Stimuli-Responsive Transformable Supramolecular Nanotubes.

Supramolecular nanotubes produced by self-assembly of organic molecules can have unique structural features such as a one-dimensional morphology with no branching, distinguishable inner and outer surfaces and membrane walls, or a structure that is hollow and has a high aspect ratio. Incorporation of functional groups that respond to external chemical or physical stimuli into the constituent organic molecules of supramolecular nanotubes allows us to drastically change the structure of the nanotubes by applying such stimuli. This ability affords an array of controllable approaches for the encapsulation, storage, and release of guest compounds, which is expected to be useful in the fields of physics, chemistry, biology, and medicine. In this article, I review the supramolecular nanotubes developed by our group that exhibit morphological transformations in response to pH, chemical reaction, light, temperature, or moisture.

Soft-Matter Nanotubes: A Platform for Diverse Functions and Applications.

Self-assembled organic nanotubes made of single or multiple molecular components can be classified into soft-matter nanotubes (SMNTs) by contrast with hard-matter nanotubes, such as carbon and other inorganic nanotubes. To date, diverse self-assembly processes and elaborate template procedures using rationally designed organic molecules have produced suitable tubular architectures with definite dimensions, structural complexity, and hierarchy for expected functions and applications. Herein, we comprehensively discuss every functions and possible applications of a wide range of SMNTs as bulk materials or single components. This Review highlights valuable contributions mainly in the past decade. Fifteen different families of SMNTs are discussed from the viewpoints of chemical, physical, biological, and medical applications, as well as action fields (e.g., interior, wall, exterior, whole structure, and ensemble of nanotubes). Chemical applications of the SMNTs are associated with encapsulating materials and sensors. SMNTs also behave, while sometimes undergoing morphological transformation, as a catalyst, template, liquid crystal, hydro-/organogel, superhydrophobic surface, and micron size engine. Physical functions pertain to ferro-/piezoelectricity and energy migration/storage, leading to the applications to electrodes or supercapacitors, and mechanical reinforcement. Biological functions involve artificial chaperone, transmembrane transport, nanochannels, and channel reactors. Finally, medical functions range over drug delivery, nonviral gene transfer vector, and virus trap.

Self-Assembly of a Pyridine-Based Amphiphile Complexed with Regioisomeric Dihydroxy Naphthalenes into Supramolecular Nanotubes with Different Inner Diameters.

A pyridine-based amphiphile complexed with 1,5-, 1,6-, 2,6-, or 2,7-dihydroxy naphthalene self-assembled in water to form nanotubes with inner diameters of 46, 38, 24, 18, and 11 nm in which the naphthalene molecules formed J-type aggregates. In contrast, the amphiphile complexed with 1,2-, 1,3-, 1,4-, 1,7-, 1,8-, or 2,3-dihydroxy naphthalene formed nanofibers in which the naphthalene molecules formed H-type aggregates. The inner diameter of the nanotubes strongly depended on the regioisomeric dihydroxy naphthalene. UV-vis, fluorescence, infrared spectroscopy, X-ray diffraction analysis, and differential scanning calorimetry showed that nanotubes with smaller inner diameters had weaker intermolecular hydrogen bonds between the tilted amphiphiles complexed with the naphthalene molecules within the membrane walls and showed larger Stokes shifts in the excimer fluorescence of the naphthalene moiety. These findings should be useful not only for fine-tuning the inner diameters of supramolecular nanotubes but also for controlling the aggregation states of functional aromatic molecules to generate nanostructures with useful optical and electronic properties in water.

Influences of Hydrogen Bonding-Based Stabilization of Bolaamphiphile Layers on Molecular Diffusion within Organic Nanotubes Having Inner Carboxyl Groups.

This paper reports molecular diffusion behavior in two bolaamphiphile-based organic nanotubes having inner carboxyl groups with different inner dimeters (10 and 20 nm) and wall structures, COOH-ONT10nm and COOH-ONT20nm, using imaging fluorescence correlation spectroscopy (imaging FCS). The results were compared to those previously obtained in a similar nanotube with inner amine groups (NH2-ONT10nm). COOH-ONT10nm, as with NH2-ONT10nm, were formed from a rolled bolaamphiphile layer incorporating triglycine moieties, whereas COOH-ONT20nm consisted of four stacks of triglycine-free bolaamphiphile layers. Imaging FCS measurements were carried out for anionic sulforhodamine B (SRB), zwitterionic/cationic rhodamine B (RB), and cationic rhodamine-123 (R123) diffusing within ONTs (1-9 µm long) at different pH (3.4-8.4) and ionic strengths (1.6-500 mM). Diffusion coefficients (D) of these dyes in the ONTs were very small (0.01-0.1 µm2/s), reflecting the significant contributions of molecule-nanotube interactions to diffusion. The D of SRB was larger at higher pH and ionic strength, indicating the essential role of electrostatic repulsion that was enhanced by the deprotonation of the inner carboxyl groups. Importantly, the D of SRB was virtually independent of nanotube inner diameter and wall structure, indicating the diffusion of the hydrophilic molecule was controlled by short time scale adsorption/desorption processes onto the inner surface. In contrast, pH effects on D were less clear for relatively hydrophobic R123 and RB, suggesting the significant contributions of non-Coulombic interactions. Interestingly, the diffusion of these molecules in COOH-ONT20nm was slower than in COOH-ONT10nm. Slower diffusion in COOH-ONT20nm was attributable to relatively efficient partitioning of the hydrophobic dyes into the bolaamphiphile layers, which was reduced in COOH-ONT10nm due to the stabilization of its layer by polyglycine-II-type hydrogen bonding networks. These results show that, by tuning the bolaamphiphile structures and their intermolecular interactions, unique environments can be created within the nanospaces for enhanced molecular separations and reactions.

Supramolecular Nanotube Reactors for Production of Imine Polymers with Controlled Conformation, Size, and Chirality.

A series of supramolecular nanotubes with inner diameters of 1, 4, 9, 12, 16, and 29 nm are prepared from amino acid lipids. The hydrophobic channels of the nanotubes act as reactors for the formation of imine polymers by not only effectively encapsulating the benzaldehyde and diacetyleneamine precursors of the imine monomers but also markedly accelerating imine formation. The nanotube inner diameter determines whether the imine monomers self-assemble into nanoparticles, nanotapes, nanocoils, or twisted nanofibers in the channels. UV-induced polymerization of the diacetylene units in the imine nanostructures followed by decomposition of the nanotubes into molecular dispersions of the constituent amino acid lipids results in expulsion of the polymerized imine nanostructures with retained conformation. The isolated nanocoils and twisted nanofibers retain the helicity and circular dichroism induced by the nanotubes, which exhibits supramolecular chirality, even though the components of the imine monomers are achiral. These supramolecular nanotubes with tunable diameters and functionalizable surfaces can be expected to be useful for the production of polymers with controlled conformation, size, and chirality without the need for rational design or chemical modification of the monomers or optimization of the polymerization conditions.

Diffusion Behavior of Differently Charged Molecules in Self-Assembled Organic Nanotubes Studied Using Imaging Fluorescence Correlation Spectroscopy.

The diffusion behavior of fluorescent molecules within bolaamphiphile-based organic nanotubes (ONTs) was systematically investigated using imaging fluorescence correlation spectroscopy (imaging FCS). Anionic sulforhodamine B, zwitterionic/cationic rhodamine B, or cationic rhodamine 123 was loaded into ONTs having cylindrical hollow structures (ca. 10 nm in inner diameter) with amine and glucose groups on the inner and outer surfaces, respectively. Wide-field fluorescence video microscopy was used to acquire imaging FCS data for dye-doped ONTs in aqueous solutions of different ionic strengths (1-500 mM) at different pH (3.4-8.4). The diffusion behavior of these dyes was discussed on the basis of their apparent diffusion coefficients ( D) that were determined by autocorrelating the time transient of fluorescence intensity at each pixel on an ONT. Molecular diffusion in the ONTs was significantly slowed by the molecule-nanotube interactions, as shown by the very small D (10-1 to 10-2 µm2/s). The pH dependence of D revealed that dye diffusion was basically controlled by electrostatic interactions associated with the protonation of the amine groups on the ONT inner surface. The pH-dependent change in D was observed over a wide pH range, possibly because of electrostatically induced variations in the p Ka of the densely packed ammonium ions on the ONT inner surface. On the other hand, the influence of ionic strength on D was relatively unclear, suggesting the involvement of non-Coulombic interactions with the ONTs in molecular diffusion. Importantly, individual ONTs of different lengths (1-5 µm) afforded similar diffusion coefficients for each type of dye at each solution condition, implying that the properties of the ONTs were uniform in terms of solute loading and release. These results highlight the characteristics of the molecular diffusion behavior within the ONTs and will help in the design of ONTs better suited for use as drug vehicles and contaminant adsorbents.

Shrinkable Nanotubes for Duplex Formation of Short Nucleotides.

Molecular monolayer nanotubes produced by self-assembly of an amphiphile modified with a 2-nitrobenzyl group as a photoresponsive unit are able to encapsulate dinucleotides via electrostatic attraction. Upon photoirradiation, the 18 nm inner diameter of the nanotubes shrinks to less than 2 nm as a result of photochemical cleavage of the 2-nitrobenzyl group in the amphiphile. This shrinking of the nanotube channels leads to a propulsive release of the dinucleotides into the bulk solution and simultaneously accelerates formation of the dinucleotide duplexes. The larger nanotube channels without photoirradiation merely release each dinucleotide into the bulk solution, indicating that the squeezing via transportation in the narrow nanotube channels is necessary for duplex formation. In addition to the size effect, water with a lower polarity confined within the narrow nanotube channels helps to stabilize the energetically unfavorable hydrogen-bonded base pair between the dinucleotides. This system should enable researchers to perform biological reactions that occur only in specific environments and conditions in living organisms.

Thermoresponsive PEG-Coated Nanotubes as Chiral Selectors of Amino Acids and Peptides.

A series of nanotubes with a dense layer of short poly(ethylene glycol) (PEG) chains on the inner surface are prepared by means of a coassembly process using glycolipids and PEG derivatives. Dehydration of the PEG chains by heating increases the hydrophobicity of the nanotube channel and fluorescent-dye-labeled amino acids are extracted from bulk solution. Rehydration of the PEG chains by cooling results in back-extraction of the amino acids into the bulk solution. Because of the supramolecular chirality of the nanotubes, amino acid enantiomers can be separated in the back-extraction procedure, which is detectable with the naked eye as a change in fluorescence as the amino acids are released from the nanotubes. The efficiency and selectivity of the chiral separation are enhanced by tuning the chemical features and inner diameter of the nanotube channels. For example, compared with wide nanotube channels (8 nm), narrow nanotube channels (4 nm) provide more effective electrostatic attraction and hydrogen bond interaction environments for the transporting amino acids. Introduction of branched alkyl chains to the inner surface of the nanotubes enables chiral separation of peptides containing hydrophobic amino acids. The system described here provides a simple, quick, and on-site chiral separation in biological and medical fields.

Preparation and Formation Process of Zn(II)-Coordinated Nanovesicles.

Mixing a glycylglycine lipid and zinc acetate has been reported to form novel supramolecular Zn(II)-coordinated nanovesicles in ethanol. In this study, we investigate in detail the formation of nanovesicles by using three lipids at different temperatures and discuss their formation process. The original lipids show extremely low solubilities and appear as plate structures in ethanol. Within a small window of lipid solubility, the formation of lipid-Zn(II) complexes occurs mainly on the solid surfaces of plate structures. Controlling of the lipid solubility by temperature affects the kinetics of complex formation and the subsequent transformation of the complexes into nanovesicles and nanotubes. An improved method of two-step control of temperature is developed for preparing all the three kinds of nanovesicles. We provide new insights into the formation process of nanovesicles based on several control experiments. A tetrahedral lipid-cobalt(II) complex similarly produces nanovesicles, whereas an octahedral complex gives sheet structures. Mixing of zinc acetate with a ß-alanyl-ß-alanine lipid can only give sheet structures, which lack a polyglycine II hydrogen-bond network and induce no morphological changes. We conclude that the formation of the lipid-Zn(II) complexes on solid plate structures, tetrahedral geometry, and polyglycine II hydrogen-bond network in the complexes shall work cooperatively for the formation of Zn(II)-coordinated nanovesicles.

Spectroscopic imaging studies of nanoscale polarity and mass transport phenomena in self-assembled organic nanotubes.

Synthetic organic nanotubes self-assembled from bolaamphiphile surfactants are now being explored for use as drug delivery vehicles. In this work, several factors important to their implementation in drug delivery are explored. All experiments are performed with the nanotubes immersed in ethanol. First, Nile Red (NR) and a hydroxylated Nile Red derivative (NR-OH) are loaded into the nanotubes and spectroscopic fluorescence imaging methods are used to determine the apparent dielectric constant of their local environment. Both are found in relatively nonpolar environments, with the NR-OH molecules preferring regions of relatively higher dielectric constant compared to NR. Unique two-color imaging fluorescence correlation spectroscopy (imaging FCS) measurements are then used along with the spectroscopic imaging results to deduce the dielectric properties of the environments sensed by mobile and immobile populations of probe molecules. The results reveal that mobile NR molecules pass through less polar regions, likely within the nanotube walls, while immobile NR molecules are found in more polar regions, possibly near the nanotube surfaces. In contrast, mobile and immobile NR-OH molecules are found to locate in environments of similar polarity. The imaging FCS results also provide quantitative data on the apparent diffusion coefficient for each dye. The mean diffusion coefficient for the NR dye was approximately two-fold larger than that of NR-OH. Slower diffusion by the latter could result from its additional hydrogen bonding interactions with polar triglycine, amine, and glucose moieties near the nanotube surfaces. The knowledge gained in these studies will allow for the development of nanotubes that are better engineered for applications in the controlled transport and release of uncharged, dipolar drug molecules.

Cross-sectional structures of a molecular monolayer nanotube explored with SAXS: evidence for the parallel orientation of the headgroups in asymmetric bolaamphiphiles.

We investigated the cross-sectional structure of a molecular monolayer nanotube self-assembled from asymmetric bolaamphiphiles having two different hydrophilic headgroups. Small-angle X-ray scattering measurements clarified that the glucose and amino headgroups form the exterior and interior surfaces of the nanotube, respectively.

Effect of Photoinduced Size Changes on Protein Refolding and Transport Abilities of Soft Nanotubes.

Self-assembly of azobenzene-modified amphiphiles (Glyn Azo, n=1-3) in water at room temperature in the presence of a protein produced nanotubes with the protein encapsulated in the channels. The Gly2 Azo nanotubes (7 nm internal diameter [i.d.]) promoted refolding of some encapsulated proteins, whereas the Gly3 Azo nanotubes (13 nm i.d.) promoted protein aggregation. Although the 20 nm i.d. channels of the Gly1 Azo nanotubes were too large to influence the encapsulated proteins, narrowing of the i.d. to 1 nm by trans-to-cis photoisomerization of the azobenzene units of the Gly1 Azo monomers packed in the solid bilayer membranes led to a squeezing out of the proteins into the bulk solution and simultaneously enhanced their refolding ratios. In contrast, photoinduced transformation of the Gly2 Azo nanotubes to short nanorings (<40 nm) with a large i.d. (28 nm) provided no further refolding assistance. We thus demonstrate that pertubation by the solid bilayer membrane wall of the nanotubes is important to accelerate refolding of the denatured proteins during their transport in the narrow nanotube channels.

Supramolecular Self-Assembly into Biofunctional Soft Nanotubes: From Bilayers to Monolayers.

The inner and outer surfaces of bilayer-based lipid nanotubes can be hardly modified selectively by a favorite functional group. Monolayer-based nanotubes display a definitive difference in their inner and outer functionalities if bipolar wedge-shaped amphiphiles, so-called bolaamphiphiles, as a constituent of the monolayer membrane pack in a parallel fashion with a head-to-tail interface. To exclusively form unsymmetrical monolayer lipid membranes, we focus herein on the rational molecular design of bolaamphiphiles and a variety of self-assembly processes into tubular architectures. We first describe the importance of polymorph and polytype control and then discuss diverse methodologies utilizing a polymer template, multiple hydrogen bonds, binary and ternary coassembly, and two-step self-assembly. Novel biologically important functions of the obtained soft nanotubes, brought about only by completely unsymmetrical inner and outer surfaces, are discussed in terms of protein refolding, drug nanocarriers, lectin detection, a chiral inducer for achiral polymers, the tailored fabrication of polydopamine, and spontaneous nematic alignment.

Imaging fluorescence correlation spectroscopy studies of dye diffusion in self-assembled organic nanotubes.

The rate and mechanism of diffusion by anionic sulforhodamine B (SRB) dye molecules within organic nanotubes self-assembled from bolaamphiphile surfactants were investigated by imaging fluorescence correlation spectroscopy (imaging-FCS). The inner and outer surfaces of the nanotubes are terminated with amine and glucose groups, respectively; the former allow for pH-dependent manipulation of nanotube surface charge while the latter enhance their biocompatibility. Wide-field fluorescence video microscopy was used to locate and image dye-doped nanotubes dispersed on a glass surface. Imaging-FCS was then used to spatially resolve the SRB transport dynamics. Mobilization of the dye molecules was achieved by immersion of the nanotubes in buffer solution. Experiments were performed in pH 6.4, 7.4 and 8.4 buffers, at ionic strengths ranging from 1.73 mM to 520 mM. The results show that coulombic interactions between cationic ammonium ions on the inner nanotube surface and the anionic SRB molecules play a critical role in governing mass transport of the dye. The apparent dye diffusion coefficient, D, was found to generally increase with increasing ionic strength and with increasing pH. The D values obtained were found to be invariant along the nanotube length. Mass transport of the SRB molecules within the nanotubes is concluded to occur by a desorption-mediated Fickian diffusion mechanism in which dye motion is slowed by its coulombic interactions with the inner surfaces of the nanotubes. The results of these studies afford information essential to the use of organic nanotubes in controlled drug release applications.

Photoinduced morphological transformations of soft nanotubes.

In water, synthetic amphiphiles composed of a photoresponsive azobenzene moiety and an oligoglycine hydrogen-bonding moiety selectively self-assembled into nanotubes with solid bilayer membranes. The nanotubes underwent morphological transformations induced by photoisomerization of the azobenzene moiety within the membranes, and the nature of the transformation depended on the number of glycine residues in the oligoglycine moiety (i.e., on the strength of intermolecular hydrogen bonding). Upon UV-light irradiation of nanotubes prepared from amphiphiles with the diglycine residue, trans-to-cis isomerization induced a transformation from nanotubes (inner diameter (i.d.) 7 nm), several hundreds of nanometers to several tens of micrometers in length, to imperfect nanorings (i.d. 21-38 nm). The cis-to-trans isomerization induced by continuous visible-light irradiation resulted in the stacking of the imperfect nanorings to form nanotubes with an i.d. of 25 nm and an average length of 310 nm, which were never formed by a self-assembly process. Time-lapse fluorescence microscopy enabled us to visualize the transformation of nanotubes with an i.d. of 20 nm (self-assembled from amphiphiles with the monoglycine residue) to cylindrical nanofibers with an i.d. of 1 nm; shrinkage of the hollow cylinders started at the two open ends with simultaneous elongation in the direction of the long axis.

Spontaneous nematic alignment of a lipid nanotube in aqueous solutions.

The dispersibility and liquid crystal formation of a self-assembled lipid nanotube (LNT) was investigated in a variety of aqueous solutions. As the lipid component, we chose a bipolar lipid with glucose and tetraglycine headgroups, which self-assembled into an LNT with a small outer diameter of 16 to 17 nm and a high axial ratio of more than 310. The LNT gave a stable colloidal dispersion in its dilute solutions and showed spontaneous liquid crystal (LC) alignment at relatively low concentrations and in a pH region including neutral pH. The LNT samples with shorter length distributions were prepared by sonication, and the relationship between the LNT axial ratio and the minimum LC formation concentration was examined. The robustness of the LNT made the liquid crystal stable in mixed solvents of water/ethanol, water/acetone, and water/tetrahydrofuran (1:1 by volume) and at a temperature of up to 90 °C in water. The observed colloidal behavior of the LNT was compared to those of similar 1D nanostructures such as a phospholipid tubule.

Retraction of "Soft Nanotubes Derivatized with Short PEG Chains for Thermally Controllable Extraction and Separation of Peptides".

[This retracts the article DOI: 10.1021/acsomega.7b00838.].

Control of self-assembled morphology and molecular packing of asymmetric glycolipids by association/dissociation with poly(thiopheneboronic acid).

The molecular packing and self-assembled morphologies of asymmetric bolaamphiphiles, N-(2-aminoethyl)-N'-(ß-d-glucopyranosyl)alkanediamide [1(n), n = 12, 14, 16, 17, 18, and 20], were precisely controlled by association/dissociation with poly(thiopheneboronic acid) (PTB). Differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy revealed that the starting film of 1(n) associated with 1 equiv of the boronic acid moiety of PTB, (Film-1(n)PTB), had antiparallel molecular packing of 1(n) moiety within the monolayer membranes. However, the molecular packing of the starting film that contained 0.5 equiv of the boronic acid moiety of PTB (Film-2eq1(n)PTB) was parallel. The dispersion of Film-1(n)PTB in water gave only nanotapes, whereas that of Film-2eq1(n)PTB in water selectively formed nanotubes, through a dissociation reaction of PTB based on the hydrolysis of the boronate esters in the complexes. The nanotapes and nanotubes memorized the antiparallel and parallel molecular packing of the starting films, respectively. Changes in the length of the oligomethylene spacer of 1(n) never affected the molecular packing or self-assembled morphologies. However, the inner diameters of the nanotubes increased irregularly in the range of 67.9-79.6 nm as the length of the oligomethylene spacer of 1(n) increased from n = 12 to n = 18.

Glycolipid nanotube templates for the production of hydrophilic/hydrophobic and left/right-handed helical polydiacetylene nanotubes.

Encapsulation and preorganization of diacetylene monomers in glycolipid nanotubes allows for the production of polydiacetylene nanotubes with hydrophilic/hydrophobic surfaces and left/right-handed helicities.