Supramolecular Amphiphiles Research Articles

Self-Repair of Structure and Bioactivity in a Supramolecular Nanostructure.

Supramolecular nanostructures formed through self-assembly can have energy landscapes, which determine their structures and functions depending on the pathways selected for their synthesis and processing and on the conditions they are exposed to after their initial formation. We report here on the structural damage that occurs in supramolecular peptide amphiphile nanostructures, during freezing in aqueous media, and the self-repair pathways that restore their functions. We found that freezing converts long supramolecular nanofibers into shorter ones, compromising their ability to support cell adhesion, but a single heating and cooling cycle reverses the damage and rescues their bioactivity. Thermal energy in this cycle enables noncovalent interactions to reconfigure the nanostructures into the thermodynamically preferred long nanofibers, a repair process that is impeded by kinetic traps. In addition, we found that nanofibers disrupted during freeze-drying also exhibit the ability to undergo thermal self-repair and recovery of their bioactivity, despite the extra disruption caused by the dehydration step. Following both freezing and freeze-drying, which shorten the 1D nanostructures, their self-repair capacity through thermally driven elongation is inhibited by kinetically trapped states, which contain highly stable noncovalent interactions that are difficult to rearrange. These states decrease the extent of thermal nanostructure repair, an observation we hypothesize applies to supramolecular systems in general and is mechanistically linked to suppressed molecular exchange dynamics.

Supramolecular Nanostructure Activates TrkB Receptor Signaling of Neuronal Cells by Mimicking Brain-Derived Neurotrophic Factor.

Brain-derived neurotrophic factor (BDNF), a neurotrophin that binds specifically to the tyrosine kinase B (TrkB) receptor, has been shown to promote neuronal differentiation, maturation, and synaptic plasticity in the central nervous system (CNS) during development or after injury and onset of disease. Unfortunately, native BDNF protein-based therapies have had little clinical success due to their suboptimal pharmacological properties. In the past 20 years, BDNF mimetic peptides have been designed with the purpose of activating certain cell pathways that mimic the functional activity of native BDNF, but the interaction of mimetic peptides with cells can be limited due to the conformational specificity required for receptor activation. We report here on the incorporation of a BDNF mimetic sequence into a supramolecular peptide amphiphile filamentous nanostructure capable of activating the BDNF receptor TrkB and downstream signaling in primary cortical neurons in vitro. Interestingly, we found that this BDNF mimetic peptide is only active when displayed on a peptide amphiphile supramolecular nanostructure. We confirmed that increased neuronal maturation is linked to TrkB signaling pathways by analyzing the phosphorylation of downstream signaling effectors and tracking electrical activity over time. Furthermore, three-dimensional gels containing the BDNF peptide amphiphile (PA) nanostructures encourage cell infiltration while increasing functional maturation. Our findings suggest that the BDNF mimetic PA nanostructure creates a highly bioactive matrix that could serve as a biomaterial therapy in injured regions of the CNS. This new strategy has the potential to induce endogenous cell infiltration and promote functional neuronal maturation through the presentation of the BDNF mimetic signal.

CO2-Enhanced Bola-Type Supramolecular Amphiphile Constructed from Pillar[5]arene-Based Host–Guest Recognition

A CO2-enhanced bola-type supramolecular amphiphile was constructed from a water-soluble pillar[5]arene and a CO2-responsive bola-amphiphile. The gas-responsive self-assembly behavior of this supramolecular amphiphile and its application in controlled release were investigated.

Synthesis of a Pillar[5]arene-Based Polyrotaxane for Enhancing the Drug Loading Capacity of PCL-Based Supramolecular Amphiphile as an Excellent Drug Delivery Platform.

A pillar[5]arene-based nonionic polyrotaxane (PR) with star-poly(ε-caprolactone) ( S-PCL) as the axle, pillar[5]arene (DEP5) as the wheel and adamantane as the end-capped group is designed and synthesized. The resulting PR is subsequently assembled with β-cyclodextrin end-capped pH-stimulated poly(acrylic acid) (CD-PAA) via a host-guest interaction to form the supramolecular pseudoblock polymer PR-PAA. This supramolecular pseudoblock polymer could self-assemble in aqueous solution to produce PR-PAA-based supramolecular vesicular nanoparticles (PR-SVNPs), which present significantly enhanced drug loading capacity (DLC, 45.6%) of DOX, much higher than those of superamphiphiles (PCL-PAA, 17.1%). Such a high DLC of PR-SVNPs can be most probably attributed to the greatly decreased crystallinity of PCL in PR. Moreover, the loaded drugs could be selectively released in an acidic microenvironment-responsive manner. Compared to free DOX, the DOX-loaded PR-SVNPs (DOX@PR-SVNPs) shows much enhanced cellular uptake and cytotoxicity against the SMMC-7721. More importantly, thanks to the enhanced permeability and retention (EPR) effect, DOX@PR-SVNPs exhibits appealing features such as extremely low toxicity, highly efficient intratumoral accumulation and substantial antitumor efficacy in vivo.

Force and time-dependent self-assembly, disruption and recovery of supramolecular peptide amphiphile nanofibers

Biological feedback mechanisms exert precise control over the initiation and termination of molecular self-assembly in response to environmental stimuli, while minimizing the formation and propagation of defects through self-repair processes. Peptide amphiphile (PA) molecules can self-assemble at physiological conditions to form supramolecular nanostructures that structurally and functionally resemble the nanofibrous proteins of the extracellular matrix, and their ability to reconfigure themselves in response to external stimuli is crucial for the design of intelligent biomaterials systems. Here, we investigated real-time self-assembly, deformation, and recovery of PA nanofibers in aqueous solution by using a force-stabilizing double-pass scanning atomic force microscopy imaging method to disrupt the self-assembled peptide nanofibers in a force-dependent manner. We demonstrate that nanofiber damage occurs at tip-sample interaction forces exceeding 1 nN, and the damaged fibers subsequently recover when the tip pressure is reduced. Nanofiber ends occasionally fail to reconnect following breakage and continue to grow as two individual nanofibers. Energy minimization calculations of nanofibers with increasing cross-sectional ellipticity (corresponding to varying levels of tip-induced fiber deformation) support our observations, with high-ellipticity nanofibers exhibiting lower stability compared to their non-deformed counterparts. Consequently, tip-mediated mechanical forces can provide an effective means of altering nanofiber integrity and visualizing the self-recovery of PA assemblies.

Self-assembly of anionic pyrene derivatives with cationic surfactants bearing a tetradecyl chain

The association of 1,3,6,8-pyrenetetrasulfonate (S4P) or 8-hydroxypyrene-1,3,6-trisulfonate (S3POH) with cationic surfactants possessing tetradecyl substituent was studied in aqueous solution at 298 K. Two types of nanoparticles were produced depending on the mixing ratio of the components. The self-assembly to negatively charged larger nanoparticles at low surfactant excess was always exothermic, whereas the formation and size diminution of the positive nanoparticles in the presence of larger amount of surfactants were practically thermoneutral. The alteration of the fluorescence spectrum upon self-organization of the constituents indicated π−π interaction between the pyrene moieties within the nanoparticles. In tetradecyltrimethylammonium bromide solution, S4P induced the formation of not only nanoparticles but also mixed micelles composed of supramolecular and conventional amphiphiles. A pH-responsive entropy-controlled transformation of nanoparticles to such mixed micelles was achieved when 1-methyl-3-tetradecyl-imidazolium cation had more than 19-fold molar excess over S3POH.

Supramolecular Assembly of Thiolated Cyclodextrin and Ferrocene Derivative for Controlled Drug Delivery

AbstractConstruction of biocompatible nanoparticles is a significant topic of research at the chemistry/biology interface. Presently, more and more researchers have focused on supramolecular amphiphiles constructed by macrocycle‐induced aggregation, a feasible and universal strategy in the fabrication of functional nanomaterials. In this work, we report a pH‐responsive nanoparticle through a noncovalent complexation between per‐6‐thiolated β‐cyclodextrin sodium salt (SACD) and amphiphilic ferrocene derivative (FC12+Br−) in water. The formation and composition of the obtained supramolecular nanoparticles were comprehensively characterized by UV/Vis absorption, dynamic laser scattering, and microscopic observations. Furthermore, the drug loading and release studies demonstrated that the supramolecular binary nanoparticles could efficiently encapsulate doxorubicin hydrochloride (DOX) in their nanoparticulate cores, and the entrapped DOX could be rapidly released in a low pH environment. The present study suggests that the obtained binary supramolecular amphiphiles with good stability, tunable assembling/disassembling behaviors, and controlled drug loading/release properties have great potential in the construction of on‐demand drug‐delivery systems.

Facile Fabrication of Reduction-Responsive Supramolecular Nanoassemblies for Co-delivery of Doxorubicin and Sorafenib toward Hepatoma Cells.

Combination of doxorubicin with sorafenib (SF) was reported to be a promising strategy for treating hepatocellular carcinoma (HCC). In this study, we designed a reduction-responsive supramolecular nanosystem based on poly (ethylene glycol)-β-cyclodextrin (PEG-CD) and a disulfide-containing adamantine-terminated doxorubicin prodrug (AD) for efficient co-delivery of doxorubicin and sorafenib. PEG-CD/AD supramolecular amphiphiles were formed through host-guest interaction between cyclodextrin and adamantine moieties, and then self-assembled into regular spherical nanoparticles with a uniform size of 166.4 nm. Flow cytometry analysis and confocal laser scanning microscopy images showed that PEG-CD/AD nanoparticles could be successfully taken up by HepG2 cells and then released doxorubicin into the cell nuclei. Moreover, sorafenib could be facilely encapsulated into the hydrophobic cores to form PEG-CD/AD/SF nanoparticles with a slightly larger size of 186.2 nm. PEG-CD/AD/SF nanoparticles sequentially released sorafenib and doxorubicin in a reduction-response manner. In vitro cytotoxicity assay showed that PEG-CD/AD/SF nanoparticles had an approximately 4.7-fold decrease in the IC50 value compared to that of PEG-CD/AD and SF physical mixtures, indicating stronger inhibitory effect against HepG2 cells by co-loading these two drugs. In summary, this novel supramolecular nanosystem provided a simple strategy to co-deliver doxorubicin and sorafenib toward hepatoma cells, which showed promising potential for treatment of HCC.

A dual redox-responsive supramolecular amphiphile fabricated by selenium-containing pillar[6]arene-based molecular recognition.

A dual redox-responsive pillar[6]arene-based supramolecular amphiphile was fabricated in water. The self-assembly behavior of this supramolecular amphiphile in response to dual redox stimuli was investigated.

A triply-responsive supramolecular vesicle fabricated by α-cyclodextrin based host-guest recognition and double dynamic covalent bonds.

The supramolecular construction of multi-stimuli assemblies is a challenging task for prospective use. In this work, a novel supramolecular amphiphile was fabricated by introducing molecules with dynamic covalent bonds into host-guest inclusion. The amphiphile formed a vesicle, which was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), 1H NMR and UV-vis spectra. Furthermore, the vesicular structure could be regulated by pH, light and redox reagent, and thus the loaded dye in the vesicles could be released in a controlled manner.

Supramolecular self-assemblies for bacterial cell agglutination driven by directional charge-transfer interactions.

Two supramolecular amphiphiles are fabricated through directional charge-transfer interactions, which self-assemble into nanofibers and nanoribbons. Due to the existence of galactose on their surface, these self-assemblies act as a cell glue to agglutinate E. coli, benefiting from multivalent interactions.

Supramolecular chemotherapeutic drug constructed from pillararene-based supramolecular amphiphile.

Based on the host-guest interaction between a CPT-conjugated prodrug amphiphile (CPT-ss-Py) and a water-soluble pillar[5]arene (P5), a GSH-responsive supramolecular chemotherapeutic drug (P5⊃CPT-ss-Py) was fabricated. Through this supramolecular formulation, internalization and anticancer efficacy were greatly increased.

An addressable packing parameter approach for reversibly tuning the assembly of oligo(aniline)-based supra-amphiphiles.

We present a newly developed approach to non-covalently address the packing parameter of an electroactive amphiphile. The pH-responsive reversible switching of a tetra(aniline)-based cationic amphiphile, TANI-pentyl trimethylammonium bromide (TANI-PTAB), between self-assembled vesicles and nanowires by acid/base chemistry in aqueous solution is used to exemplify this approach. Trifluoroacetic acid (TFA) was selected as a prototypical acid to form emeraldine salt (ES) state (TANI(TFA)2-PTAB) vesicles for this new class of small-molecule supramolecular amphiphiles. UV-vis-NIR spectroscopy, transmission electron microscopy (TEM), tapping-mode atomic force microscopy (AFM), and fluorescence spectroscopy were used to investigate the reversible structural transformation from vesicles to nanowires. We show that utilising different protonic acid-dopants for TANI-PTAB can regulate the packing parameter, and thus the final self-assembled structures, in a predictable fashion. We envisage potential application of this concept as smart and switchable delivery systems.

Melatonin-directed micellization: a case for tryptophan metabolites and their classical bioisosteres as templates for the self-assembly of bipyridinium-based supramolecular amphiphiles in water.

The bulk solution properties of amphiphilic formulations are derivative of their self-assembly into higher ordered supramolecular assemblies known as micelles and of their ordering at the air-water interface. Exerting control over the surface-active properties of amphiphiles and their propensity to aggregate in pure water is most often fine-tuned by covalent modification of their molecular structure. Nevertheless structural constraints which limit the performance of amphiphiles do emerge when trying to develop more sophisticated systems which undergo for example, shape-defined controlled assembly and/or respond to external stimuli. In this regard, the template-modulated assembly of the so-called "supramolecular amphiphiles" continues to make progress ordering molecules that otherwise have very little to no driving force to aggregate in a prescribed manner in aqueous solutions. Herein we describe the template-modulated micellization and ordering at the air-water interface of bipyridinium-based supramolecular amphiphiles triggered by host-guest interactions with high specificity for the neurotransmitter melatonin over its biosynthetic synthon l-tryptophan and the thermodynamic parameters governing the template-modulated micellization process. When bound to the bipyridinium units of micellized surfactant molecules, melatonin effectively serves as "molecular glue" capable of lowering the CMC by 52% as compared to untemplated solutions. Analysis of this system suggests that a hallmark of donor-acceptor template-modulated micellization in water is a strong positively correlated temperature dependence of the CMC and the absence of a U-shaped CMC-temperature curve. Our findings make a case for the incorporation of l-tryptophan-based metabolites and their classical synthetic pharmaceutical bioisosteres as potential targets/components of donor-acceptor CT-based supramolecular amphiphile systems/materials operating in water.

Host-guest supramolecular amphiphile enhanced photodecomposition with responsive room-temperature phosphorescence signals

Photolyzable matric belongs to photo-responsive system that experiences irreversible decomposition after irradiation. While the self-aggregation of photosensitizers in aqueous media often results in lower photosensitizing ability. In this work, an enhanced photolyzable system is constructed through host-guest recognition between amphiphilic 6-bromoisoquinoline functionalized alkoxyanthracene (AnBq) and cucurbit[7]uril (CB[7]). In addition, a visible room-temperature phosphorescence (RTP) signal occurs along with the photolysis reaction as the suppression of intramolecular photoinduced electron transfer (PET) process from the anthracene moiety to phosphorous 6-bromoisoquinoline moiety. The formation of the host-guest assembly and the photolysis of AnBq are clearly corroborated through UV–Vis, NMR and MS spectroscopy. This photo-responsive host-guest assembly provides some hints for the design of photodegradable materials.

Effect of Headgroup Variation on the Self-Assembly of Cationic Surfactants with Sulfonatocalix[6]arene.

The effect of headgroup variation on the association of supramolecular amphiphiles composed of 4-sulfonatocalix[6]arene (SCX6) and cationic surfactant possessing tetradecyl substituent was studied in aqueous solutions at pH 7. When the surfactant contained hydrophilic trimethylammonium, pyridinium, or 1-methylimidazolium headgroup, highly reversible temperature-responsive nanoparticle-supramolecular micelle transformation could be attained at appropriately chosen component mixing ratios and NaCl concentrations. In these cases, the substantial negative molar heat capacity change (ΔCp) rendered nanoparticle formation strongly endothermic at low temperature, whereas the assembly to supramolecular micelle was always accompanied by enthalpy gain. The ΔCp values became less negative when the charge density and the hydrophilic character of the surfactant headgroup diminished. The association of the more hydrophobic 6-methoxyquinolinium and quinolinium surfactants with SCX6 did not lead to supramolecular micelle formation because the self-assembly into nanoparticles was highly exothermic.

Theranostic Prodrug Vesicles for Imaging Guided Codelivery of Camptothecin and siRNA in Synergetic Cancer Therapy.

The construction of prodrugs has been a popular strategy to overcome the limitations of chemotherapeutic drugs. However, complicated synthesis procedures and laborious purification steps make the fabrication of amphiphilic prodrugs rather difficult. By harnessing the concept of host-guest interaction, we designed and prepared a supra-amphiphile consisting of a dendritic cyclodextrin host and an adamantane/naphthalimide-modified camptothecin guest through glutathione-responsive disulfide linkage. This host-guest complex could self-assemble in aqueous solution to give nanosized vesicles. When the disulfide bond in adamantane/naphthalimide-modified camptothecin was cleaved by glutathione, the fluorescence of the freed adamantane/naphthalimide unit showed a significant red shift with enhanced intensity. Such glutathione-responsive fluorescence change allows for intracellular imaging and simultaneous monitoring of drug release in real time. On account of abundant positively charged amine groups on the supramolecular vesicle surface, siRNA (siPlK1) could be efficiently loaded on the vesicle. The gel retardation and fluorescence experiments proved that the siPlK1 was successfully bonded to the supramolecular vesicle. The vesicle with dendritic cyclodextrin ring exhibited negligible cytotoxicity even at high concentrations, avoiding the shortcoming of cytotoxicity from commonly used gene vectors. In vitro studies demonstrated that the loaded siRNA was transported into cancer cells to improve cancer therapeutic efficacy. Thus, we developed a prodrug-based supramolecular amphiphile via the host-guest interaction with better therapeutic performance than free camptothecin. The assembled system was utilized as a drug/gene vector to achieve combinational gene therapy and chemotherapy with a synergistic effect, providing an alternative strategy to deliver both prodrug and therapeutic gene.

A triply-responsive supramolecular amphiphile fabricated by a thermal-responsive pillar[5]arene-based host–guest recognition motif

A novel molecular recognition motif was built between a neutral water soluble pillar[5]arene and decyltrimethylammonium bromide in water. Its thermal-controlled complexation with G1 in water was investigated. Furthermore, based on this new thermal responsive host–guest recognition motif, we further constructed a supramolecular amphiphile between this pillar[5]arene and a trimethylammonium bromide derivative containing an azobenzene group at the other end. This supramolecular amphiphile showed triply-responsiveness, that is, thermal responsiveness of the host–guest complex, photo-responsiveness of the azobenzene group and chemical-responsiveness by adding β-CD.

Controlled enzymatic stability and release characteristics of supramolecular chiral peptide amphiphile nanofiber gels

Supramolecular bioarchitectures formed by assembly of achiral or chiral building blocks play important roles in various biochemical processes. Stereochemistry of amino acids is important for structural organization of peptide and protein assemblies and structure-microenvironment interactions. In this study, oppositely charged peptide amphiphile (PA) molecules with L-, D- and mixture of l- and d-amino acid conformations are coassembled into supramolecular nanofibers and formed self-supporting gels at pH 7.4 in water. The enzymatic stability of the PA nanofiber gels was studied in the presence of proteinase K enzyme, which digest a broad spectrum of proteins and peptides. The structural changes on the chiral PA nanofibers were also analyzed at different time periods in the presence of enzymatic activity. Controlled release of a model cargo molecule through the chiral PA nanofiber gels was monitored. The diffusivity parameters were measured for all gel systems. Release characteristics and the enzymatic stability of the peptide nanofiber gels were modulated depending on organization of the chiral PA molecules within the supramolecular assemblies.

Dual-Responsive Bola-Type Supra-Amphiphile Constructed from Water-Soluble Pillar[5]arene and Naphthalimide-Containing Amphiphile for Intracellular Drug Delivery.

Supramolecular construction of multistimuli platform for drug delivery is a challenging task. In this work, a pH and GSH (glutathione) dual-responsive bola-type supramolecular amphiphile was successfully fabricated by the complexation between a water-soluble pillar[5]arene (WP5) and a bolaform naphthalimide guest (G) in water. The resulting bola-type amphiphile further self-assembled into supramolecular binary vesicles, which could be disassembled by low pH, a high-GSH-concentration environment, or both. Furthermore, the results of drug loading and releasing tests showed that doxorubicin (DOX), the hydrophobic anticancer drug, could be successfully encapsulated into the Stern region of the obtained supramolecular vesicles and generated the DOX-loaded vesicles with good drug-loading efficiency. Moreover, the obtained DOX-loaded vesicles displayed efficient and rapid DOX release at a simulated tumor microenvironment with low-pH or excess-GSH conditions or both. Significantly, cytotoxicity experiments revealed that the DOX-loaded supramolecular vesicles could obviously improve the anticancer efficiency of free DOX for tumor cells while remarkably reducing its side effects for normal cells. In vitro cellular uptake and subcellular localization assays further proved that these smart drug nanovehicles, entering cancer cells mainly via endocytosis, could cause excellent drug accumulation in cancer cells. The present study provides a successful example with which to rational design an effective bola-type stimuli-responsive supramolecular nanocarrier, which might have wide potential applications in the construction of various controlled drug-delivery systems.