-responsive bola-type supramolecular amphiphile. (b) Schematic representation of the bola-type supramolecular amphiphile treatment by paraquat or H+. Reproduced with permission from ref 510. Copyright 2014 The Royal Society of Chemistry.

Figure 46. Top: the illustration of the aggregate transformation from micelles based on 36 to vesicles based on WP6I⊃36. TEM images: (a) 36; (b) WP6I⊃36; (c) WP6I⊃36 when the solution pH is 4.0; (d) WP6I⊃36 when the solution pH is 7.4. Insets are TEM images of the corresponding samples stained by osmium tetroxide. Reproduced with permission from ref 511. Copyright 2014 The Royal Society of Chemistry.

macrocyclic host, while retained the wall thickness of the selfassemblies. Upon complexation with WP5A, the electronic coupling of the quinquephenyl aromatic rings in the complex was suppressed effectively on account that the two bulky heads on the bola-type supramolecular amphiphile inhibited the close π−π stacking of the quinquephenyl aromatic rings. Therefore, the fluorescence of the self-assemblies from the supramolecular amphiphile (WP5A)2⊃35 was about 20 times higher than that of free 35. Owing to the adaptive nature of (WP5A)2⊃35 and the simultaneous dramatic fluorescence change on host−guest complexation, the supramolecular amphiphile was used as a sensor to detect highly toxic paraquat (PQ), which was a competitive guest for WP5A with a much higher association constant. The fluorescence of quinquephenyl aromatic rings was quenched immediately upon addition of PQ associated with the transformation from vesicles to sheet-like aggregates, which was caused by the dissociation of the supramolecular amphiphile (WP5A)2⊃35. Furthermore, this bola-type supramolecular amphiphile could serve as a pH sensor due to the pH-responsiveness of WP5A (Figure 45b). Upon protonation of the carboxylate groups by adjusting the solution pH, neutral WP5H precipitated from the aqueous solution, and the

displayed high binding strength in water with an association constant of 3.21 × 106 M−1. The driving forces for the formation of supramolecular amphiphile WP6I⊃36 were multiple electrostatic interactions, hydrophobic interactions, and π−π stacking interactions between the benzene rings on WP6I and 36. In comparison to 36 that formed micelles in water (Figure 46a), the supramolecular amphiphile WP6I⊃36 self-assembled into bilayered vesicles with an average diameter of about 85 nm (CAC = 3.44 × 10−4 M) (Figure 46b). On the other hand, the host−guest interactions between WP6I and 36 exhibited pH-responsiveness. The morphology of the selfassemblies between micelles and vesicles could be reversibly transformed by simply controlling the solution pH (Figure 46c,d), which resulted from the threading/dethreading switch of the host−guest complexes due to the protonation and deprotonation of 36. The pH-responsive self-assembly of this supramolecular amphiphile was further applied in the controlled release of calcein. The vesicles acted as nanocarriers to encapsulate hydrophilic guest molecules within their interiors under neutral or weakly basic condition, and these AP

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encapsulated molecules were released in response to a decrease in pH because of the collapse of the vesicles into micelles. 6.4. Photoresponsive Self-Assembly Based on a Water-Soluble Pillar[6]arene and an Azobenzene-Containing Amphiphile in Water

Although pillar[5]arenes and α-cyclodextrin have similar internal cavity size, water-soluble pillar[5]arenes cannot complex with trans-azobenzene group, while α-cyclodextrin can bind the azobenzene derivatives in water. The reason is that the hydrophobic cavity of α-cyclodextrin provides a desired binding site for the hydrophobic azobenzene group. Moreover, pillar[5]arenes have a rigid pillar structure, while α-cyclodextrin has a flexible truncated conic cavity where the azobenzene group can thread into the cavity of α-CD from the relatively larger rim. From our previous work, we knew that the azobenzene group in the trans-state could not penetrate the cavity of pillar[5]arenes, while it could thread into the cavity of pillar[6]arenes to form a [2]pseudorotaxane-type host−guest complex due to the difference in cavity sizes.512 On the other hand, the size of the cis-form azobenzene is larger than the internal cavity diameter of pillar[6]arenes. A photoresponsive azobenzene-based guest migrates outside of the pillar[6]arene upon UV irradiation, and penetrates into the cavity of pillar[6]arene again upon visible light irradiation. Threading− dethreading switch can be reversibly achieved upon UV and visible light irradiation due to the trans−cis photoisomerization of the azobenzene group (Figure 47).

Figure 48. Top: cartoon representation of the photoresponsive selfassembly between WP6A and 37 in water. TEM images: (a) trans-37 aggregates in water; (b) WP6A and trans-37 aggregates in water; (c) enlarged image of part b; (d) after irradiation with UV light at 365 nm of part b; (e) after further irradiation with visible light at 435 nm of part d; (f) enlarged image of part e. Reproduced with permission from ref 513. Copyright 2014 The Royal Society of Chemistry.

included multiple electrostatic interactions, hydrogen bonds, and π−π stacking interactions between WP6A and trans-37. For the supramolecular amphiphile, it self-assembled into vesicles with an average diameter of ∼200 nm (Figure 48b,c). The steric hindrance and the electrostatic repulsion generated from WP6A were responsible for the morphology changes from solid spheres to vesicles in the presence of WP6A. Upon UV irradiation, trans-37 was photoisomerized into cis37, and the trimethylammonium group on cis-37 was bound by a rim of WP6A, while the rest of guest cis-37 was outside the cavity of WP6A (Figure 48). The association constant decreased from 4.13 × 105 M−1 for WP6A⊃trans-37 to 5.89 × 104 M−1 upon UV irradiation, because the complexation between WP6A and cis-37 was insufficient. UV irradiation influenced the packing arrangement of the amphiphilic building blocks and resulted in the self-assembly morphology turning to solid nanaparticles with an average diameter of ∼60 nm (Figure 48d). Moreover, the transitions between nanoparticles and vesicles could be reversibly controlled by UV and visible light

Figure 47. Chemical structures of 1,4-bis(propoxy)pillar[6]arene and an azobenzene-based guest and cartoon illustration of photoresponsive host−guest complexation between them.512

Inspired by this phenomena, Huang and co-workers designed a photoresponsive supramolecular amphiphile containing an azobenzene-containing guest (37) and a water-soluble pillar[6]arene WP6A (Figure 48).513 The azobenzene-based amphiphilic guest itself self-assembled into solid nanoparticles (CAC = 2.19 × 10−5 M) (Figure 48a). Upon complexation with WP6A, the CAC value corresponding to the supramolecular amphiphile WP6A⊃37 improved to be 2.85 × 10−5 M. In the host−guest complex WP6A⊃37, the positive trimethylammonium group was close to the oxygen atoms on WP6A while the benzene ring near the cationic group was located in the cavity of WP6A with the other benzene ring outside of the cavity. The driving forces for the formation of the host−guest complex AQ

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irradiation (Figure 48e,f), which was ascribed to the trans−cis isomerization of the guest. This photoresponsive self-assembly could be used to fabricate nanostructures exhibiting potential applications in various fields such as controlled release, nanoreactors, and supramolecular polymers.

Amphiphilic 38 with the tetraphenylethene unit as the hydrophobic part and four n-butyltrimethylammonium bromide units as the hydrophilic part self-assemblied into spherical micelles with a diameter of ∼300 nm (Figure 49a,b). Mainly driven by electrostatic interactions between WP6A and 38, a four-armed supramolecular amphiphile (WP6A)4⊃38 was obtained. In comparison to the micelles formed by 38 alone, the morphology of the aggregates formed by (WP6A)4⊃38 was a wheel-like structure (Figure 49d,e). The combination of electrostatic interactions and aromatic stacking between WP6A and 38 contributed to the formation of the wheel-like structure and accounted for the stability of the resulting aggregates in aqueous solution. Upon addition of WP6A, the spontaneously formed pseudorotaxane-type host− guest complexes effectively restricted the intramolecular rotation of the phenyl rings and prohibited energy dissipation via nonradiative relaxation channel, thus resulting in the strong emission of (WP6A)4⊃38 in dilute solution. Furthermore, the supramolecular amphiphile (WP6A)4⊃38 was utilized as a fluorescence “turn-off” probe to detect paraquat (PQ). PQ worked as a competitive guest to trigger the disassociation of the supramolecular amphiphile due to its much higher binding affinity. As a consequence, a significant quenching of the fluorescence intensity was monitored by the gradual addition of paraquat into a solution of (WP6A)4⊃38. This supramolecular strategy of host−guest complexation induced emission provided a sophisticated pathway for guiding the future design of supramolecular functional materials.

6.5. Four-Armed Supramolecular Amphiphile with Complexation-Induced Emission

Compared with the AIE-active fluorogens which permit the use of concentrated solutions of luminogens or their aggregate suspensions for sensing applications, the traditional sensors work based on the ACQ effect of dilute solutions of conventional luminophores. Exploitation of new approaches to make AIE molecules more emissive in dilute solution which can further act as chemosensors not only in the aggregated state but also in dilute solution is a meaningful issue.514−517 Huang and co-workers developed a novel strategy to tune the emission behavior of a four-armed TPE derivative 38 in dilute aqueous solution by employing the host−guest complexation between WP6A and 38 (Figure 49).518 TPE derivative 38 exhibited excellent solubility and was nearly nonemissive in water, because the intramolecular rotation of phenyl rings of 38 induced the efficient nonradiative annihilation process.

6.6. Supramolecular Amphiphiles as Multiwalled Carbon Nanotube Dispersants

Considering their excellent electronic conductivity, chemical inertness, mechanical toughness, and elasticity, carbon nanotubes (CNTs) have attracted much interest in diverse areas of nanoscience.519,520 However, exploring the chemistry of CNTs at molecular level is greatly limited because of their inherently difficult purification and lack of solubility in water and organic solvents. Various covalent and noncovalent modifications and solubilizations of carbon nanotubes have been developed to functionalize CNTs.521,522 Compared with the cases of covalent modifications which often lead to disrupt the extended πnetworks on their surfaces, supramolecular functionalization approaches are especially important for the modification of CNTs, because their unique properties can be preserved to the greatest degree. Actually, supramolecular amphiphiles based on host−guest recognition have been used as dispersants of CNTS into water as shown below. 6.6.1. pH-Responsive Water-Soluble Pillar[6]areneBased Supramolecular Amphiphile. Huang and co-workers designed and synthesized a water-soluble pillar[6]arene (WP6S) bearing anionic carboxylate groups on both rims (Figure 50).523 Electrostatic interactions and hydrophobic interactions between the anionic host and cationic guest (39) were realized to form a stable [2]pseudorotaxane-form host− guest complex with an association constant of 3.26 × 105 M−1. On the basis of the molecular recognition between WP6S and 39, a pH-responsive supramolecular amphiphile was fabricated. For the amphiphilic guest 39, it self-assembled into bilayered structral nanotubes with an average diameter of ∼300 nm (CAC = 4.88 × 10−5 M) (Figure 50a), of which the adjacent pyrene aromatic rings undergo considerable overlap through π−π stacking interactions to form an H-aggregation.

Figure 49. Top: cartoon representation of the formation of the luminescent supramolecular inclusion complex and its application in the detection of paraquat. TEM images: (a) 38; (b) enlarged image of part a; (d) (WP6A)4⊃38; (e) enlarged TEM image of part d. (c) Cartoon representation of the structure of micelles formed by 38. (f) Cartoon representation of the formation of the superstructure from 38 and WP6A. Reproduced with permission from ref 518. Copyright 2014 The Royal Society of Chemistry. AR

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transformed between nanotubes and vesicles by changing the solution pH, which was attributed to the pH-responsive host− guest complexation. Furthermore, the authors employed the hydrophobic cavity of WP6S to interact with a neutral guest (PyB) containing a πrich pyrenyl ring through hydrophobic interactions. The resultant supramolecular amphiphile WP6S⊃PyB was further used as a dispersant to disperse multiwalled carbon nanotubes (MWNTs) in water (Figure 50d−f). Because of the pHresponsiveness of WP6S, the dispersion of the MWNTs could be reversibly controlled by adjusting the solution pH. 6.6.2. UV-Responsive Water-Soluble Pillar[6]areneBased Supramolecular Amphiphile. It is well-known that 2-nitrobenzyl ester moiety is a photoresponsive group, which can be photocleaved into 2-nitrobenzaldehyde upon UV irradiation. By introduction of this photoactive group, Huang and co-workers constructed a UV-responsive supramolecular amphiphile based on host−guest interactions between a watersoluble pillar[6]arene (WP6S) and a UV-responsive guest (40) bearing the 2-nitrobenzyl ester moiety (Figure 51).524 Driven by π−π stacking interactions between pyrenyl groups, 40 selfassembled in water to form two-dimensional nanosheets with a CAC value of 1.1 × 10−7 M (Figure 51a,e,f). In the presence of WP6S, the CAC value of WP6S⊃40 increased to 1.0 × 10−6 M, which was caused by the stable host−guest complexation between WP6S and 40. The morphology of the self-assemblies formed by this supramolecular amphiphile was nanorods that were composed of nanospheres (Figure 51b,c,g). As shown in TEM images, the average diameter of the nanorods was measured to be about 500 nm. Upon addition of WP6S, the anionic hosts inserted into the hydrophilic membrane of nanosheets due to the host−guest interactions, making the membrane curvature increase caused by the steric hindrance and electrostatic repulsion, thereby resulting in the transition from nanosheets to nanospheres. Moreover, the cores of the nanospheres further adhered to the neighboring ones and formed nanorods driven by the high interactions between the exposed pyrene blocks to minimize the portion of the hydrophobic segment. Both the nanosheets formed by 40 alone and the nanorods formed by the supramolecular amphiphile WP6S⊃40 disappeared by exposing the corresponding solution to UV light for 30 min due to the photocleavage of 40 (Figure 51d,h). This supramolecular system was employed to disperse MWNTs in aqueous solution, and the dispersion behavior of MWNTs could be controlled by UV light irradiation. The MWNTs clustered seriously for the sake of the photocleavage of the hydrophilic segment from the hybrids (Figure 51i−l). It should be noted that this photoresponsive regulation was irreversible, which was different from that of the above-mentioned pH-responsive MWNTs dispersion.

Figure 50. Top: schematic representations of the reversible transformations between nanotubes and vesicles. TEM images: (a) 39 aggregates; (b) WP6S⊃39; (c) WP6S⊃39 aggregates when the pH was adjusted to 6.0; (d) MWNTs; (e) PyB and MWNTs; (f) WP6S⊃PyB/MWNTs. (g) Cartoon illustration of the pH-responsive solubility of the MWNTs in the presence of WP6S⊃PyB. Reproduced with permission from ref 523. Copyright 2012 American Chemical Society.

Generally, high membrane curvature favors nanotubular structures, while a vesicular structure is ascribed to a lowcurvature membrane. Upon complexation, WP6S inserted into the membrane of the nanotubes and formed 1:1 [2]pseudorotaxanes, thus generating steric hindrance and the electrostatic repulsion. As a result, the straight 39 arrays along the axis became curved, and the morphology of the selfassemblies transformed from nanotubes to vesicles with low curvature (Figure 50b). Moreover, the supramolecular systems exhibited pH-responsiveness, because the carboxylate groups were protonated into insoluble −COOH groups, resulting in the decomplexation of WP6S⊃39 (Figure 50c). Therefore, the morphologies of the supramolecular system could be reversibly

6.7. Supramolecular Amphiphiles Constructed on the Basis of Pillararene/Paraquat Recognition

6.7.1. pH-Responsive Supramolecular Amphiphiles on the Basis of Molecular Recognition between Pillar[n]arenes (n = 6, 7, and 10) and Paraquat. Mainly driven by the cooperativity of multiple electrostatic interactions, hydrophobic interactions, and π−π stacking interactions, WP6S showed a strong binding affinity with paraquat with an association constant of 1.02 × 108 M−1,525 because the internal cavity of pillar[6]arenes was suitable for paraquat. On the basis of this new pillar[6]arene/paraquat recogntion motif in water, AS

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Figure 52. (a) Tyndall effect of free 41 (left) and WP6S⊃41 complex (right). [41] = [WP6S] = 5.00 × 10−5 M. (b) The concentrationdependent conductivity of 41 in the presence of WP6S. (c) Tyndall effect of free 41 (left) and WP6S⊃41 complex (right). [41] = [WP6S] = 5.00 × 10−4 M. TEM images: (d) 41; (e) WP6S⊃41; (f) enlarged image of part e (scale bar = 100 nm); (g) the intermediate state from vesicles to micelles (scale bar = 100 nm); (h) WP6S⊃41 when the solution pH is 6.0 (scale bar = 200 nm); (i) WP6S⊃41 when the solution pH is 7.4 (scale bar = 200 nm). (j) The illustration of the formation of the aggregates and the process of pH-responsive release of calcein molecules. (k) Application of WP6S/paraquat molecular recognition in the treatment of paraquat poisoning. Reproduced with permission from ref 525. Copyright 2012 American Chemical Society.

Figure 51. Top: schematic representation of UV-responsive selfassembly of 40 in water. TEM images: (a) 40; (b) WP6S⊃40; (c) intermediate state of WP6S⊃40; (d) WP6S⊃40 treated with UV light irradiation. Fluorescence microscopic images: (e) 40 (bright field); (f) 40; (g) WP6S⊃40; (h) WP6S⊃40 treated with UV light irradiation. TEM images: (i) MWNTs; (j) MWNTs treated with WP6S⊃40; (k) enlarged image of WP6S⊃40/MWNTs; (l) WP6S⊃40/MWNTs treated with UV light irradiation. Reproduced with permission from ref 524. Copyright 2014 The Royal Society of Chemistry.

52e,f), which arose from the generation of steric hindrance and the electrostatic repulsion upon insertion of the WP6S molecules. The aggregation nanostructure of this supramolecular system could be controlled reversibly by changing the solution pH due to the pH responsive complexation between WP6S and 41. After acidification of the solution to pH 6.0, micelles with an average diameter of about 7.0 nm reappeared (Figure 52h). On the contrary, vesicles rather than micelles formed in solution again with the same thickness of the membrane as formed by WP6S⊃41 when the solution pH was adjusted to 7.4 (Figure 52i). More importantly, the intermediate state from vesicles to micelles provided convincing evidence for the pH-responsive self-assembly (Figure 52g). The reversible pH-triggered vesicles−micelles transitions were further employed for controlled release. The vesicles

Huang and co-workers applied it to construct a supramolecular amphiphile and utilized it in controllable self-assembly. Amphiphilic 41 containing a long alkyl chain as the hydrophobic part and 4,4′-bipyridinium unit as the hydrophilic part was chosen as the guest. For 41 alone, it self-assembled into micelles around 7.0 nm in diameter with the CAC value of 3.44 × 10−4 M (Figure 52d). However, the CAC value of the supramolecular amphiphile WP6S⊃41 decreased pronouncedly to 1.95 × 10−5 M due to the host-induced aggregation (Figure 52b). The morphology of the self-assemblies changed dramatically upon addition of WP6S. The micelles disappeared, replaced instead by the formation of bilayered structural vesicles with an average diameter of about 170 nm (Figure AT

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formed by WP6S⊃41 possessed hydrophilic interiors, which were used to encapsulate hydrophilic calcein under neutral or weakly basic condition. The vesicles collapsed into micelles associated with the decrease of the solution pH, resulting in the concomitant release of the encapsulated calcein molecules (Figure 52j). More interestingly, the toxicity of paraquat was reduced significantly by the formation of a stable host−guest complex with WP6S (Figure 52k). The reason was that less opportunity for paraquat to interact with the reducing agent in the cells was achieved when the guest penetrated into the hydrophobic cavity of WP6S. On the other hand, the reduction and oxidation processes of PQ changed significantly upon complexation with WP6S, making generation of toxic radical cations more difficult. Moreover, the generation of HO• may be catalyzed by traces of transition metal ions wrapped by WP6S due to the existence of six carboxylate anions on both sides. Similarly, a water-soluble pillar[7]arene (WP7A) was also used as a host to construct a pH-responsive supramolecular amphiphile with 41.526 By the introduction of 14 anionic carboxylate groups at its two rims, the Ka value of the host− guest complex WP7A⊃41 was further enhanced to 2.96 × 109 M−1. The morphology and the self-assembly mechanism of this WP7A⊃41 supramolecular amphiphile were also similar to the analogous WP6A⊃41, except that the diameter of the vesicles formed by WP7A⊃41 was smaller than that formed by WP6A⊃41. Moreover, Huang and co-workers synthsized a water-soluble pillar[10]arene (WP10A) and fabricated a pHresponsive supramolecular amphiphile.527 The binding affinity between WP10A and the dicationic paraquat group was measured to be 1.25 × 107 M−1 in water, mainly attributed to the multiple electrostatic interactions. The morphology of the self-assemblies between nanoribbons formed by the paraquat-based guest (CAC = 8.87 × 10−6 M) alone and nanosheets formed by the supramolecular amphiphile (CAC = 4.06 × 10−5 M) could be reversibly controlled by adjusting the solution pH, which was ascribed to the association and disassociation of the host−guest complex. 6.7.2. Supramolecular Hybrid Nanostructures Based on Pillar[6]arene Modified Gold Nanoparticles/Nanorods and Their Application in pH- and NIR-Triggered Controlled Release. On the basis of WP6A/paraquat recognition, Huang and co-workers prepared hybrid supramolecular amphiphiles by employment of WP6A modified gold nanoparticles/nanorods and an amphiphilic paraquat derivative (PQA) (Figure 53).528 Upon addition of PQA (0.0400 mM) into a solution of WP6A stabilized AuNPs, hybrid micelles were obtained with an average diameter of about 3.2 nm, because the hydrophilic parts of this hybrid system were much larger than the hydrophobic parts. Therefore, these hybrid micelles were almost hydrophilic and monodispersed in water. When the concentration of PQA increased to 0.100 mM, the hybrid supramolecular amphiphile self-assembled into spherical micelles (∼10 nm) with the WP6A stabilized AuNPs as the coronas and the hydrophobic groups as the cores, because the hydrophobic part of the hybrid supramolecular amphiphile became larger. Due to the pH-responsive host−guest complexation between WP6A and the paraquat group, the obtained micelles could be used to encapsulate hydrophobic Nile Red, which was released from the hydrophobic cores of the micelles by decreasing the solution pH due to the destruction of the hybrid micelles. By further increasing the concentration of PQA to 0.150 mM, the hybrid supramolecular amphiphile aggregated into

Figure 53. (a) Chemical structures of hydrophobic chain functionalized paraquat derivative PQA and a water-soluble pillar[6]arene WP6A and schematic illustration of self-assembly of WP6A stabilized gold nanoparticles and PQA into various hybrid nanostructures in water. (b) Schematic representation of a NIR-triggered vesicle-tomicelle transition and the subsequent release of encapsulated calcein. Reproduced with permission from ref 528. Copyright 2014 The Royal Society of Chemistry.

multilayer onion-like micelles with an average diameter of ∼250 nm. The morphological transition from spherical micelles to onion-like disks was caused by the improvement of hydrophobicity of the supramolecular hybrid amphiphile. The interfacial tension became so large as to overwhelm the other free energy terms, resulting in complete stretching of the core and forming a flat interface. More interestingly, hollow vesicles composed of an inside cavity and an outer thick wall formed when the concentration of PQA was further raised to 0.250 mM. Owing to the more extensive hydrophobicity of the hybrid system relative to the hydrophilic part under this condition, the steric hindrance became greater, thus forming a vesicular structure with low curvature. Furthermore, hybrid vesicles ∼500 nm in diameter were prepared by utilizing WP6A stabilized gold nanorods (AuNRs) as the hydrophilic part of the supramolecular amphiphile instead of WP6A stabilized AuNPs (WP6A/PQA = 1.6:1). AuNRs possess excellent photothermal conversion capability that rapidly converts the light absorbed at their SPR wavelengths into thermal energy to heat up the surrounding medium. NIR-induced deconstruction of the nanorod hybrid vesicles into irregular aggregates was induced by irradiating with a 785 nm diode laser at 2 W/cm2 for 2 min (Figure 53b). The encapsulated hydrophilic calcein fluorescent probe was released from the vesicles associated with the collapse of the hybrid vesicles caused by the increase of the solution temperature. On the other hand, the loaded calcein was released from the hybrid vesicles in response to a pH decrease because of the pHresponsiveness of WP6A. The development of supramolecular hybrid amphiphiles on the basis of stimuli-responsive host− guest recognition can enable their broad applications in biosensing, multimodality imaging, and theranostic nanomedicine. AU

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6.8. Water-Soluble Pillar[6]arene-Based Supramolecular Vesicles for Drug Delivery

Over the past several decades, targeted drug delivery systems (DDSs) have drawn strong attention from both the pharmacology and chemistry fields.529−533 A major goal in drug delivery is to effectively deliver drugs to their intended biological target without deleterious side effects. Various biocompatible nanoparticles or hollow vesicles with different nanostructures and compositions, such as metals, quantum dots, polymers, oxides, and nanomagnets, have been employed as DDSs to cancer cells.534−539 Among them, supramolecular aggregates self-assembled from supramolecular amphiphiles with stimuli-responsive properties are extremely promising in developing DDSs, because they can not only self-assemble into well-defined structures, but also undergo conformational transitions in response to environmental stimuli.540−542 However, only few nanocarriers based on supramolecular amphiphiles driven by host−guest interactions between macrocyclic hosts and guests have been reported. Construction of stimuli-responsive DDSs from novel supramolecular amphiphiles through host−guest interactions is of great interest and importance in application of drug/gene delivery. Wang and co-workers reported a novel pillar[6]arene-based host−guest molecular recognition motif between ferrocenium and per-butylated pillar[6]arene in organic solvent.543 The neutral ferrocene exhibited weak binding affinity, while ferrocenium strongly binds per-butylated pillar[6]arene. This redox-responsive molecular recognition motif was quite different from that of ferrocene/ferrocenium with β-CD in aqueous solution, where ferrocene could bind β-CD strongly through hydrophobic interactions in aqueous solution, while the binding affnity between ferrocenium and β-CD was extremely low. Furthermore, Wang and co-workers developed a new ferrocene/WP6S moelcular recognition motif in water by using the hydrophobic cavity of the water-soluble macrocycle (Figure 54).544 The association constant of the host−guest complex WP6S⊃42 could reach 1.27 × 105 M−1 with a 1:1 binding stoichiometry. After oxidation of ferrocene to ferrocenium, the related association constant with WP6S was enhanced to be 8.68 × 107 M−1, much higher than that of WP6S⊃42 due to the participation of electrostatic interactions between ferrocenium and anionic WP6S. The host−guest inclusion complex WP6S⊃42 possessed an amphiphilic property where the WP6S residue exhibited hydrophilicity and the alkyl chain residue showed hydrophobicity. This inclusion complex acted as a supramolecular amphiphile in water with the best molar ratio of 1:20 (WP6S:42), and a CAC value of 1.27 × 10−4 M. WP6S⊃42 self-assembled into hollow spherical morphology with an average diameter of ∼130 nm (Figure 54a). The thickness of the hollow vesicles was ∼7 nm (Figure 54b), confirming that the vesicles possessed a bilayered structure with two hydrophilic carboxylate shell layers and one hydrophobic alkyl chain core layer. The self-assembly of the supramolecular amphiphile showed pH sensitivity. The binary vesicles disassembled at pH 6.0, which was ascribed to the pH-responsiveness of WP6S (Figure 54c). Considering the low cytotoxicity, these supramolecular vesicles were further used as nanocarriers to encapsulate anticancer drug mitoxantrone (MTZ) with the encapsulation efficiency of 11.2% (Figure 54e,f). The release behavior of MTZ from the vesicles could be controlled by regulating the

Figure 54. Top: schematic illustration of the formation of supramolecular vesicles and their pH-responsive drug release. TEM images: (a) WP6S + 42 aggregates; (b) enlarged image of (b); (c) WP6S + 42 aggregates after the solution pH was adjusted to 6.0; (d) WP6S + 42 aggregates after the solution pH was adjusted to 7.4; (e, f) MTZloaded vesicles. (g) Effect of unloaded vesicles, MTZ, and MTZloaded vesicles on viability of NIH3T3 cells at different times. (h) Anticancer activity of free MTZ and MTZ-loaded vesicles in SMMC7721 cells at different times. Reproduced with permission from ref 544. Copyright 2013 American Chemical Society.

solution pH. Rapid release was observed under acidic condition in the first 5 min by a pH triggered vesicle collapse. The cytotoxicity of MTZ-loaded vesicles was effectively reduced to normal cells (Figure 54g), whereas the MTZ-loaded vesicles exhibited comparable anticancer activity in vitro as free MTZ to cancer cells (Figure 54h). The reason was that the MTZ-loaded vesicles showed excellent stability in the physiological environment (pH = 7.4), and disassembled in cancer cells due to their weakly acidic intracellular environment. This study suggests that such supramolecular vesicles constructed from the supramolecular amphiphile WP6S⊃42 in water have great potential applications in controlled release and drug delivery. Recently, Wang and co-workers developed a new molecular recognition motif between WP6S and a pyridinium salt-based guest, and constructed a multi-stimuli-responsive supramolecular amphiphile.545 This supramolecular amphiphile selfassembled into binary vesicles, which exhibited pH-, Ca2+-, and thermal- responsivenesses. Interestingly, the encapsulated calcein in the vesicles could be released either by adjusting the solution pH to acidic condition, or by adding a certain amount of Ca2+ due to the disruption of vesicules. More importantly, an anticancer drug (DOX) could be successfully loaded in the hydrophobic Stern layer of the vesicles, and the loaded DOX was released from the vesicles efficiently with the pH adjustment or the introduction of Ca2+. As a consequence, AV

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the cytotoxicity of the drug-loaded vesicles was reduced obviously to normal cells, while the therapeutic effect for cancer cells was maintained.

7. SUPRAMOLECULAR AMPHIPHILES CONSTRUCTED BY OTHER MACROCYCLE-BASED HOST−GUEST MOLECULAR RECOGNITIONS In addition to the above-discussed macrocyclic hosts (including crown ethers, cyclodextrins, calixarenes, cucurbiturils, and pillararenes), other macrocycles can also be employed in the fabrication of supramolecular amphiphiles. Furthermore, functional groups can be introduced into these hosts, endowing the obtained supramolecular systems with interesting properties. Although the reports on the supramolecular amphiphiles constructed from other macrocycle-based host−guest molecular recognition motifs are not so rich, the distinctive molecular motifs between these hosts and the corresponding guests as well as the packing modes of the resultant supramolecular amphiphiles inevitably bring something fresh and unique into this field. 7.1. Switchable Nanoporous Sheets from Aqueous Self-Assembly of Aromatic Macrobicycles

Lee and co-workers employed an aromatic macrobicycle 43 with a hydrophilic oligoether dendron attached to its basal plane as a building block to prepare 2D porous sheets in aqueous solution (Figure 55).546 Driven by π−π stacking interactions, 43 formed dimeric micelles with a face-to-face stacking of the aromatic basal diacetylene groups, which were polymerized to generate covalently linked dimers by irradiation of the solution with UV light for 6 h. These small, discrete micelles (approximately 3.5 nm in diameter) further aggregated laterally through side-to-side hydrophobic interactions to form nanosheets (Figure 55a), which was attributed to the slipped packing arrangement of the very thin aromatic cores. As monitored by high-resolution TEM (Figure 55b), the rugged surfaces of the nanosheets were covered with uniform micelles and in-plane nanopores with an average diameter of around 4 nm. Coronene acted as a guest molecule through π−π stacking interactions and hydrophobic interactions in aqueous solution. Upon addition of coronene, a bola-type supramolecular amphiphile formed with the aromatic host−guest complex as the hydrophobic segment and the oligoether dendrons as the hydrophilic part. The flat conjugated aromatic guest was sandwiched between the two aromatic basal planes of the dimeric micelles, improving the layer thickness from 2.1 to 2.5 nm (Figure 55f). By formation of host−guest complexes, the in-plane dimeric micelles packed more tightly due to the conformational inversion of the basal planes. As a result, the diameter of the in-plane micelles decreased effectively from 3.5 to 2.5 nm (Figure 55d), concurrent with the disappearance of the nanopores in the sheets (Figure 55e). The increased thickness of the aromatic cores and the nonslipped arrangement of the aromatic basal planes increased the hydrophobicity of the supramolecular amphiphile upon intercalation of coronene, which strengthened the side-to-side hydrophobic interactions, thus closing the nanopores. Upon removal of the coronene by extraction with toluene, the sheets reverted to the original state with a porous structure. Notably, the open/closed gating motion of the in-plane nanopores were regulated reversibly without affecting the 2D structure. The permeability of the porous sheets was easily adjusted by reversibly

Figure 55. Top: molecular structure and schematic representation of 43 with dendrons attached to its basal plane. Cryo-TEM images: (a) 43 (200 μM); (d) 43⊃coronene (100 μM). Negatively stained TEM images: (b) 43 (100 μM); (e) 43⊃coronene (100 μM). The insets show magnified images and the line profiles along the yellow lines. AFM images and the corresponding cross-sectional analyses: (c) 43 (50 μM); (f) 43⊃coronene (50 μM). Reproduced with permission from ref 546. Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

controlling the pores in the open state or the closed state, making these self-assemblies potentially useful as intelligent materials with simultaneous biological and electro-optical functions. 7.2. Multi-Stimuli-Responsive Supramolecular Diblock Copolymers

Mechanically interlocked molecules (MIMs), particularly catenanes and rotaxanes, have attracted increasing attention not only because of their topological importance, but also due to their application in the fabrication of nanodevices, functional supramolecular polymers, artificial molecular machines, and so AW

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on.547−549 Developed by Stoddart and collaborators, cyclobis(paraquat-p-phenylene) (CBPQT4+) , a rigid tetracationic cyclophane with two 4,4′-bipyridinium units locked in place at 7 Å separation, has been investigated extensively as a ring when employing templates to make MIMs.550 Mainly driven by dipole−dipole and charge-transfer interactions, this electrondeficient cyclophane has been widely employed as a molecular host to encircle electron-rich guests, such as hydroquinone (HQ), 1,5-dioxynaphthalene (DNP), and tetrathiafulvalene (TTF), to fabricate various sophisticated architectures.551,552 On the basis of the molecular recognition between CBPQT4+ and TTF (or DNP), multi-stimuli-responsive supramolecular diblock copolymers were constructed by Stoffelbach, Cooke, Woisel, and co-workers.553 A novel CBPQT4+ end-functionalized poly(n-butyl acrylate) 44 prepared through reversible addition−fragmentation chain transfer (RAFT) polymerization was used as a macromolecular host, and 46a (46b, 47a, or 47b) acted as the complementary guest (Figure 56). It should be emphasized that both the nature of the guest and the polymer chain played significant roles in the association constants. Due to the stronger π-electron donor character of the TTF unit, 47a (or 47b) exhibited stronger binding affinity with 44 than 46a (or 46b).

These pseudorotaxane-like supramolecular diblock copolymers showed multiple responsivenesses to stimuli, such as electrochemical oxidation/reduction, temperature changes, and the addition of competitive (macro) molecular guests (Figure 56a). Effective decomplexation occurred at relatively high temperature (343 K), and the host−guest complex reformed at low temperature (288 K) due to the dynamic nature of the host−guest interactions. Upon reduction of the CBPQT4+ unit into its diradical dicationic state or oxidation of TTF group into its cationic form, guest 47b dethreaded from the CBPQT2·+ cavity, resulting in the disassociation of the supramolecular polymeric amphiphile. Additionally, the diblock polymer 44/ 46a was disrupted (upon addition of TTF) or transformed into a new diblock polymer (upon addition of 47b) by competitive complexation, because the binding affinity of CBPQT2·+⊃TTF was higher than that of CBPQT2·+⊃DNP. The supramolecular diblock polymer 44/47b self-assembled into micelles with a diameter of around 24 nm (Figure 56b), in good agreement with the result obtained from cryo-TEM (Figure 56c). Moreover, the morphology of the self-assembly was closely related to the sample preparation. As depicted in the AFM images, 44/47b in spin-coated solution was favored to form spherical micelles (Figure 56d), whereas the drop-cast films containing 44/47b preferred to form a lamellar-type phase (Figure 56e). For the thin film obtained by spin coating from an equimolar solution of 47b and a control poly(n-butyl acrylate) without CBPQT4+ unit, only rough macrophase domains existed, confirming that the supramolecular linkage played a significant role in the self-assembly process. Zhao, Li, and co-workers also utilized CBPQT4+/TTF molecular recognition to regulate the self-assembly of a TTFbased molecule bearing two amide side chains.554 The amphiphilic guests aggregated face-to-face into monolayered vesicles in methanol where the peripheral aliphatic chains might fold to entangle each other along the TTF cores and the more polar amide units might be exposed to the polar solvent. The driving forces for the formation of the vesicles mainly came from the cooperativity of π−π stacking between their TTF units, van der Waals force between the appended alkyl chains, and S···S interactions of the TTF units. The vesicles formed by the guest alone were transformed into microtubes immediately by adding CBPQT4+ to a mixture of acetonitrile and water (97:3) due to the host−guest interactions between CBPQT4+ and TTF group (Ka = 4400 M−1). The microtubes possessed a bilayered structure (wall thickness ∼3.4 nm) with the hydrophilic complexed parts being exposed to the polar environment. Furthermore, the morphological transformation between vesicles and microtubes was manipulated reversibly by introducing pristine TTF into the supramolecular system due to its competitive complexation. 7.3. Assembly of Amphiphilic Baskets into Stimuli-Responsive Vesicles

An amphiphilic molecular basket 48 with three positively charged groups at the northern edge and the larger hydrophobic segment on its southern edge was elegantly created by Badjić and co-workers (Figure 57).555 This deep cavity host (V = 477 Å3) effectively encapsulated organophosphorus nerve agents. The basket 48 (1.0 mM) self-assembled into vesicles 200−500 nm in diameter with an average hydrodynamic diameter of 350 nm (Figure 57a). The membrane thickness of the vesicles was estimated to be 4 nm (Figure 57b), close to two extended lengths of 48 (1.8 nm), demonstrating that the

Figure 56. Top: chemical structures of CBPQT4+, 44, 45, 46, and 47. (a) Schematic representation of multi-stimuli-responsive supramolecular diblock copolymers. (b) DLS data for 47b and 44/47b in water at 298 K at 0.5 mM. (c) Cryo-TEM image for micelles obtained from 44/47b in water at 298 K at 0.5 mM. AFM topographic images of 44/47b thin films (∼150 nm) self-assembled on glass substrates prepared by spin-coating (d) and drop-casting (e) from a THF solution of 44/47b at 5 wt %. Reproduced with permission from ref 553. Copyright 2014 The Royal Society of Chemistry. AX

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recognition of anions mainly through electrostatic interactions. Sessler and co-workers developed a novel imidazolium-based tetracationic cyclophane, namely a “Texas-sized” molecular box, which could be utilized as a sophisticated supramolecular host to complex anionic guests with different sizes and charges within its central core.561 Kumar et al. designed a benzimidazolium-based tetracationic cyclophane BIMCP-1, and further fabricated a supramolecular amphiphile by employing sodium dodecylbenzenesulfonate SDBS (or sodium dodecyl sulfate, SDS) as the guest (Figure 58).562 By the formation of 1:2 stoichiometric host−guest

Figure 57. Top: chemical structures of 48 and DMPP. (a, b) TEM images of 48 (1.0 mM in H2O) deposited on a copper grid and stained with uranyl acetate. Proposed packing of basket 48 in the bilayer of vesicles. (c) DLS result for 48 (1.0 mM in H2O) containing DMPP (19.4 mM). (d) HR-TEM image of an H2O solution of 48 (1.0 mM) containing DMPP (19.4 mM). Reproduced with permission from ref 555. Copyright 2013 American Chemical Society.

Figure 58. Top: chemical structures of BIMCP-1, SDBS, and SDS. SEM (a, b) and confocal (c, d) images, respectively, of BIMCP-1 with SDBS (a,c) and SDS (b,d). (e) Enlarged image of part a. (f) Enlarged image of part e. (g) Model for encapsulation of the anionic surfactant showing electrostatic/π−π interactions with hydrophobic tails extending outside for stabilization: (h) lateral view of part f; (i) top to bottom view of part f. Reproduced with permission from ref 562. Copyright 2013 American Chemical Society.

two baskets packed in a tail-to-tail way to form a curved unilamellar membrane. The hydrophobic cages stayed inside the lipid-like bilayer, whereas the hydrophilic ammonium caps resided at the outer edges exposed to water. Upon addition of dimethyl phenylphosphonate (DMPP, 184 Å3) to an aqeuous solution of 48, the host−guest complex 48⊃DMPP formed mainly driven by hydrophobic interactions with an association constant of 1.3 × 103 M−1. Taking into account the host−guest interactions, a supramolecular amphiphile was obtained with the P−C6H5 group oriented in the cavity of 48. In sharp contrast with the vesicular structure formed by 48 alone, 1⊃DMPP self-aseembled into multilayer nanoparticles with a diameter of ∼100 nm (Figure 57c). The morphological transformation from vesicles to nanoparticles originated from the change in the shape of 48, which affected its packing mode (Figure 57d). As a consequence, the critical packing parameter decreased from ∼0.59 to ∼0.32 upon addtion of DMPP to render the aggregation of the host−guest complexes into nanoparticles.

complexes, the CAC value decreased significantly from 1.5 mM to