Stimuli-responsive Supramolecular Polymer Research Articles

Responsive Supramolecular Polymers for Diagnosis and Treatment.

Stimuli-responsive supramolecular polymers are ordered nanosized materials that are held together by non-covalent interactions (hydrogen-bonding, metal-ligand coordination, π-stacking and, host-guest interactions) and can reversibly undergo self-assembly. Their non-covalent nature endows supramolecular polymers with the ability to respond to external stimuli (temperature, light, ultrasound, electric/magnetic field) or environmental changes (temperature, pH, redox potential, enzyme activity), making them attractive candidates for a variety of biomedical applications. To date, supramolecular research has largely evolved in the development of smart water-soluble self-assemblies with the aim of mimicking the biological function of natural supramolecular systems. Indeed, there is a wide variety of synthetic biomaterials formulated with responsiveness to control and trigger, or not to trigger, aqueous self-assembly. The design of responsive supramolecular polymers ranges from the use of hydrophobic cores (i.e., benzene-1,3,5-tricarboxamide) to the introduction of macrocyclic hosts (i.e., cyclodextrins). In this review, we summarize the most relevant advances achieved in the design of stimuli-responsive supramolecular systems used to control transport and release of both diagnosis agents and therapeutic drugs in order to prevent, diagnose, and treat human diseases.

An Antitumor Dual‐Responsive Host‐Guest Supramolecular Polymer Based on Hypoxia‐Cleavable Azocalix[4]arene

AbstractThe exploitation of specific guests which can respond to external stimuli is the main approach for the construction of stimuli‐responsive supramolecular polymers (SPs) based on host–guest interactions. Most functional guests, however, fail to manifest stimuli‐responses. Herein, a hypoxia‐responsive dimeric azocalixarene (D‐SAC4A) with outstanding hosting properties was used as the macrocyclic building block for the preparation of host stimuli‐responsive SPs. Since azocalixarenes can also be compatible with stimuli‐responsive guests, an antitumor drug, camptothecin (CPT), was chosen and linked via a disulfide‐containing linker to afford a glutathione (GSH)‐responsive ditropic guest (D‐CPT). A unique dual‐responsive SP was obtained by 1 : 1 mixing of D‐SAC4A and D‐CPT in water, which further assembled into SP nanoparticles (DSPNs). DSPNs displayed outstanding stability against dilution and biological interferants, as well as precise CPT‐release under GSH and hypoxia conditions. In vitro and in vivo experiments demonstrated the good biosafety and tumor‐suppressive effects of DSPNs.

An Antitumor Dual-Responsive Host-Guest Supramolecular Polymer Based on Hypoxia-Cleavable Azocalix[4]arene.

The exploitation of specific guests which can respond to external stimuli is the main approach for the construction of stimuli-responsive supramolecular polymers (SPs) based on host-guest interactions. Most functional guests, however, fail to manifest stimuli-responses. Herein, a hypoxia-responsive dimeric azocalixarene (D-SAC4A) with outstanding hosting properties was used as the macrocyclic building block for the preparation of host stimuli-responsive SPs. Since azocalixarenes can also be compatible with stimuli-responsive guests, an antitumor drug, camptothecin (CPT), was chosen and linked via a disulfide-containing linker to afford a glutathione (GSH)-responsive ditropic guest (D-CPT). A unique dual-responsive SP was obtained by 1 : 1 mixing of D-SAC4A and D-CPT in water, which further assembled into SP nanoparticles (DSPNs). DSPNs displayed outstanding stability against dilution and biological interferants, as well as precise CPT-release under GSH and hypoxia conditions. In vitro and in vivo experiments demonstrated the good biosafety and tumor-suppressive effects of DSPNs.

Synthesis of stimuli-responsive pillararene-based supramolecular polymer materials for the detection and separation of metal ions

A stimuli-responsive supramolecular polymer network (G-(CN)2⊂BXDSP5) with aggregation-induced emission (AIE) properties has been efficiently constructed by host–guest interactions between pillar[5]arene derivative BXDSP5 and a homoditopic guest G-(CN)2, which shows not only excellent fluorescence properties due to the AIE effect but also desirable ion-sensing abilities in both solution and solid states, holding great potential in the applicable fluorescence detection for Fe3+. The resultant G-(CN)2⊂BXDSP5 can be transformed into supramolecular polymer gel at high concentration via multiple noncovalent interactions, showing multi-stimuli-responsiveness in response to temperature change, mechanical force, and competitive agent. Meanwhile, the xerogel of supramolecular polymer material has been successfully used to remove Fe3+ from water with high adsorption efficiency. In addition, an ion-responsive film based on supramolecular polymer has also been developed, which can serve as a practical and convenient fluorescence test kit for detecting Fe3+.

Autonomous Chemistry Enabling Environment-Adaptive Electrochemical Energy Storage Devices

Autonomous Chemistry Enabling Environment-Adaptive Electrochemical Energy Storage Devices

Multistimuli responsive supramolecular polymer networks via host-guest complexation of pillararene-containing polymers and sulfonium salts

A stimuli-responsive supramolecular polymer network has been constructed based on the host-guest interactions between the copolymer poly-P[5]A with pendent pillararene units and bis(sulfonium) diction guest G2. The formation mechanism of the supramolecular polymer network has been explored by the intensive study. With the addition of the competitive molecules and heating, the supramolecular polymer network could be dissociated and lead to clear changes in NMR spectroscopy and viscosity property.

Supramolecular hydrogelation via host-guest anion recognition: Lamellar hydrogel materials for the release of cationic cargo

Supramolecular hydrogelation via host-guest anion recognition: Lamellar hydrogel materials for the release of cationic cargo

Dynamic enzymatic synthesis of γ-cyclodextrin using a photoremovable hydrazone template

Dynamic enzymatic synthesis of γ-cyclodextrin using a photoremovable hydrazone template

Discordant Supramolecular Fibres Reversibly Depolymerised by Temperature and Light.

Synthetic stimuli responsive supramolecular polymers attract increasing interest for their ability to mimic the unique properties of natural assemblies. Here we focus on the well‐studied benzene‐1,3,5‐tricarboxamide (BTA) motif, and substitute it with two (S)‐3,7‐dimethyloctyl groups and an azobenzene photoswitch. We demonstrate the UV (λ=365 nm) induced depolymerisation of the helical hydrogen‐bonded polymers in methylcyclohexane (MCH) through circular dichroism and UV‐vis spectroscopy in dilute solution (15 μm), and NMR and iPAINT super‐resolution microscopy in concentrated solution (300 μm). The superstructure can be regenerated after thermal depolymerization, whilst repeated depolymerisation can be reversed without degradation by irradiating at λ=455 nm. Molecular dynamics simulations show that the most energetically favourable configuration for these polymers in MCH is a left‐handed helical network of hydrogen‐bonds between the BTA cores surrounded by two right‐handed helices of azobenzenes. The responsiveness to two orthogonal triggers across a broad concentration range holds promise for use in, for example, photo‐responsive gelation.

Tri-pillar[5]arene-Based Multifunctional Stimuli-Responsive Supramolecular Polymer Network with Conductivity, Aggregation-Induced Emission, Thermochromism, Fluorescence Sensing, and Separation Properties

Multifunctional stimuli-responsive supramolecular polymers have applications in the field of smart materials. Herein, a tri-pillar[5]arene-based multifunctional stimuli-responsive supramolecular po...

Stimuli-responsive supramolecular polymer network based on bi-pillar[5]arene for efficient adsorption of multiple organic dye contaminants

A novel supramolecular polymer network gel has been successfully prepared via bi-pillar[5]arene and a tripodal guest, exhibiting multi-stimuli-responsiveness and efficient adsorption of organic dyes.

Transparency and AIE tunable supramolecular polymer hydrogel acts as TEA-HCl vapor controlled smart optical material.

Stimuli-responsive optical materials attract lots of attention due to their broad applications. Herein, a novel smart stimuli-responsive supramolecular polymer was successfully constructed using a simple tripodal quaternary ammonium-based gelator (TH). The TH self-assembles into a supramolecular polymer hydrogel (TH-G) and shows aggregation-induced emission (AIE) properties. Interestingly, the transparency and fluorescence of the TH-G xerogel film (TH-GF) could be reversibly regulated by use of triethylamine (TEA) and hydrochloric acid (HCl) vapor. When alternately fumed with TEA and HCl vapor, the optical transmittance of the TH-GF was changed from 8.9% to 92.7%. Meanwhile, the fluorescence of the TH-G shows an "ON/OFF" switch. The reversible switching of the transparency and the fluorescence of the TH-GF is attributed to the assembly and disassembly of the supramolecular polymer TH-G. Based on these stimuli-response properties, the TH-GF could act as an optical material and shows potential applications as smart windows or fluorescent display material controlled by TEA and HCl vapor.

GSH and light dual stimuli-responsive supramolecular polymer drug carriers for cancer therapy

Glutathione (GSH)/light dual-responsive supramolecular drug carriers (abbreviated as CPAP) based on CD-PEG⊃Azo-PCL were fabricated for intracellular delivery of doxorubicin (DOX). The carriers were spherical with a diameter of 70–90 nm and exhibited GSH/light sensitivity. The GSH response attributed to disulfide bonds between PEG and β-cyclodextrin (β-CD), and the light response was achieved by a simple host-guest interaction between β-CD and azobenzene. DOX was encapsulated into the hydrophobic core of CPAP. The drug loaded CPAP (CPAP@DOX) displayed the fastest drug release in the presence of GSH and light simultaneously. The cytotoxicities of CPAP and CPAP@DOX were explored by SKOV3 cells and HEK293T cells. The results of cell experiments indicated that CPAP@DOX could effectively inhibit cancer cells while had reduced toxicity to normal cells. We believe that CPAP@DOX drug delivery system may present promising application for precisely controllable drug release.

Cover Feature: Counter Cation Dependent and Stimuli Responsive Supramolecular Polymers Constructed by Calix[4]pyrrole Based Host–Guest Interactions (Eur. J. Org. Chem. 4/2019)

The Cover Feature shows the counter cation dependent and pH-responsive supramolecular polymers based on the host–guest recognition motif of a well-known macrocycle calix[4]pyrrole and its tethered carboxylate unit. Unlike its congener tetrabutylammonium cation, when cetyltrimethylammonium (CTA) was used as the counter cation, they were found to be a direct part of supramolecular polymer via cation-π interactions between cone-shaped calix[4]pyrroles and CTA. This allowed supramolecular polymers to establish further hydrophobic interactions and to form gels at elevated concentrations. More information can be found in the Full Paper by A. Aydogan et al.

Counter Cation Dependent and Stimuli Responsive Supramolecular Polymers Constructed by Calix[4]pyrrole Based Host–Guest Interactions

Carboxylate tethered calix[4]pyrroles in the form of their tetrabutylammonium (TBA) and cetyltrimethylammonium (CTA) salts were synthesized via an acid base reaction between the corresponding carboxylic acid functionalized calix[4]pyrrole and tetrabutyl‐ or cetyltrimethylammonium hydroxide. The host–guest recognition motif based on these calix[4]pyrrole macrocycles and tethered carboxylate units was employed to construct novel A–B type supramolecular polymers from low molecular weight monomers in chloroform. These supramolecular polymers were found to be dependent on the counter cation in terms of the properties of supramolecular polymers. 1H‐, DOSY‐, NOESY‐NMR spectroscopic analyses, viscosity measurements, and SEM results were used to characterize supramolecular polymers and revealed that the CTA cation becomes a direct part of supramolecular polymer via cation–π interactions between the ammonium part of CTA and carboxylate‐bound calix[4]pyrrole, effecting the overall properties of supramolecular polymers such as viscosity, gel formation, and drawing fibers. Additionally, reversible pH‐ and thermo‐responsiveness of the supramolecular polymers were demonstrated for the first time for an anion recognition induced calix[4]pyrrole based supramolecular polymer.

Mutual Complexation between π–π Stacked Molecular Tweezers

Aromatic and heterocyclic molecules which form electronically complementary π–π stacked complexes have recently found extensive application in functional materials, molecular machines, and stimuli-responsive supramolecular polymers. Here we describe the design and synthesis of model compounds that self-assemble through complementary stacking motifs, paralleling those postulated to exist in high-molecular weight, healable, supramolecular polymer systems. Complexation studies using 1H NMR and UV–vis spectroscopy indicated formation of a complementary complex between a π-electron rich dipyrenyl tweezer-motif and a tweezer-like, π-electron deficient bis-diimide. The binding stoichiometry in solution between the chain-folding diimide and the pyrenyl derivative was equimolar with respect to the two binding motifs, and the resulting association constant was measured at Ka = 1200 ± 90 M–1. Single crystal X-ray analysis of this “tweezer–tweezer” complex showed a low-energy conformation of the triethylenedioxy link...

A supramolecular polymer network gel with stimuli-responsiveness constructed by orthogonal metal ion coordination and pillar[5]arene-based host–guest recognition

A novel external stimuli-responsive supramolecular polymer network gel was fabricated by orthogonal Ag-coordination and pillar[5]arene-based host–guest interactions.

Tunable assembly and disassembly of responsive supramolecular polymer brushes

Tunable assembly and disassembly of stimuli-responsive supramolecular polymer brushes are induced by using host–guest interactions between β-cyclodextrin and azobenzene groups.

Photoregulated Living Supramolecular Polymerization Established by Combining Energy Landscapes of Photoisomerization and Nucleation-Elongation Processes.

The significant contribution of conventional living polymerization to polymer science assures that living supramolecular polymerization will also lead to a variety of novel phenomena and applications. However, the monomer scope still remains limited in terms of the self-assembly energy landscape; a kinetic trap that retards spontaneous nucleation has to be coupled with a supramolecular polymerization pathway, which is challenging to achieve by molecular design. Herein, we report a rational approach to addressing this issue. We combined the supramolecular polymerization and photoisomerization processes to build the energy landscape, wherein the monomer can be activated/deactivated by light irradiation. In this way, the supramolecular polymerization and kinetic trap can be independently designed in the energy landscape. When the "dormant" monomer was activated by light in the presence of the seed of the supramolecular polymer, the "activated" free monomer was polymerized at the termini of the seed in a chain-growth manner. As a result, we achieved supramolecular polymers with controlled lengths and a narrow polydispersity. Although photoisomerization has been extensively employed in supramolecular polymer chemistry, most studies have focused on the stimuli responsiveness. In this respect, the present study would provoke supramolecular chemists to revisit stimuli-responsive supramolecular polymer systems as potential candidates for devising living supramolecular polymerization.

Host-Guest Binding-Site-Tunable Self-Assembly of Stimuli-Responsive Supramolecular Polymers.

Despite the remarkable progress made in controllable self-assembly of stimuli-responsive supramolecular polymers (SSPs), a basic issue that has not been consideration to date is the essential binding site. The noncovalent binding sites, which connect the building blocks and endow supramolecular polymers with their ability to respond to stimuli, are expected to strongly affect the self-assembly of SSPs. Herein, the design and synthesis of a dual-stimuli thermo- and photoresponsive Y-shaped supramolecular polymer (SSP2) with two adjacent β-cyclodextrin/azobenzene (β-CD/Azo) binding sites, and another SSP (SSP1) with similar building blocks, but only one β-CD/Azo binding site as a control, are described. Upon gradually increasing the polymer solution temperature or irradiating with UV light, SSP2 self-assemblies with a higher binding-site distribution density; exhibits a flower-like morphology, smaller size, and more stable dynamic aggregation process; and greater controllability for drug-release behavior than those observed with SSP1 self-assemblies. The host-guest binding-site-tunable self-assembly was attributed to the positive cooperativity generated among adjacent binding sites on the surfaces of SSP2 self-assemblies. This work is beneficial for precisely controlling the structural parameters and controlled release function of SSP self-assemblies.