Host–guest complexation between calix5arene and aggregation‐induced emission luminogen (AIEgen) can significantly turn off both the energy dissipation pathways of intersystem crossing and thermal ...deactivation, enabling the absorbed excitation energy to mostly focus on fluorescence emission. The co‐assembly of calix5arene amphiphiles and AIEgens affords highly emissive supramolecular AIE nanodots thanks to their interaction severely restricting the intramolecular motion of AIEgens, which also show negligible generation of cytotoxic reactive oxygen species. In vivo studies with a peritoneal carcinomatosis‐bearing mouse model indicate that such supramolecular AIE dots have rather low in vivo side toxicity and can serve as a superior fluorescent bioprobe for ultrasensitive fluorescence image‐guided cancer surgery.
Calix5arene‐based supramolecular AIE nanodots were synthesized with high quantum yields in water by virtue of the host–guest complexation. The absorbed excitation energy was mostly focused on fluorescence emission, leading to an ultrahigh signal‐to‐background ratio in fluorescence‐image‐guided cancer surgery.
Calixarenes (CAs), representing the third generation of supramolecular hosts and one of the most widely studied macrocyclic scaffolds, offer (almost) unlimited structure and application possibilities ...due to their ease of modification, which allows one to establish a large molecular library as a material basis for diverse biomedical applications. Moreover, CAs and their derivatives engage in various noncovalent interactions for the facile recognition of guests including bioactive molecules and are also important building blocks for the fabrication of supramolecular architectures. In view of their molecular recognition and self‐assembly properties, CAs are extensively applied in biosensing, bioimaging, and drug/gene delivery. Additionally, some CA derivatives exhibit biological activities and can therefore be used as new therapeutic agents. Herein, we summarize the diverse biomedical applications of CAs including in vitro diagnosis (biosensing), in vivo diagnosis (bioimaging), and therapy.
Calixarenes (CAs) represent the third generation of supramolecular hosts and one of the most widely studied macrocyclic scaffolds. They offer almost unlimited structural possibilities due to their ease of modification, providing a tremendous molecular library as a material basis for diverse biomedical applications.
Conspectus Developments in macrocyclic chemistry have led to supramolecular chemistry, a field that has attracted increasing attention among researchers in various disciplines. Notably, the ...discoveries of new types of macrocyclic hosts have served as important milestones in the field. Researchers have explored the supramolecular chemistry of several classical macrocyclic hosts, including crown ethers, cyclodextrins, calixarenes, and cucurbiturils. Calixarenes represent a third generation of supramolecular hosts after cyclodextrins and crown ethers. Easily modified, these macrocycles show great potential as simple scaffolds to build podand-like receptors. However, the inclusion properties of the cavities of unmodified calixarenes are not as good as those of other common macrocycles. Calixarenes require extensive chemical modifications to achieve efficient endo-complexation. p-Sulfonatocalixnarenes (SCnAs, n = 4–8) are a family of water-soluble calixarene derivatives that in aqueous media bind to guest molecules in their cavities. Their cavities are three-dimensional and π-electron-rich with multiple sulfonate groups, which endow them with fascinating affinities and selectivities, especially toward organic cations. They also can serve as scaffolds for functional, responsive host–guest systems. Moreover, SCnAs are biocompatible, which makes them potentially useful for diverse life sciences and pharmaceutical applications. In this Account, we summarize recent work on the recognition and assembly properties unique to SCnAs and their potential biological applications, by our group and by other laboratories. Initially examining simple host–guest systems, we describe the development of a series of functional host–guest pairs based on the molecular recognition between SCnAs and guest molecules. Such pairs can be used for fluorescent sensing systems, enzymatic activity assays, and pesticide detoxification. Although most macrocyclic hosts prevent self-aggregation of guest molecules, SCnAs can induce self-aggregation. Researchers have exploited calixarene-induced aggregation to construct supramolecular binary vesicles. These vesicles respond to internal and external stimuli, including temperature changes, redox reactions, additives, and enzymatic reactions. Such structures could be used as drug delivery vehicles. Although several biological applications of SCnAs have been reported, this field is still in its infancy. Continued exploration of the supramolecular chemistry of SCnAs will not only improve the existing biological functions but also open new avenues for the use of SCnAs in the fields of biology, biotechnology, and pharmaceutical research. In addition, we expect that other interdisciplinary research efforts will accelerate developments in the supramolecular chemistry of SCnAs.
Classic prodrug strategies rely on covalent modification of active drugs to provide systems with superior pharmacokinetic properties than the parent drug and facilitate administration. Supramolecular ...chemistry is providing a new approach to developing prodrug-like systems, wherein the characteristics of a drug are modified in a beneficial manner by creating host-guest complexes that then permit the stimulus-induced release of the active species in a controlled manner. These complexes are termed "supramolecular prodrugs". In this review, we outline the concept of supramolecular drugs via host-guest chemistry and detail progress made in the area. This summary is designed to highlight the many advantages of supramolecular prodrugs, including ease-of-preparation, molecular-level protection, sensitive response to bio-stimuli, traceless release, and adaptability to different drugs. Limitations of the approach and opportunities for future growth are also detailed.
Heteromultivalency, which involves the simultaneous interactions of more than one type of ligand with more than one type of receptor, is ubiquitous in living systems and provides a powerful strategy ...to improve the binding efficiency of heterotopic species such as proteins and membranes. However, the design and development of artificial heteromultivalent receptors is still challenging owing to tedious synthesis processes and the need for precise control over the spatial arrangement of the binding sites. Here, we have designed a heteromultivalent platform by co-assembling cyclodextrin and calixarene amphiphiles, so that two orthogonal, non-covalent binding sites are distributed on the surface of the co-assembly. Binding with model peptides shows a synergistic effect of the two receptors, (hetero)multivalency and self-adaptability. The co-assembly shows promise for inhibition of the fibrillation of amyloid-β peptides and the dissolution of amyloid-β fibrils, substantially reducing amyloid cytotoxicity. This self-assembled heteromultivalency concept is easily amenable to other ensembles and targets, so that versatile biomedical applications can be envisaged.
Hypoxia plays crucial roles in many diseases and is a central target for them. Present hypoxia imaging is restricted to the covalent approach, which needs tedious synthesis. In this work, a new ...supramolecular host–guest approach, based on the complexation of a hypoxia‐responsive macrocycle with a commercial dye, is proposed. To exemplify the strategy, a carboxyl‐modified azocalix4arene (CAC4A) was designed that binds to rhodamine 123 (Rho123) and quenches its fluorescence. The azo groups of CAC4A were selectively reduced under hypoxia, leading to the release of Rho123 and recovery of its fluorescence. The noncovalent strategy was validated through hypoxia imaging in living cells treated with the CAC4A–Rho123 reporter pair.
A supramolecular strategy for fluorescent hypoxia imaging is proposed based on the host–guest complexation of azomacrocycles with commercial dyes.
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•Overview of the current status of type I PDT achieved by inorganic PSs.•Demonstration of strategies employed for transformation of organic PSs from type II to type I ...pathway.•Emphasize the potentiality of supramolecular assembly as a novel non-covalent strategy to promote type I PDT.
Photodynamic therapy (PDT) is a promising approach for treatment of cancer and bacterial infection. Upon excitation by light, photosensitizers (PSs) produce reactive oxygen species (ROS), which could induce cell destruction. ROS could be produced via two kinds of photoreactions, which are type I (electron transfer) mechanism producing superoxide anions, hydrogen peroxides and hydroxyl radicals, and type II (energy transfer) mechanism generating singlet oxygen. Traditional type II PDT suffers from the problem of oxygen-dependent. Fortunately, type I mechanism provides a promising solution that makes PDT practically operated in hypoxic environment. In this review, we attempt to provide a systemic overview of a variety of approaches to generate and improve type I PDT. Inorganic PSs possess the intrinsic feature of generating electron-hole pairs under irradiation, resulting in a charge separated state which is favorable for type I pathway. Organic PSs are generally involved in type II PDT. Strategies of covalent modification and metal coordination are employed for transformation from type II to type I pathway. Provided examples focus on macrocycles and ruthenium(II) complex. We finally emphasize the potentiality of supramolecular assembly as a novel non-covalent strategy to promote type I PDT. It provides a facile method to fabricate nanomaterials with multiple functional building blocks, which could tune type I/II PDT without tedious synthesis. It is also involved in optimizing PSs delivery owing to their unique, nanoscale related properties.
Enhanced drug delivery can improve the therapeutic efficacy of drugs and help overcome side effects. However, many reported drug‐delivery systems are too complex and irreproducible for practical use. ...In this work, the design of a hypoxia‐responsive molecular container based on calixarene, called CAC4A, which presents a significant advance in practical, hypoxia‐targeted drug‐delivery, is reported. CAC4A enables a wide variety of clinical drugs to be quantitatively loaded to improve their solubility and stability, as well as enable the administration of reduced doses. Furthermore, as a result of its azo functional groups, which are sensitive to reduction within a hypoxic environment, it is possible to achieve tumor‐targeted drug‐release with reduced side effects. CAC4A fulfils all essential requirements for a drug‐delivery system in addition to multiple advantages, including facile preparation, well‐defined molecular weight, and structure, and universal applicability. Such features collectively enable supramolecular prodrugs to be formulated simply and reproducibly, with potential for bench‐to‐bedside translation. Moreover, CAC4A is amenable to other therapy modalities and can be facilely decorated with functional groups and hybridized with nanomaterials, providing ample possibilities for its role in future drug‐delivery systems.
Carboxylated azocalix4arene is designed as a hypoxia‐responsive molecular container, which affords strong binding toward a series of chemotherapeutic drugs, and improves the drugs’ solubility and stability, demonstrating its universality as a supramolecular drug carrier. Taking one supramolecular prodrug as an example, the efficacy of this hypoxia‐targeted therapy is validated in vitro and in vivo.
Perfluorinated alkyl substances, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are toxic materials that are known to globally contaminate water, air, and soil resources. ...Strategies for the simultaneous detection and removal of these compounds are desired to address this emerging health and environmental issue. Herein, we develop a type of guanidinocalix5arene that can selectively and strongly bind to PFOS and PFOA, which we use to demonstrate the sensitive and quantitative detection of these compounds in contaminated water through a fluorescent indicator displacement assay. Moreover, by co-assembling iron oxide nanoparticle with the amphiphilic guanidinocalix5arene, we are able to use simple magnetic absorption and filtration to efficiently remove PFOS and PFOA from contaminated water. This supramolecular approach that uses both molecular recognition and self-assembly of macrocyclic amphiphiles is promising for the detection and remediation of water pollution.
Excess accumulation of amyloid‐β (Aβ) protein in the brain is the primary pathogenesis of Alzheimer's disease (AD). Inhibition of Aβ fibrillation and disaggregation of Aβ fibrils is an attractive ...therapeutic and preventive strategy for Aβ‐induced AD. Here, near infrared (NIR) light‐responsive nanoparticles (NPs) composed of amphiphilic guanidinocalix5arene (GC5A), 4‐(dodecyloxy)benzamido‐terminated methoxy poly(ethylene glycol), and photothermal conjugated polymer PDPP are fabricated. The NIR light‐responsive NPs can efficiently penetrate the blood‐brain barrier (BBB), inhibit amyloid‐β 42 (Aβ42) fibrillation, and disaggregate fibrils after NIR light irradiation. Through the advantage of containing GC5A, the NPs exhibit extremely strong binding affinity for the Aβ42 protein. Interestingly, upon NIR light irradiation, benefiting from the high photothermal conversion efficiency of PDPP, NPs generate local heat and effectively promote the BBB permeability. Moreover, NPs are multifunctional platforms for the inhibition of Aβ42 fibrillation and disaggregation of fibrils after irradiation with NIR light, distinctly reducing cytotoxicity and eliminating Aβ42 plaques in the hippocampus of AD mice. Hence, NPs provide an interesting strategy for the inhibition and disaggregation of Aβ42 fibrillation and present an excellent therapeutic strategy for amyloidosis.
The near infrared (NIR) light‐responsive nanoparticles (NPs) composed of calixarene (GC5A), and a conjugated polymer (PDPP) exhibit efficient permeability through the blood‐brain barrier and inhibit and disaggregate Aβ42 fibrillation. Upon NIR light irradiation, the NPs generate local heat and efficiently disaggregate Aβ42 fibrils, leading to the cytotoxicity of Aβ42 fibrils reduce, and eliminate Aβ42 plaques in Alzheimer's disease mouse brain.