Dendrimer-conjugated isotretinoin for controlled transdermal drug delivery.

BACKGROUND: In the present study, we aimed to develop a novel isotretinoin delivery model for treating skin diseases, revealing its potential advantages in drug delivery and targeted therapy. Using a self-assembly strategy, we grafted a dendrimer, based on a well-defined branched structure for nanomedical devices, with a well-defined nanoarchitecture, yielding spherical, highly homogeneous molecules with multiple surface functionalities. Accordingly, a self-assembled dendrimer-conjugated system was developed to achieve the transdermal delivery of isotretinoin (13cRA-D). RESULTS: Herein, 13cRA-D showed remarkable controlled release, characterized by slow release in normal tissues but accelerated release in tissues with low pH, such as sites of inflammation. These release characteristics could abrogate the nonteratogenic side effects of isotretinoin and allow efficient skin permeation. Moreover, 13cRA-D exhibited high therapeutic efficacy in acne models. Based on in vitro and in vivo experimental results, 13cRA-D afforded better skin penetration than isotretinoin and allowed lesion targeting. Additionally, 13cRA-D induced minimal skin irritation. CONCLUSION: Our findings suggest that 13cRA-D is a safe and effective isotretinoin formulation for treating patients with skin disorders.

Spontaneous Chirality Induction in the Assembly of a Single Layer 2D Network with Switchable Pores.

Although two-dimensional (2D) chiral sheet structures are attractive because of their unique chemical and physical properties, single layer 2D chiral network structures with switchable pore interior remain elusive. Here we report spontaneous chirality induction in a single layer 2D network structure formed from the self-assembly of tetrapod azobenzene molecules. The chirality induction arises from multiple sublayers slipped in a preferred direction in which the sublayer consists of unidentical molecular arrangements in the in-plane a and b directions, breaking both the plane of symmetry and inversion symmetry. The protruded azobenzene units in the pore interior can be selectively isomerized upon UV irradiation, resulting in a reversible deformation of the chiral pores while maintaining the 2D frameworks. The chiral network can thus selectively entrap one enantiomer from a racemic solution with near perfect enantioselectivity, and then release it upon UV irradiation.

Switchable Aromatic Nanopore Structures: Functions and Applications.

Nanopore structures in nature play a crucial role in performing many sophisticated functions such as signal transduction, mass transport, ion channel, and enzyme reaction. Inspired by pore-forming proteins, considerable effort has been made to design self-assembling molecules that are able to form nanostructures with internal pores in aqueous media. These nanostructures offer ample opportunity for applications because their internal pores are able to perform a number of unique functions required for a confined nanospace. However, unlike nanopore assembly in nature, the synthetic nanopore structures are mostly based on a fixed pore that impedes performing adaptable regulation of properties to environmental change. This limitation can be overcome by integration of hydrophilic oligo(ethylene oxide) dendrons into aromatic building blocks for nanopore self-assembly, because the dendritic chains undergo large conformational changes triggered by environmental change. The transition of the oligoether chains triggers the aromatic nanopore assembly to undergo reversible pore deformation through closing, squeezing, and shape change without structural collapse. These switching properties allow the aromatic nanopore structures to perform adaptable, complex functions which are difficult to achieve using a fixed pore assembly.In this Account, we summarize our recent progress in the development of switchable nanopore structures by self-assembly of rigid aromatic amphiphiles grafted by hydrophilic oligo(ethylene oxide) dendrons in aqueous media. We show that combining oligoether chains into aromatic segments generates switchable aromatic nanopore structures in aqueous media such as hollow tubules, toroidal structures, and 2D porous sheets depending on the shape of the aromatic building block. Next, we discuss the chemical principle behind the switching motion of the aromatic nanopore structures triggered by external stimuli. We show that the internal pores of the aromatic nanostructures are able to undergo reversible switching between open-closed or expanded-contracted states triggered by external stimuli such as temperature, pH, and salts. In the case of toroidal structures, closed ring-like aromatic frameworks can be spirally open triggered by heat treatment, which spontaneously initiate helical polymerization. Additionally, we discuss switchable functions carried out by the aromatic nanopores such as driving helicity inversion of DNA, consecutive enzymatic action, reversible actuation of lipid vesicles, and pumping of captured guests out of internal pores. By understanding the underlying chemical principle required for dynamic mechanical motion, aromatic assembly can be exploited more broadly to create emergent nanopore structures with functions as complex as those of biological systems.

Self-assembly of propeller-shaped amphiphilic molecules: control over the supramolecular morphology and photoproperties of their aggregates.

The aggregation-induced emission (AIE) effect is an important feature for luminescence studies, which can offer a broader range of applications for fluorescent materials. Herein, we report the morphological control and photoproperties of amphipathic propeller-shaped rod-coil molecules based on a benzene-1,3,5-tricarboxamide (BTA) unit, which restricts the intramolecular rotation and leads to the AIE effect during the self-assembly process. Investigations on the assembly of these molecules have revealed that tetragonal perforated lamella, hexagonal columnar, body-centered tetragonal micellar, and hexagonal close-packed nanostructures were spontaneously formed in the solid-state. In the solution-state, these molecules assemble into nanosheet-like aggregates, bowl-like objects, and spherical nanoparticles, respectively. The morphology of the molecular aggregates can be controlled by modifying the molecular chain length or introducing lateral methyl groups in the coil chain. Notably, these molecular assemblies exhibit strong AIE phenomena in a mixed THF/H2O solution and can be used as smart soft materials due to the restriction of their intramolecular motion.

Porous Nanosheet Assembly for Macrocyclization and Self-Release.

Macrocyclic structures are challenging synthetic targets owing to various potential applications ranging from drug discovery to nanomaterials. Their use, however, is highly limited due to synthetic difficulties arising from an entropic penalty for folding of linear chains. Here, we report single-layered porous nanosheets with 2D ordered internal cavities that act as a highly efficient macrocycle generator, changing linear substrates to release as macrocycles in aqueous methanol solution. The nanosheets with hydrophobic cavities encapsulate a linear substrate with nearly perfect uptake, perform clean cyclization, and then spontaneously release as a pure macrocycle. The self-separation of the macrocycle that precipitates from the solution leads to repeated cycles of macrocycle generation; thereby, the single-layered porous materials enabling catch and release offer a powerful novel strategy for repeated macrocycle generation.

The relationship between molecular structure and supramolecular morphology in the self-assembly of rod-coil molecules with oligoether chains.

Controlling the morphology of rod-coil molecular aggregates is crucial for studying and obtaining functional materials with exceptional properties. In this paper, we report the construction of rod-coil molecular nanoaggregates with well-defined structures. The rod-coil molecules, labeled 1a-1d, consist of a rod section, composed of phenyl and biphenyl groups, and oligoether chains with 7 and 12 repeating units. The final assembled structures showed either oblique or hexagonal columnar structures, depending on the length of the coils in the bulk state. Interestingly, in water, molecules 1a and 1c self-assemble into scrolled nanofibers and cylindrical micelles. Instead, molecules 1b and 1d, which have methyl groups decorated at the interface of the rod and coil sections, self-organize into helical nanofibers and nanorings, respectively. Thus, controlling the length of the coil chains and inserting lateral methyl groups is an effective strategy to construct precise rod-coil molecular assemblies in the bulk and in aqueous solution.

Switching between Stacked Toroids and Helical Supramolecular Polymers in Aqueous Nanotubules.

Although significant advances have been made in supramolecular tubules, reversible polymerization in the tubular walls while maintaining their intact structure remains a great challenge. Here, reversible helical supramolecular polymerization of stacked toroids is reported, while maintaining tubular structures in aqueous solution. At room temperature, the tubules consist of discrete toroid stackings with hydrophobic interior. Upon heating, the tubules based on toroid stackings undergo a reversible helical supramolecular polymerization to transform into helical tubules by interconnecting between spirally open toroids. The helical polymerization arises from a tilting transition of the closed toroids that transform into spirally open toroids driven by the thermal dehydration of a hydrophilic oligoether dendron surrounding the toroid frameworks.

Nanomechanical Properties of a Supramolecular Helix Stabilized by Non-Covalent Interactions.

Supramolecular helices have unique properties and many potential applications, such as chiral separation and asymmetric catalysis. Mechanical property (stability) of the supramolecular helix plays important roles in their functions. Due to the limitation of detection method, it is quite challenging to investigate nanomechanical properties of individual supramolecular helices stabilized by pure supramolecular interactions. Here atomic force microscopy (AFM)-based single molecule force spectroscopy (SMFS) is used to study the nanomechanical properties of a thermal-responsive supramolecular helix. The unwinding force plateau is observed in the force-extension curve, and the rupture force of the helix is dependent on the loading rate. In addition, the force-induced unwinding process is reversible and there is almost no energy dissipation in the process. Furthermore, the result of thermal shape-fluctuation analysis shows that the persistence length of the supramolecular helix is about 222 nm, which is much larger than helical structure formed by double-stranded DNA (dsDNA). However, because of its unique backbone structure, the supramolecular helix exhibits higher dynamic flexibility during force-induced deformation, since the persistence length determined from the stretching experiment is much smaller (1.1 nm).

Two-Dimensional Cationic Networks and Their Spherical Curvature with Tunable Opening-Closing.

Despite many cationic nanomaterials that have been developed for efficient adsorption of anionic pollutants, tailoring a stable shape with denser cations on the surface for advanced removal capability remains challenging. Here, a new strategy is presented for fabricating two-dimensional (2D) cationic laminas and their curvature based on cross-linking of 2D supramolecular networks from hydrogen-bonded trimesic amide derivatives. Owing to the distribution of most cations on the surface, two cationic nanostructures from cross-linking of supramolecular networks show fast sorption kinetics for anionic pollutants. Notably, the removal capacity of the capsule-like curvature adsorbent is more than twice that of lamina  adsorbent for sufficient space around cationic sites in hollow aperture. Moreover, the capsule-like adsorbent is triggered to open and spontaneously release the adsorbed pollutants upon the addition of halogen anions, which can be recovered by subsequent dialysis. Strategy of a capsule-like pocket with tunable opening-closing will provide a new insight for storage and adsorption.

Single-Layered Chiral Nanosheets with Dual Chiral Void Spaces for Highly Efficient Enantiomer Absorption.

Although considerable effort in recent years has been devoted to the development of two-dimensional nanostructures, single-layered chiral sheet structures with a lateral assembly of discrete clusters remain elusive. Here, we report single-layered chiral 2D sheet structures with dual chiral void spaces in which discrete clusters of planar aromatic segments are arranged with in-plane AB order in aqueous methanol solution. The chirality of the sheet is induced by the slipped-cofacial stacks of rectangular plate-like aromatic segments in the discrete clusters which are arranged laterally with up and down packing, resulting in dual chiral void spaces. The chiral nanosheets function as superfast enantiomer separation nanomaterials, which rapidly absorb a single enantiomer from a racemic mixture with greater than 99 % ee.

Asymmetric Transformation Driven by Confinement and Self-Release in Single-Layered Porous Nanosheets.

Reported here is the use of single-layered, chiral porous sheets with induced pore chirality for repeatable asymmetric transformations and self-separation without the need for chiral catalysts or chiral auxiliaries. The asymmetric induction is driven by chiral fixation of absorbed achiral substrates inside the chiral pores for transformation into enantiopure products with enantioselectivities of greater than 99 % ee. When the conversion is completed, the products are spontaneously separated out of the pores, enabling the porous sheets to perform repeated cycles of converting achiral substrates into chiral products for release without compromising pore performance. Confinement of achiral substrates into two-dimensional chiral porous materials provides access to a highly efficient alternative to current asymmetric synthesis methodologies.

Impact of Positional Isomerism on Pathway Complexity in Aqueous Media.

Pathway complexity has become an important topic in recent years due to its relevance in the optimization of molecular assembly processes, which typically require precise sample preparation protocols. Alternatively, competing aggregation pathways can be controlled by molecular design, which primarily rely on geometrical changes of the building blocks. However, understanding how to control pathway complexity by molecular design remains elusive and new approaches are needed. Herein, we exploit positional isomerism as a new molecular design strategy for pathway control in aqueous self-assembly. We compare the self-assembly of two carboxyl-functionalized amphiphilic BODIPY dyes that solely differ in the relative position of functional groups. Placement of the carboxyl group at the 2-position enables efficient pairwise H-bonding interactions into a single thermodynamic species, whereas meso-substitution induces pathway complexity due to competing hydrophobic and hydrogen bonding interactions. Our results show the importance of positional engineering for pathway control in aqueous self-assembly.

Precisely Controlled Multidimensional Covalent Frameworks: Polymerization of Supramolecular Colloids.

Rapid and selective removal of micropollutants from water is important for the reuse of water resources. Despite hollow frameworks with specific functionalized porous walls for the selective adsorption based on a series of interactions, tailoring a stable shape of nanometer- and micrometer-sized architectures for the removal of specific pollutants remains a challenge. Here, exactly controlled sheets, tubes, and spherical frameworks were presented from the crosslinking of supramolecular colloids in polar solvents. The frameworks strongly depended on the architecture of original supramolecular colloids. As the entropy of colloids increased, the initial laminar framework rolled up into hollow tubules, and then further curled into hollow spheres. These shape-persistent frameworks showed unprecedented selectivity as well as specific recognition for the shape of pollutants, thus contributing to efficient pollutant separation.

Substrate-Driven Transient Self-Assembly and Spontaneous Disassembly Directed by Chemical Reaction with Product Release.

The chemical reactivity of molecules can be significantly enhanced when they are trapped in a confined space. Although such a confinement effect can be found in many self-assembled nanostructures, dissipation after completing the reaction to release the product remains elusive. Here we report substrate-directed transient self-assembly for accelerating a chemical reaction and spontaneous disassembly with releasing the products. The hydrophobic substrates mediate self-assembly of a dissolved pyridine-based amphiphile to provide a confined space to promote an aromatic nucleophilic substitution (SNAr) reaction in water. The chemical reaction triggers disassembly of the aggregates with simultaneous release of the product that can be spontaneously separated out of the solution by precipitation. Neutralization of the amphiphilic molecule leads to a new cycle of self-assembly entrapping substrates and disassembly with releasing the product.

Homochiral porous nanosheets for enantiomer sieving.

Protein pores are highly specific in binding to chiral substrates and in catalysing stereospecific reactions, because their active pockets are asymmetric and stereoselective1,2. Chiral binding materials from molecular-level pores with high specificity have not been achieved because of problems with pore deformation and blocking 3 . A promising solution is the self-assembly of single sheets where all pores are exposed to the environment, for example as metal-organic frameworks 4 , polymers5,6 or non-covalent aromatic networks7-10, but, typically, the pores are distant from the internal cavities with chirality. Here, we report the synthesis of homochiral porous nanosheets achieved by the 2D self-assembly of non-chiral macrocycles, with open/closed pore switching. Pore chirality is spontaneously induced by a twisted stack of dimeric macrocycles. The porous 2D structures can serve as enantiomer sieving membranes that exclusively capture a single enantiomer in a racemic mixture solution, with uptake capacity greater than 96%. Moreover, the entrapped guests inside the pores can be pumped out by pore closing triggered by external stimuli. This strategy could provide new opportunities for controlled molecule release, as well as for artificial cells.

Short Peptides Directing 1D Helical Arrays of Polyoxometalates with Controllable Pitches.

A series of cationic peptides with alternating hydrophilic and hydrophobic residues were elaborately designed and synthesized. These kinds of short peptides with protonated lysine groups can interact with anionic polyoxometalate nanoclusters through multivalent ionic bonds and hydrogen bonds, resulting in the formation of helical polyoxometalate arrays in aqueous solution. Fourier transform infrared (FTIR) spectroscopy, circular dichroism (CD), transmission electron microscopy (TEM), and dynamic light scattering (DLS) were utilized to characterize the self-assembled structures. TEM revealed that the polyoxometalate clusters form periodic arrays within the helical nanofibers. This work reports that the handedness of the helical fibers was attributed to the precise chirality expression of peptides. The l-type peptide directed the formation of left-handed polyoxometalate arrays, whereas right-handed polyoxometalate arrays were observed when the peptide was constituted by d-amino acids. It was also found that the pitch of the helical nanofibers is inversely proportional to the hydrophobicity of peptides with less hydrophobicity giving a larger helical pitch.

Supramolecular Nanotubules as a Catalytic Regulator for Palladium Cations: Applications in Selective Catalysis.

Despite the recent development of highly efficient and stable metal catalysts, conferral of regulatory characteristics to the catalytic reaction in heterogeneous systems remains a challenge. Novel supramolecular nanotubules were prepared by alternative stacking from trimeric macrocycles, which was found to be able to coordinate with Pd cations. The Pd complexes exhibited a high catalytic performance for C-C coupling reaction. Notably, the tubular catalyst was observed to be controlled by supramolecular reversible assembly and showed superior heterogeneous catalytic activity, which was maintained for a number of cycles or reuse under an aerobic environment. Furthermore, the supramolecular catalyst showed unprecedented selectivity for the multifunctional coupling reaction and was able to serve as a new constructor of asymmetrical compounds.

Reversible, Short α-Peptide Assembly for Controlled Capture and Selective Release of Enantiomers.

Although significant progress has been achieved with short peptide nanostructures, the construction of switchable membrane assemblies remains a great challenge. Here we report short α-peptide assemblies that undergo thermo-reversible switching between assembly and disassembly states, triggered by the conformational change of laterally grafted short peptides from a folded α-helix to a random coil conformation. The α-helical peptide based on two oligoether dendron side groups forms flat disks, while the peptide helix based on three dendron side groups forms hollow vesicles. The vesicular membrane can spontaneously capture a racemic mixture through the self-formation of vesicular containers upon heating and enantioselectively release the chiral guest molecule through preferential diffusion across the vesicular walls.

Engineering the Ionic Self-Assembly of Polyoxometalates and Facial-Like Peptides.

The self-assembly behavior of polyoxometalates (PMs) and facial-like cationic peptides carrying lysine residues were systematically investigated. Circular dichroism and UV/Vis spectra demonstrated that the multivalent electrostatic attractions between polyanionic PMs and short peptides with protonated lysine residues initiated the conformational transition of peptide molecules from random-coil to ß-sheet state, and subsequently the co-assembly. TEM and atomic force microscopy (AFM) measurements showed that uniform nanofibers formed with decreasing size of the PMs or increasing the intermolecular forces of the peptides, such as through hydrogen-bonding, hydrophobic, and/or π-π interactions. Additionally, the stability of the nanostructures can be improved by rational suppression of the electrostatic repulsion of the shell peptides covering the surface of the nanostructures. These results provide new insight into understanding the ionic self-assembly of peptides and PMs and controlling their final morphology.

Switching of carbohydrate nanofibers for regulating cell proliferation.

We report switchable, fluorescent carbohydrate nanofibers formed through the self-assembly of aromatic rod amphiphiles with a combination of mannose epitopes and thermoresponsive oligoether dendrons. The carbohydrate nanofibers undergo reversible switching between carbohydrate-exposed and hidden states on their surface in response to a thermal signal, and have the ability to regulate cell proliferation.