Pillararene-based supramolecular systems for theranostics and bioapplications

As an emerging type of important macrocycles for supramolecular chemistry,pillararenes and their derivatives have been widely studied and applied in numerous fields,which intensively promotes the development of chemistry,materials science and biology.Pillararene-based theranostic systems are of special interest in the biological and medical areas as they have shown very promising results.Owing to easy preparation,reliable guest affinity,good biocompatibility and stability,pillararenes are frequently used to construct functional biomaterials.On one hand,pillararenes can either be used individually or form diversiform self-assemblies such as micelles,nanoparticles and vesicles to increase water solubility and biocompatibility of drugs.On the other hand,it is promising to modify solid materials like framework materials,silica nanoparticles and graphene oxides with pillararene derivatives to enhance their functions and controllability.In this review,we summarize recent endeavors of pillararene-based supramolecular systems with theranostics and other biological applications comprising drug delivery/chemotherapy,photodynamic/photothermal therapy,antimicrobials,bioimaging,etc.By introducing several typical examples,the design principles,preparation strategies,identifications and bio-applications of these pillararene-based supramolecular systems are described.Future challenges and directions of this field are also outlined.

Calixarene/pillararene-based supramolecular selective binding and molecular assembly

Calixarenes and pillararenes are cyclic oligomers containing repeating units of phenol and methane. The modification of ionized groups bring calixarenes and pillararenes derivates both good water solubility and strong binding affinities towards various organic/inorganic/biological guest molecules in both water and the solid state. Meanwhile, the pre-organized structures of these compounds are indispensable in constructing of stimuli-responsive supramolecular assembly. With these properties, the supramolecular selective binding and molecular assembly based on calixarene/pillararene are widely used in enzyme tandem assay, stimuli-responsive nanostructure, drug delivery, organelle fluorescent imaging, photo-controlled morphological change, organic and inorganic hybrid material, solid tunable photo-luminescence and so on. This review summarized the recent research progresses on the calixarene/pillararene-based supramolecular systems and discussed the expectation of the future development.

The emerging applications of pillararene architectures in supramolecular catalysis

Over the last decade,numerous research efforts have been devoted to pillar[n]arenes since their debut.The popularity of pillararenes is a reflection of current research trend in supramolecular and macrocyclic chemistry in general.Among the vast applications(such as chemosensors,drug delivery,transmembrance channels,and separation)of pillararenes,their utilization in catalysis is a relatively less explored area.However,soaring attention has been paid by researchers in recent years and this field has seen gradual increasing publications.Therefore,in this review we will discuss progress in the emerging applications of pillararene architectures in catalysis based on various reaction genre including reduction,oxidation,coupling,decomposition and others.Furthermore,this review not only focuses on the pillararenes based current progress in catalysis,but also provides the signs for future development in this research field.

Enhanced photocatalytic hydrogen production performance of pillararene-doped mesoporous TiO_(2) with extended visible-light response

Pillararenes are a new type of supramolecular hosts,and they have been widely applied in drug delivery,catalysis,separation process,and sensors.However,they have rarely been used to produce hydrogen.Here,we report that pillararenes were used as functional molecules to explore photocatalysts and efficiently promoted hydrogen production from water.The most common and easily synthesized pdimethoxy pillar[5]arene(PI-OMe) was employed to form an organic-inorganic hybrid material with titanium dioxide(TiO_(2)),denoted as PI-OMe-TiO_(2).using a convenient sol-gel method.When the material was loaded with Pt nanoparticles,the resulting Pt/PI-OMe-TiO_(2)had a good activity and stability in catalyzing water splitting to produce hydrogen under visible light.The optimized catalyst Pt/PI-OMe-TiO_(2)(5.2 wt%)had a photocatalytic hydrogen production rate of 1736 μmol g^(-1)h^(-1) under visible light(λ> 420 nm)irradiation.The catalyst with a Pt loading of 0.5 wt% and a PI-OMe content of 5.2 wt% also showed good long-term durability after 10 cycles of 50 h testing.The total amount of hydrogen produced was65.01 mmol/g,and the corresponding turnover number(TON) value was 2084.Our findings suggest that pillararene derivatives are promising functional molecules to make efficient and stable hybrid photocatalysts with TiO_(2)and open a new door to hydrogen production using visible light.

Pillararene/Calixarene-based systems for battery and supercapacitor applications

Pillararene/calixarene-based functional materials have garnered significant attention for their unique topological/chemical structures and physicochemical properties,and their extended applications in electro-chemistry have given rise to a promising area of research.This review details current advance in developing electrochemical energy materials based on pillararene/calixarene systems from the viewpoint of both fundamental theoretical simulations and research on practical applications.First,we discuss the underlying mechanisms of applying pillararene/calixarene-based systems for electrochemical energy applications.Second,we summarize simulation studies on pillarquinone and calixquinone with intrinsic structures for applications in batteries.In addition,state-of-the-art applications of pillararene/calixarene-based systems in electrochemical energy storage devices such as lithium/sodium-ion batteries and supercapacitors are highlighted.The diverse roles they play and the various design strategies that have been investigated for high-performance pillararene/calixarene-based batteries are analyzed.Finally,we discuss the prospects for further developments in this emerging field.This review not only describes recent advances in pillararene/calixarene-based batteries and supercapacitors but also lays a firm groundwork for their further application in electrochemical energy engineering.

Pillararene-based fluorescent sensors for the tracking of organic compounds

Fluorescent chemosensors based on pillararene complexes represent a new, promising branch in sensor technology. Because of CH-π interactions, aliphatic chains are well suited for the columnar cavities of pillararenes and bulky or sheet-like(sub)structures can be arranged on the portals. Thus, pillararenes form versatile receptors and an alteration of the fluorescence behavior upon complexation ensures the function of these chemosensors as the reporter. Although this field of research exists only since a few years, remarkable chemosensors were developed for substances as diverse as medical drugs,biochemicals, herbicides and explosives.

Icing on the cake: combining a dual PEG-functionalized pillararene and an A-D-A small molecule photosensitizer for multimodal phototherapy

The design of photosensitizers with multimodal antitumor activity and the construction of nanocarriers with specific targeting are two magic weapons to achieve highly efficient tumor phototherapy. Here we developed an A-D-A fused-ring conjugated small molecule photosensitizer DPIC and proposed a new strategy of constructing phototherapy agents, namely using supramolecular vesicles constructed by the self-assembly of a novel dual PEG-functionalized pillararene WP5-2 PEG to load DPIC. These new nanocarriers had excellent water solubility and drug encapsulation rates. The prepared DPIC NPs had a better water solubility compared with DPIC molecules and had a uniform hollow spherical morphology, which is beneficial for cell endocytosis. Under laser irradiation(808 nm), the DPIC NPs had a photothermal conversion efficiency(PTCE) of 55% and a PTCE of 49% under980-nm laser irradiation. The DPIC NPs also displayed dual type I and type II photodynamic activity. DPIC NPs had superior biocompatibility and stability and can also inhibit tumor growth in vitro and in vivo, demonstrating their potential for highly efficient cancer phototherapy.

Tailoring two-dimensional surfaces with pillararenes based host-guest chemistry

The two-dimensional surfaces have been fueled by the infinite possibility they offe red fo r basic re search,and for novel technologies in nanoelectronics.To realize many of these promises,the effective strategies were to design and control their surface chemistry,which plays a vital role in determining the chemical and physical properties.Macrocyclic host-guest chemistry with the reversible noncovalent interactions between macrocyclic hosts and suitable guests can be readily used for constructing multifunctional surfaces.Macrocyclic pillararenes,possessed the unique structure,have attracted the attentions of researchers in recent years.This feature article covers the recent development of pillararene-based twodimensional inte rfaces,including the fabrication and function of the hybrid composite.The combination of pillararenes and materials platform exhibited the novel property because of the characte ristic of cavity of macrocyclic host and confined spaces of surfaces.We anticipate that this review will be helpful to the researchers working in the fields of supramolecular chemistry and materials science.

A meso–molecular muscle based on copillar[5]arenes

A meso–molecular muscle was prepared by capping the[c2]daisy chain based on a mono-functionalized copillar[5]arene with an imidazolium group in its axle.From its crystal structure,we observed that it was a cyclic dimer composed of two mirror image subcomponents,a pR-and a pS-copillar[5]arene.Their conformations were fixed by the doubly interlocked mechanical bond.By comparison of the^1H NMR and COSY spectra,we found that the length of this meso–molecular muscle could be controlled not only by the solvents,but also by the counter anions.

Rim-differentiation vs. mixture of constitutional isomers: A binding study between pillar[5]arene-based glycoclusters and lectins from pathogenic bacteria

Macrocycle-based glycoclusters, on account of their promising anti-adhesive properties against bacteria,are potential therapeutic alternatives to classic antibiotics through the much less explored anti-adhesive strategy. In this study, a series of constitutionally-pure pentavalent glycoclusters was prepared by conjugating assorted azido-carbohydrates onto a penta-propargyl rim-differentiated pillar[5]arene(RD-P[5])scaffold through Cu(I)-catalyzed azide–alkyne cycloaddition “click” reactions. Their binding towards therapeutically relevant bacterial lectins, such as Lec A and Lec B from Pseudomonas aeruginosa and concanavalin A(Con A), were evaluated subsequently by isothermal titration calorimetric studies. Most of these isomerfree RD-P[5] pentavalent glycoclusters, except the fucosylated ones, display good affinities to lectins.Nonetheless, the dissociation constants observed are similar to those displayed by an analogous pentavalent glycocluster consisting of four P[5] constitutional isomers, in which the RD-P[5] component merely accounts for 7% in the mixture. Our results revealed that high constitutional purity is not essential for achieving effective multivalent interactions between P[5]-based glycoclusters and lectins, presumably as a result of the conformationally labile nature of the P[5] scaffold. This information provides valuable design principles for low-cost and facile syntheses of glycosylated P[5]s for biomedical applications.

Self-assembly of partially oxidized pillar[5]arenes induced by intermolecular charge transfer interactions

Supramolecular interactions such as t-stacking interaction and charge transfer interaction have drawn much attention in the design and construction of various supramolecular assemblies.Herein,partially oxidized pillar[5]arene(P5A),pillar[4]arene[1]quinone(P4A1Q),pillar[3]arene[2]quinone(P3A2Q),and pillar[2]arene[3]quinone(P2A3Q)were synthesized by one-step reaction.As indicated by experimental characterization data and density function theory modeling results,charge transfer interaction among partially oxidized P5A plays a significant role in host-host self-assembly behavior and corresponding packing morphology.This work provides a unique strategy for the construction of functional macrocyclic assemblies through host-host self-assembly.

All-in-one functional supramolecular nanoparticles based on pillar[5]arene for controlled generation,storage and release of singlet oxygen

The storage and controlled release of singlet oxygen(^(1)O_(2))have attracted increasing attention due to the wide application and microsecond lifetime of^(1)O_(2)in water.Herein we provide an integrated nanoplatform consisting of a diphenylanthracene derivative,a water-soluble pillar[5]arene and a photosensitizer tetrakis(4-hydroxyphenyl)porphyrin(TPP),that may provide the controlled generation,storage and release of singlet oxygen.We design a new diphenylanthracene derivative with two trimethylammonium bromide groups on both ends that can be well recognized by the pillar[5]arene.The formed nanocarriers can be used to load TPP through their supramolecular self-assembly.The resulting nanoparticles show good water-solubility and uniform spherical morphology.After laser irradiation(660 nm),the nanoparticles exhibit excellent ability for the generation and storage of^(1)O_(2).When the irradiated nanoparticles are heated above 80°C,^(1)O_(2)can be released from the system.Therefore,in this paper we pioneer the use of noncovalent interaction to integrate the diphenylanthracene derivatives and photosensitizers into one functional system,which provides a new strategy for the controlled generation,storage and release of singlet oxygen.We believe this groundbreaking strategy will have a great potential in providing necessary amounts of^(1)O_(2)for the photodynamic therapy of tumors in dark.

Artificial Water Channels—Progress Innovations and Prospects

The design of artificialwater channels(AWCs)aims to mimic natural proteins that effectively mediate the selective transport of water across the bilayer and artificial polymeric membranes.Currently,impressive progress on synthetic backbones,including selfassembled channels,helical unimolecular,and other functional organic molecules,has been made to provide artificial alternatives and applications in real systems for promising product development.In this review,several synthetic channels exploited during the last fewyears are summarized according to their backbone architecture for water transport and ion transport respectively,showing their potential as natural transporter analogs and the importance of AWCs for industrial,environmental,and medical applications.

pH-Responsive Host-Guest Complexation between a Water-soluble Pillar[7]Arene and a 2,7-Diazapyrenium Salt and Its Application in Controllable Self-assembly

A novel host-guest recognition motif based on a water-soluble pillar[7]arene （WP7） and a 2,7-diazapyrenium salt （DMDAP） was prepared. According to the integrated results of ^1H NMR, 2D NOESY, UV-vis spectroscopy and fluorescence titration experiments, we demonstrated that the molecular recognition of WP7 to DMDAP in water not only has high association constant but also has pH-responsiveness. Subsequently, we took advantage of this molecular recognition motif to fabricate a supra-amphiphile based on WP7 and an amphiphilic 2,7-diazapyrenium derivative DAPAC. Its controllable self-assembly in water was also investigated by means of TEM and DLS techniques.

Supramolecular Prodrug Micelles Constructed by Drug-Drug Conjugate with Water Soluble Pillar[6]arene for Controllable and Rapid Drug Release

The first attempt of constructing supramolecular prodrug micelles based on the host-guest interaction between water-soluble pillar[6]arene(WP6)and a novel doxorubicin(DOX)-based drug-drug conjugate(G)is reported,in which the drug-drug conjugate is synthesized by conjugating anticancer drug DOX with another drug isoniazide via the acid-cleavable hydrazone bond.The obtained WP6⊃G micelles are stable under physiological conditions,whereas the cumulative release of DOX is approximate to 100%within 30 min at pH 5.5 by simulating the endo-lysosomal environment at 37℃.Therefore,this WP6-based prodrug micelles can achieve efficient DOX ac-cumulation in the acidic tumor cells within a short period of time,which is very important and valuable;meanwhile it can also reduce the unexpected premature burst release under physiological condition.Furthermore,cellular in-ternalization and localization experiments demonstrated that these prodrug micelles enter cancer cells mainly via endocytosis and can lead to significant drug accumulation in SKOV3 cancer cells,implying its promising future for cancer therapy.

Hexnut[12]arene and its derivatives: Synthesis, host-guest properties, and application as nonporous adaptive crystals

Hexnut[12]arene(HN[12])and its derivatives,a new class of sixfold macrocyclic arenes,were designed and synthesized in reasonable yield by a one-pot reaction at room temperature using dimethoxymethane as a methylene source.HN[12],which bears a large,symmetric,and rigid cavity,was easily functionalized at both the methylene bridges and the hydroquinone units.A water-soluble fluorescent HN[12]was synthesized and used as a host to encapsulate benzyl viologen dichloride in water with a high binding affinity of(3.4±0.2)×10^(6)M^(-1).The nonporous adaptive crystal(NAC)of HN[12]was found to capture not only inorganic molecules(iodine)but also trace amounts of large organic molecules(basic fuchsine)from water,which greatly expands the scope of NACs for adsorption.

Complexation of Linear Aliphatic Ester,Aldehyde and Ketone Guests by Per-ethylated Pillar[5]arene

The complexation of four neutral guest molecules containing carbon-oxygen double bonds,i.e.,1,6-diacetoxy-hexane(1),dimethyl hexanedioate(2),hexanal(3),and 2-hexanone(4),by per-ethylated pillar[5]arene is reported.These guests show remarkably different binding affinities.For example,ester 1 could be fully engulfed by the host cavity to form a[2]pseudorotaxane-type inclusion complex,while for 2,no obvious host-guest interaction was ob-served.

Smart supramolecular vesicles based on glutathione-reactive pillar[6]arene and acid-labile prodrug:Dual drug loading and sequential release

Glutathione thiol-reactive pillar[6]arene(TWP6)is designed and synthesized as the first example of reducing agent-reactive host molecule.TWP6 shows high affinity binding towards suitable anti-tumor drugs and guests.Doxorubicin-based acid-labile prodrugs and TWP6 are used to construct supramolecular vesicles,which are also loaded with camptothecin.The supramolecular vesicles loaded with two drugs demonstrate glutathione-and acid-responsive drug release as well as sequential release to both stimuli types.Supramolecular vesicles show combination therapeutic effect towards tumor cells in vitro.

Controllable Fabrication of Various Supramolecular Nanostructures Based on Nonamphiphilic Azobenzene Derivatives and Pillar[6]arene

Various novel types of supramolecular nanostructures formed by nonamphiphilic azobenzene derivatives,G1 or G2 have been successfully fabricated,where G2 is structurally similar with G1 but an extra phenoxy group is con-nected with the azobenzene motif.Micellar structures can be obtained from the self-assembly of G1,which further transform to large-sized spindle structures;while nanorods can be initially formed by G2,which will gradually ag-gregate to form layered structures with much larger size.Moreover,it is found that upon addition of WP6,which can form inclusion-complex with G1 or G2,separately,the nonamphiphilic G1 and G2 thus converse to supramolecular amphiphiles WP6⊃G1 and WP6⊃G2,respectively.Consequently,both of the above WP6⊃G1 and WP6⊃G2 complexes can further assemble to form supramolecular binary vesicles,which will gradually transform to nanotubes(WP6⊃G1)or well-ordered nanosheets(WP6⊃G2).

A Pillar[6]arene-[2]pseudorotaxane Based pH-Sensitive Molecular Switch

A novel pH-responsive[2]pseudorotaxane based on ethylated pillar[6]arene and bis(1,2,3-triazolium)butane cation was constructed.The dethreading and rethreading could be reversibly controlled by adding base and acid,i.e.,the deprotonation and reprotonation of the guest.In contrast,such responsible switching behavior does not occur for the complexation between the guest and ethylated pillar[5]arene,since both the cationic axle and the deprotonated one can be strongly bound by ethylated pillar[5]arene.Furthermore,the bis(1,2,3-triazolium)butane⊂pillar[6]-arene-[2]pseudorotaxane can also disassemble upon the addition of competitive ethylated pillar[5]arene.