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![Examples of (A) common macrocycle structures discussed in this review. Adapted with permission from references [8,16,29]. Copyright 2017 Royal Society of Chemistry; Copyright 2012 Royal Society of Chemistry; Copyright 2014 John Wiley and Sons, respectively. (B) Common triggers for stimuli-responsive materials. Figure adapted with permission from reference [3]. Copyright 2018 John Wiley and Sons.](publication/333397901/figure/fig3/AS:763149464633350@1558960419736/Examples-of-A-common-macrocycle-structures-discussed-in-this-review-Adapted-with.png)
Examples of (A) common macrocycle structures discussed in this review. Adapted with permission from references [8,16,29]. Copyright 2017 Royal Society of Chemistry; Copyright 2012 Royal Society of Chemistry; Copyright 2014 John Wiley and Sons, respectively. (B) Common triggers for stimuli-responsive materials. Figure adapted with permission from reference [3]. Copyright 2018 John Wiley and Sons.
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Host-guest motifs are likely the most recognizable manifestation of supramolecular chemistry. These complexes are characterized by the organization of small molecules on the basis of preferential association of a guest within the portal of a host. In the context of their therapeutic use, the primary application of these complexes has been as excipi...
Contexts in source publication
Context 1
... to virtually all macrocycle chemistries, there are other features and properties specific to each class of macrocycles which might contribute to improved functionality for a specific application. As such, there are many choices when it comes to macrocycles that may be considered in the context of their use in stimuli-responsive drug delivery, (Fig. 3A) and many of these different classes of macrocycles are discussed in greater detail ...
Context 2
... have been numerous efforts to prepare stimuli-responsive drug carriers (Fig. 3B), including several efforts designed to respond to disease-relevant stimuli [5][6][7]. In terms of supramolecular materials, common stimuli alter material swelling or promote bond rupture through hydrolysis or enzymatic action [77]. For host-guest systems particularly, the ability to precisely control the formation of a complex and link ...
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Citations
... The phenomena would simplify material construction by leveraging spontaneity, modularity, and self-correcting abilities, thereby reducing batch-to-batch inconsistencies. 68 Although numerous assemblies, including liposomes and lipid nanoparticles are in kinetic traps, their sizes can be conventionally standardized through post-drug loading extrusion processes, leveraging the dynamic and reversible characteristics of noncovalent interactions. For water-soluble siRNA, lipid nanoparticle formulations can be prepared by rapidly mixing lipid components in ethanol with an aqueous drug solution at specic pH and ow rates, triggering in situ self-assembly driven by hydrophobic interactions and drug loading through forming inverted micellar structures surrounding siRNA caused by the electrostatic interactions between cationic lipids and siRNA. ...
Complex diseases and diverse clinical needs necessitate drug delivery systems (DDSs), yet the current performance of DDSs is far from ideal. Supramolecular interactions play a pivotal role in various aspects of drug delivery, encompassing biocompatibility, drug loading, stability, crossing biological barriers, targeting, and controlled release. Nevertheless, despite having some understanding of the role of supramolecular interactions in drug delivery, their incorporation is frequently overlooked in the design and development of DDSs. This perspective provides a brief analysis of the involved supramolecular interactions in the action of drug delivery, with a primary emphasis on the DDSs employed in the clinic, mainly liposomes and polymers, and recognized phenomena in research, such as the protein corona. The supramolecular interactions implicated in various aspects of drug delivery systems, including biocompatibility, drug loading, stability, spatiotemporal distribution, and controlled release, were individually analyzed and discussed. This perspective aims to trigger a comprehensive and systematic consideration of supramolecular interactions in the further development of DDSs. Supramolecular interactions embody the true essence of the interplay between the majority of DDSs and biological systems.
... HGDDSs have attracted extensive attention because of their easy preparation, molecular-level protection, quantitative drug loading by the precise cavity-loading mode and quantified binding constant, adaptability to various drugs, and reproducibility [24][25][26][27]. Initially, macrocyclic hosts were applied as excipients to improve the solubility and stability of drugs in physiological environments [28][29][30]. In order to achieve accurate tumor targeting, numerous targeting strategies have been incorporated into HGDDSs [1,18,20]. ...
... Another type of supramolecular assemblies extensively used for pharmaceutical applications are cyclodextrin (CD) complexes [25]. CDs are a family of natural cyclic oligosaccharides composed of glucopyranose units linked by glycosidic bonds to form a hollow, cone-shaped structure. ...
... These results demonstrate that the SiTE can accumulate in tumour tissue, and an infusion of the small molecule AMD can disassemble SiTE to release the CD3 Fab from the tumour tissue. Most supramolecular chemistry-based strategies for controllable chemotherapeutic release have only been tested in in vitro studies 36,46,47 , and only a few in vivo controllable drug release strategies have been reported 48,49 . These previous investigations may have been limited to mostly in vitro studies because the developed technologies require internalization by cancer cells, and a, A mouse model with expression of human HER2 antigen in the liver was constructed using a piggyback transposon system delivered via LNPs encapsulating two plasmids, pCMV-hyPBase and pPB7 TBG.human HER2.P2A. ...
The broader clinical use of bispecific T cell engagers for inducing anti-tumour toxicity is hindered by their on-target off-tumour toxicity and the associated neurotoxicity and cytokine-release syndrome. Here we show that the off-tumour toxicity of a supramolecular bispecific T cell engager binding to the T cell co-receptor CD3 and to the human epidermal growth factor receptor 2 on breast tumour cells can be halted by disengaging the T cells from the tumour cells via the infusion of the small-molecule drug amantadine, which disassembles the supramolecular aggregate. In mice bearing human epidermal growth factor receptor 2-expressing tumours and with a human immune system, high intravenous doses of such a ‘switchable T cell nanoengager’ elicited strong tumour-specific adaptive immune responses that prevented tumour relapse, while the infusion of amantadine restricted off-tumour toxicity, cytokine-release syndrome and neurotoxicity. Supramolecular chemistry may be further leveraged to control the anti-tumour activity and off-tumour toxicity of bispecific antibodies.
... In turn, the macrocycle's outer shell exposes hydrophilic sites. 5 Previous studies have demonstrated that macrocyclic systems can be customized to incorporate multiple drug moieties and display targeting elements on the construct's surface. 6,7 The MC amphiphiles utilized in our study were first synthesized by Mitra et al. 8 , who described their self-assembly into various supramolecular nanostructures. ...
Drug delivery systems based on amphiphilic supramolecular macrocycles have garnered increased attention over the past two decades due to their ability to successfully formulate nanoparticles. Macrocyclic (MC) materials can self-assemble at lower concentrations without the need for surfactants and polymers, but surfactants are required to form and stabilize nanoparticles at higher concentrations. Using MCs to deliver both hydrophilic and hydrophobic guest molecules is advantageous. We developed two novel types of amphiphilic macrocycle nanoparticles (MC NPs) capable of delivering either Nile Red (NR) (a hydrophobic model) or Rhodamine B (RhB) (a hydrophilic model) fluorescent dyes. We extensively characterized the materials using various techniques to determine size, morphology, stability, hemolysis, fluorescence, loading efficiency (LE), and loading capacity (LC). We then loaded the CDK4/6 inhibitor Palbociclib (Palb) into both MC NPs using a solvent diffusion method. This yielded Palb-MC NPs in the size range of 65-90 nm. They exhibited high stability over time and in fetal bovine serum with negligible toxicity against erythrocytes. Cytotoxicity was minimal when tested against RAW macrophages, human fibroblast HDFn , and adipose stromal cells (ASCs) at higher concentrations of MC NPs. Cell viability studies were conducted with different concentrations of MC NPs, Palb-MC NPs, and free Palb against RAW macrophages, human U-87 GBM, and human M14 melanoma cell lines in vitro. Flow cytometry experiments revealed that blank MC NPs and Palb-MC NPs were selectively targeted to melanoma cells, resulting in cell death compared to the other two cell lines. Future work will focus on studying the biological effect of MC NPs including their binding affinity with molecules/receptors expressed on the M14 and other melanoma cell surface by molecular docking simulations. Subsequently, we will evaluate the MCs as a component of combination therapy in a murine melanoma model.
Graphical abstract
... 29 Host-guest systems are more straightforward models for studying hydrophobic and non-covalent interactions because they are dramatically simpler than proteins and nucleic acids. They are also of practical interest in their own right, as they have applications as pharmaceutical excipients, [30][31][32][33] toxin scavengers, 34 building blocks for synthetic receptors and chemosensors, 35,36 and components of self-healing and smart materials. [37][38][39][40][41] Host-guest binding data are also used extensively to evaluate the accuracy of computational methods, notably in the SAMPL series of blinded prediction challenge. ...
The thermodynamic parameters of host–guest binding can be used to describe, understand, and predict molecular recognition events in aqueous systems. However, interpreting binding thermodynamics remains challenging, even for these relatively simple molecules, as they are determined by both direct and solvent-mediated host–guest interactions. In this contribution, we focus on the contributions of water to binding by studying binding thermodynamics, both experimentally and computationally, for a series of nearly rigid, electrically neutral host–guest systems and report the temperature-dependent thermodynamic binding contributions ΔGb(T), ΔHb(T), ΔSb(T), and ΔCp,b. Combining isothermal titration calorimetry (ITC) measurements with molecular dynamics (MD) simulations, we provide insight into the binding forces at play for the macrocyclic hosts cucurbit[n]uril (CBn, n = 7–8) and β-cyclodextrin (β-CD) with a range of guest molecules. We find consistently negative changes in heat capacity on binding (ΔCp,b) for all systems studied herein – as well as for literature host–guest systems – indicating increased enthalpic driving forces for binding at higher temperatures. We ascribe these trends to solvation effects, as the solvent properties of water deteriorate as temperature rises. Unlike the entropic and enthalpic contributions to binding, with their differing signs and magnitudes for the classical and non-classical hydrophobic effect, heat capacity changes appear to be a unifying and more general feature of host–guest complex formation in water. This work has implications for understanding protein–ligand interactions and other complex systems in aqueous environments.
... Macrocycles are chemically stable, easy to functionalize, and can serve as receptors for a wide variety of analytes as guest molecules [3,4]. The cyclization of various motifs based on aryl groups coupled via short linkers can result in macrocycles with a hydrophobic inner portion and a hydrophilic outer part with a range of functions [5]. ...
... Cyclodextrin (CD), a cyclized glucose polysaccharide with α-1,4-linkage that can have variable cavity sizes, is one of the most often utilized macrocyclic hosts [5]. The inner portion of CDs is hydrophobic, whereas the outer portion contains hydroxyl moieties that aid in water solubility. ...
Supramolecular fexofenadine sensors have been constructed. Although noncovalent intermolecular and intramolecular interactions, which are far weaker than covalent contacts, are the main focus of supramolecular chemistry, they can be used to create sensors with an exceptional affinity for a target analyte. The objective of the current research study is to adapt two PVC membrane sensors into an electrochemical approach for the dosage form determination of histamine H1-receptor antagonists: fexofenadine. The general performance characteristics of two new modified potentiometric membrane sensors responsive to fexofenadine hydrochloride were established. The technique was based on the employment of γ-cyclodextrin (CD) (sensor 1), 4-tert-butylcalix[8]arene (calixarene) (sensor 2) as an ionophore, potassium tetrakis (4-chlorophenyl) borate (KTpClPB) as an ion additive, and (o-NPOE) as a plasticizer for sensors 1 and 2. The sensors showed fast responses over a wide fexofenadine concentration range (1 × 10−2 to 4.5 (4.7) × 10−6 M), with detection limits of 1.3 × 10−6 M and 1.4 × 10−6 M for sensors 1 and 2, respectively, in the pH range of 2–8. The tested sensors exhibit the fexofenadine near-Nernstian cationic response at 56 and 58 mV/decade for sensors 1 and 2, respectively. The sensors exhibit good stability, fast response times, accuracy, precision, and longer life for fexofenadine. Throughout the day and between days, the sensors exhibit good recovery and low relative standard deviations. Fexofenadine in its pure, dose form has been identified with success using the modified sensors. The sensors were employed as end-point indications for the titration of fexofenadine with NaTPB.
... Materials capable of efficient property change upon an external effect have been attracting considerable attention due to their versatile applications, for example in drug delivery [1], regenerative medicine [2], modification of cell behavior [3], development of sensors [4], and molecular machines [4,5]. Macrocyclic compounds are particularly popular building blocks for the construction of stimuli-responsive supramolecular nanoassemblies exhibiting structural transformations [6][7][8]. They are also employed in nanocarriers for the regulated liberation or monitoring of the biologically active compounds [9][10][11]. ...
... A spatial-controlled targeted drug delivery can be achieved because the environment significantly changes along the gastrointestinal tract and the pH in tumours differ from that of healthy cells [16]. For example, the low pH in the lysosomes of cancer cells was exploited to induce apoptosis by the in situ protonation-activated particle formation between pyridyl-functionalized tetraphenylethylene and cucurbit [8]uril [17]. The acidity change of guest compounds upon encapsulation was used to construct pH-triggered self-sorting system [18]. ...
... However, the complexity of natural macrocycles renders chemists to design simple artificial systems for exploring the mechanism behind them [3]. In this regard, macrocycle-based host-guest systems are considered as one of the options that can fulfill this task more or less in functioning as encapsulation and release modules [4]. Multiple-responsive host-guest systems are particularly interesting in terms of their versatility in applications under various operative conditions with the aid of acid/base [5][6][7], light [8,9], and competitive guests [10,11]. ...
Research on stimuli-responsive host–guest systems is at the cutting edge of supramolecular chemistry, owing to their numerous potential applications such as catalysis, molecular machines, and drug delivery. Herein, we present a multi-responsive host–guest system comprising azo-macrocycle 1 and 4,4′-bipyridinium salt G1 for pH-, photo-, and cation- responsiveness. Previously, we reported a novel hydrogen-bonded azo-macrocycle 1. The size of this host can be controlled through light-induced E↔Z photo-isomerization of the constituent azo-benzenes. The host is found in this work to be capable of forming stable complexes with bipyridinium/pyridinium salts, and implementing guest capture and release with G1 under light in a controlled manner. The binding and release of the guest in the complexes can also be easily controlled reversibly by using acid and base. Moreover, the cation competition-induced dissociation of the complex 1a2⊃G1 is achieved. These findings are expected to be useful in regulating encapsulation for sophisticated supramolecular systems.
... system co-delivered semiconductor QDs (Ag 2 S QDs) and doxorubicin (DOX) to tumors, exhibiting strong reactive oxygen species (ROS) generation capability and stimuli-responsive release of drugs and QDs in acidic microenvironments (pH 5.5). [21][22][23] Ag 2 S QDs were chosen for self-assembled nanostructure formation due to their ultra-small size of ~4 nm, which facilitated the formation of ordered structures driven by hostguest interactions. 24 The surface of Ag 2 S QDs modified with a ligand with -COOH groups can interact with CP6, driving Ag 2 S QDs to form ordered self-assembled nanostructures. ...
Combining photodynamic therapy (PDT) and chemotherapy (CHT) by loading an anti-cancer drug and a photosensitizer (PS) into the same delivery nanosystem has been proposed as an effective approach to achieve synergistic effects for a safe cancer treatment. However, exploring an ideal delivery nanosystem has been challenging, because the noncovalent interactions must be maintained between the multiple components to produce a stable yet responsive nanostructure that takes into account the encapsulation of drug molecules. We addressed this issue by engineering the interfacial interaction between Ag2S quantum dots (QDs) using a pillararene derivative to direct the co-self-assembly of the entire system. The high surface area-to-volume ratio of the Ag2S QDs provided ample hydrophobic space to accommodate the anti-drug molecule doxrubicine. Moreover, Ag2S QDs served as PSs triggered by 808 nm near-infrared (NIR) light and also as carriers for high-efficiency delivery of drug molecules to the tumor site. Drug release experiments showed smart drug release under the acidic microenvironments (pH 5.5) in tumor cells. Additionally, the Ag2S QDs demonstrated outstanding PDT ability under NIR light, as confirmed by extracellular and intracellular reactive oxygen species generation. Significant treatment efficacy of the chemo-photodynamic synergistic therapy for cancer using the co-delivery system was demonstrated via in vitro and in vivo studies. These findings suggest that our system offers intelligent control of CHT and PDT, which will provide a promising strategy for constructing hybrid systems with synergistic effects for advanced applications in biomedicine, catalysis, and optoelectronics.
