Controlled Regulation of Cell Membrane Receptor Activation Using Programmable DNA Nano-Modulators and Host–Guest Interactions

Supramolecular Nanohelix Fabricated by Pillararene-Based Host–Guest System for Chirality Amplification, Transfer, and Circularly Polarized Luminescence in Water

The host-guest inclusion complexes of cucurbiturils with alkyl viologen have interesting architectures, chemical properties, and potential applications in sensors and nanotechnology. A highly hydrated triclinic crystal of cucurbit[8]uril (CB[8]) complexed by methyl hexadecyl viologen (MVC16) is characterized by the unprecedented coexistence in the crystal of three host-guest complexes with 3:2, 2:2, and 1:1 stoichiometries. In all these complexes, the hook-shaped alkyl chain of the MVC16 is hosted in the CB[8] macrocycles, while the methyl viologen moieties have various environments. In the Z-shaped 3:2 complex, a central CB[8] unit hosts two viologen heads in the cavity, while the 2:2 complex is held together by π-stacking interactions between two viologen units. In the square 2D tiling crystal packing of CB[8] macrocycles, the same site which favors the dimerization observed in the 2:2 complex is also statistically occupied by a single methyl viologen moiety of the 1:1 complex. The rational interpretation of the crystal structure represented an intriguing challenge, due to the complicated statistical disorder in the alkyl chains hosted in CB[8] units and in the methyl viologen moieties of 2:2 and 1:1 complexes. In contrast with the solution behavior dominated by the 2:1 complex, the coexistence of three host-guest complexes with 3:2, 2:2, and 1:1 ratios highlights the fundamental importance of packing effects in the crystallized supramolecular complexes. Therefore, the crystallization process has permitted us to capture different host-guest systems in a single crystal, revealing a supramolecular landscape in a single photo.

Pagoda[5]arene (P5), which is composed of five 2,6-dimethoxylanthracene (2,6-DMA) subunits bridged by methylene groups at 1,5 positions, was conveniently synthesized in 43% by trifluoroacetic acid ...

This thesis has been concerned with DNA templated self-assembly, with the long term goal to create well-defined nano-architectures based on p-conjugated molecules. Before realizing this goal, single-stranded DNA has been investigated to see if it can be used as a template to bind organic guests, such as p-conjugated molecules, via hydrogen (H) bonding. Furthermore, experimental techniques and theoretical models have been used to characterize these DNA templated assemblies and to determine how the guests are distributed on the templates. In Chapter 2, oligothymine templates of different length have been used to organize naphthalene based small molecules having a complementary diaminotriazine H bonding unit, to create monodisperse assemblies in which the length is defined by the template. The structure of these hybrid assemblies has been characterized in detail by a combined experimental and theoretical study. These experiments have revealed that the DNA templated self-assemblies have a right-handed helical arrangement and are held together by p-p, hydrophobic, and H bond interactions. Through the use of a theoretical mass-action model for the templated selfassembly, the host-guest and guest-guest interaction energies have been estimated by fitting the spectroscopic data. A qualitative theoretical picture of the way in which the guests are physically distributed on the templates has been obtained. Short templates are filled one-by-one at moderate fractions of bound sites. For larger templates first alternating sequences of filled and empty sections appear, before at larger fractions of bound sites, virtually all of the binding sites for all template lengths are filled. In Chapter 3, the binding of p-conjugated oligomers with DNA has been explored as a first step towards the construction of well-defined stacks in which the position of the p– conjugated molecules is directed by the DNA template via H bonding. These studies have revealed that large p-conjugated molecules in water have a strong tendency to self-assembly in a nontemplated fashion, which limits their application for DNA templated self-assembly. Increased guest–guest interaction energy between guests on the template can change the supramolecular organization of the templated self-assembly and can induce further aggregation into assemblies larger than the size of the template. Peptide nucleic acids have also been used as a template for the self-assembly of p-conjugated molecules in organic solvents. Here, the nontemplated self-assembly can be suppressed, yielding PNA templated self-assemblies of a discrete size. In Chapter 4, the use of electrospray ionization mass spectroscopy to characterize the DNA templated self-assemblies has been investigated. The highest complex mass detected is 15 kDa: a 20 component self-assembled object. Gas phase breakdown experiments on single and multiple guest–DNA assemblies have given qualitative information on the fragmentation pathway and the relative complex stability. The guest molecules are removed from the template one by one in a controlled way. The stabilities of the complexes depend mainly on the molecular weight of the guest molecules, suggesting that the complexes collapse in the gas phase. The use of oligomeric guest molecules to enhance the stability of the DNA templated assemblies have been explored in Chapter 5. The analyses performed on the DNA hybridization in this chapter have shown that binding guest strands with multiple binding sites stabilizes the complex significantly. Furthermore, it has been found that guest–guest interactions additionally stabilize the DNA hybridization of smaller oligomeric guest strands to a larger template strand. This concept has also been successfully applied to a synthetic guest molecule. In Chapter 6, a naphthalene based guest equipped with a diaminopurine H bonding unit is synthesized to enhance the stability of the DNA templated self-assemblies by increasing the guest–guest interaction. Temperature and concentration dependent UV–vis and circular dichroism data have shown that the guest–guest interaction is indeed improved, but unfortunately the host–guest interaction energy is slightly lower compared to the earlier reported oligothymine templated self-assemblies. These DNA templated self-assembly have also been studied at different pH values. Upon protonation of the guests the templated self-assembly undergoes a helix reversal which leads to an increased host–guest and guest–guest interaction energy.

We present an extensive analysis of one- and two-photon absorption processes in some organic host-guest (H-G) complexes using linear and quadratic response theory within the framework of time-dependent density functional theory. For this purpose, we have considered all possible 20 host-guest complexes constructed from 4 host and 5 guest molecules. We have analysed how the one- and two-photon activity of the host and guest molecules are transferred to the respective host-guest complexes and how the electron donating and electron accepting ability of host-guest complexes affect their two-photon activity. Based on an analysis using the concept of channel interference, we have performed an in-depth analysis of the two-photon absorption processes in all these systems and provided a microscopic explanation for their variation among different complexes.

Cucurbiturils are cage-like macrocyclic molecules that can form strong host–guest inclusion complexes, offering remarkably higher selectivity over conventional macrocycles towards guests with particular sizes and shapes. Here we use a combination of molecular docking, semiempirical quantum-chemical (PM6, PM7) and high-level DFT calculations along with all-atom molecular dynamics (MD) simulations to characterize 1:1 host-guest complexation between the cucurbit[n]urils (CB[n], where n = 6–8) and biologically active 2-[[5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]thio]acetic acid (PTTA). While the molecular docking and the semiempirical calculations suggest that PTTA favors inserting into larger size cavities of CB[7] and CB[8], the classical OPLS-AA MD simulations of the potential of the mean force (PMF) in an aqueous solution demonstrate the favorable free binding energy of PTTA with all three studied CB[n]s (n = 6–8). These findings were further examined by refining the binding energy of the MD-derived PTTA-CB[n] structures by the high-level dispersion-corrected DFT calculations. Our combined MD/DFT approach provides the detailed host-guest complexation mechanism and suggests that the stability of the host-guest inclusion complex of PTTA with CB[n]s decreases in the order CB[6]>CB[7]>CB[8]. Finally, the formation of the stable inclusion complex of PTTA with CB[6] was validated by thermogravimetric analysis and differential scanning calorimetry measurements, pointing out that low-level quantum-chemical methods might be unable to capture the correct thermodynamics of host-guest supramolecular structures based on cucurbituril macrocycles.

Open AccessCCS ChemistryCOMMUNICATIONS22 Dec 2022A Cleavable Self-Inclusion Conjugate with Enhanced Biocompatibility and Antitumor Bioactivity Han Wu, Tian Xia, Feilong Qi, Shan Mei, Yu Xia, Jiang-Fei Xu and Xi Zhang Han Wu Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 , Tian Xia MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 , Feilong Qi Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 , Shan Mei Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 , Yu Xia MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 , Jiang-Fei Xu *Corresponding author: E-mail Address: [email protected] Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 and Xi Zhang Key Laboratory of Organic Optoelectronics and Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084 https://doi.org/10.31635/ccschem.022.202202410 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The effective encapsulation of antitumor drugs by dynamic host–guest interactions at the submicromolar level remains a challenge. Herein, we report a cleavable self-inclusion camptothecin-cucurbit[7]uril (CPT-CB[7]) conjugate. The binding affinity of CB[7] to CPT is greatly enhanced owing to the intramolecular self-inclusion, demonstrating a concentration-independent encapsulation efficiency of nearly 100%. The disulfide linker of CPT-CB[7] conjugate can be cleaved in the reductive tumor microenvironment, transforming the self-inclusion into a binary host–guest complexation pattern, thus releasing the CPT thoroughly. The enhanced biocompatibility and antitumor bioactivity of the cleavable self-inclusion conjugate have been confirmed by in vitro and in vivo experiments. This line of research will open new horizons for supramolecular drug delivery systems operating in diluted and competitive conditions. Download figure Download PowerPoint Introduction Supramolecular drug delivery systems based on host–guest interactions are of great interest owing to their optimized pharmacokinetic properties, precise structures and controlled drug release.1–11 The bioactivity of antitumor drugs can be disguised by host–guest complexation and then recovered upon dissociation.12–16 To date, many kinds of supramolecular drugs have been developed to show higher biocompatibility as well as better therapeutic effects,17–19 such as oxaliplatin-cucurbit[7]uril (CB[7]),12,20–23 melphalan-β-cyclodextrin,24 and chlorambucil-calix[5]arene complexes.25 Nevertheless, for a wide range of antitumor drugs, the half maximal inhibitory concentration (IC50) is as low as about 100 nM to several μM.26–31 Considering the concentration-dependent nature of host–guest complexation, it remains a challenge for these drugs to form stable supramolecular drugs under sub-μM concentrations with both high encapsulation efficiency and stimuli-triggered release properties. Self-inclusion refers to intramolecular complexation of a host–guest conjugate that enhances the binding affinity of the host to the linked guest on account of the reduced entropic penalty.32–37 We can find proteins with the self-inclusion structure in the nature. For example, gasdermin D, a key protein for cell pyroptosis, effectively inhibits its bioactivity through intramolecular association of the functional fragments. Once cleaving the linkage between the assembled fragments, its bioactivity is recovered by dissociating the functional fragments.38,39 Inspired by this entropy-driven association, as shown in Scheme 1a, we assumed that a host-drug conjugate could be designed to form a self-inclusion supramolecular drug that would work under highly diluted conditions. Scheme 1 | (a) A schematic diagram of supramolecular drugs on the basis of the binary host–guest complexation and the cleavable self-inclusion conjugate proposed in this work; (b) the chemical structure of the cleavable host-drug conjugate CPTSSCB, and a schematic illustration of the GSH triggered drug release. Download figure Download PowerPoint To this end, as shown in Scheme 1b, a camptothecin (CPT) was linked with a CB[7] via a linkage containing a disulfide bond to construct a cleavable host-drug conjugate named CPTSSCB. CPT is a plant-derived antitumor drug which can form a ternary complex with topoisomerase I and DNA to inhibit DNA replication and induce cell apoptosis.25,40 The IC50 of CPT is about 100 nM. For the host-drug conjugate CPTSSCB, on the one hand, the CPT fragment can effectively bind with CB[7] by self-inclusion to form a stable supramolecular drug even under 100 nM. On the other hand, the disulfide linkage can be cleaved in the reductive tumor microenvironment,13,41–43 transforming the self-inclusion supramolecular drug into a binary host–guest complexation pattern, thus thoroughly releasing the CPT on account of the concentration-dependent dissociation. Results and Discussion The host-drug conjugate CPTSSCB was synthesized via mild reactions and characterized by NMR spectroscopy and high-resolution electrospray ionization mass spectrometry (ESI-MS; see the synthesis and characterization part in Supporting Information Figures S1–S6). We wondered whether the CPTSSCB could self-include to form a supramolecular drug. 1H NMR experiments were employed to study the host–guest complexation of CPTSSCB. As shown in the 1H NMR spectrum of 150 μM CPTSSCB in D2O (Figure 1bi), the chemical shift values of aromatic protons of the CPT fragment are in the 7.0–9.0 ppm range. After addition of a competitive molecule p-Xylylenebis(trimethylammonium bromide) (PXTM), a strong guest that can bind CB[7] with a binding constant as high as 1010 M−1 (See the chemical structure of PXTM in Figure 1a. Its synthetic method is shown in the synthesis and characterization part in the Supporting Information, and the characterization of the binding constant between PXTM and CB[7] is shown in Supporting Information Figure S7.), the four peaks at 7.1–7.6 ppm shifted downfield to 7.7–8.2 ppm. This suggests that the terminal benzene unit of CPT moiety was encapsulated in the cavity of CB[7]. In addition, the legible and sharp peaks of CPTSSCB shown in Figure 1b suggest that CPTSSCB does not self-assemble into large aggregates. Meanwhile, the diffusion coefficient of the saturated CPTSSCB aqueous solution (around 350 μM) was determined to be 2.30 × 10−10 m2s−1 through diffusion-ordered NMR spectroscopy, which is close to that of the CB[7] (3.11 × 10−10 m2s−1).35 The above results indicate that CPTSSCB forms a single-molecule host–guest complex in aqueous solution. Figure 1 | (a) Chemical structures of PXTM and CPTSSCB; (b) partial 1H NMR spectra of 150 μM CPTSSCB (i), 150 μM CPTSSCB + 3.0 equiv PXTM (ii), the peaks marked red belong to the benzene unit of CPT moiety, and chemical structure of PXTM, 800 MHz, D2O, 298.1 K; (c) ion mobility spectra of CPTSSCB (m/z = 951.2) under 10 μM, 1.0 μM, and 100 nM; (d) ion mobility spectrum of the 1.0 μM CPTSSCB with 10 μM PXTM (m/z = 1061.8). K0 stands for reduced mobility. Download figure Download PowerPoint The self-inclusion structure of CPTSSCB was further confirmed by trapped ion mobility spectrometry-time-of-flight mass spectrometry.34,35,44,45 As shown in Figure 1c, the collision cross section (CCS) of CPTSSCB under 10 μM was determined to be 425 Å2, which is close to that of a host–guest complex of CB[7] and viologen (335 Å2), while far less than that of a di-CB[7] conjugate (730 Å2, Supporting Information Figure S13). In addition, through diluting the CPTSSCB solution to 1.0 μM and 100 nM, the CCS values remained unchanged, clearly indicating their concentration-independent complexation property. Furthermore, as shown in Figure 1d, after an addition of excess PXTM to dissociate the complex, the CCS value increased to 461 Å2, indicating the release of the CPT fragment from the self-inclusion complex. By combining these results, we can conclude that CPTSSCB indeed forms a self-inclusion supramolecular drug under sub-μM concentrations. To calculate the encapsulation efficiency of CPTSSCB, we employed isothermal titration calorimetry to study the binding constant of self-inclusion. As shown in Supporting Information Figure S8, through titrating PXTM into CPTSSCB, the competitive binding constant was determined to be 1.05 × 107 M−1. By comparing it with the binding constant of PXTM with CB[7] (2.43 × 1010 M−1), the binding constant of the self-inclusion of CPTSSCB was calculated to be 2.31 × 103. Such a high binding affinity of self-inclusion ensures the encapsulation efficiency of CPTSSCB as high as 99.96% while not being affected by concentration. In comparison, the encapsulation ratio of CPT by CB[7] through the binary host–guest complexation pattern was estimated to be only 0.28% under 1.0 μM.46 In addition, the solubility of CPTSSCB was about 350 μM in water, which is about 100-fold higher than that of the pristine CPT, indicating the significantly improved water solubility through effective self-inclusion.47 Furthermore, as shown in Supporting Information Figure S9, after incubation with human serum albumin (HSA) for 2 h, the free CPTSSCB remained about 29.5% as measured by fluorescence intensity while for CPT, only 0.4% remained. This result indicates that CPTSSCB is able to resist adsorption and hydrolysis in the presence of HSA owing to the strong binding affinity of self-inclusion. In other words, the self-inclusion supramolecular drug shows enhanced stability against HSA. The above results demonstrate that the encapsulation efficiency of self-inclusion is nearly 100%, and the formation of a self-inclusion supramolecular drug significantly enhances the solubility and stability of CPT. To test the drug release efficiency of CPT from CPTSSCB, high-performance liquid chromatography (HPLC) experiments were carried out. As shown in Figure 2a, the retention time of CPTSSCB (9.3 min) is shorter than that of CPT (12.1 min), which could be the benefit from its better water solubility. Due to the poor binding affinity (2800 M−1),48 most CPT in the binary host–guest complex of CPT and CB[7] are in the free form, leading to the same retention time of [email protected][7] and CPT. A small peak at 11.2 min can be ascribed to the host–guest complex of [email protected][7] in the binding form. As shown in Figure 2b, upon addition of 10 mM glutathione (GSH) to a 40 μM CPTSSCB solution, the peak that belongs to CPTSSCB gradually turns to that of CPT with the extension of reaction time, indicating the release of CPT. The release efficiency can be calculated based on the relative peak areas of HPLC curves, and the release efficiency is about 95.4% at 60 min ( Supporting Information Figure S11). This result demonstrates that the cleavage of disulfide linkage in CPTSSCB transforms the self-inclusion pattern into binary complexation pattern, thus releasing CPT by the dissociation of the binary complex under low concentrations. The ESI-MS was employed to analyze the intermediate product of this reduction reaction ( Supporting Information Figure S10). A proposed mechanism of this reaction process is shown in Figure 2c. Therefore, CPT can be thoroughly released from the self-inclusion supramolecular drug through the reduction of GSH. Figure 2 | (a) HPLC elution curves of CPT, [email protected][7], and CPTSSCB (10 μM); (b) HPLC elution curves of CPTSSCB (40 μM) reacted with 10 mM GSH at different reaction time; (c) proposed mechanism for releasing CPT from CPTSSCB by GSH. Download figure Download PowerPoint To investigate whether the cleavable self-inclusion conjugate can exhibit high antitumor bioactivity, the cytotoxicity of CPTSSCB against tumor cells was evaluated by CCK-8 assay after incubating them for 48 h. As shown in Figure 3a, the supramolecular drug CPTSSCB displayed a remarkable cytotoxicity against HCT116 cells, whose IC50 was calculated to be 224 nM. On the contrary, CPTSSCB showed the weaker antitumor bioactivity than the pristine CPT on health colorectal cells (NCM 460, as shown in Supporting Information Figure S14). In addition, the CPTSSCB also showed a high antitumor bioactivity against Hela cells with the IC50 of 179 nM ( Supporting Information Figure S12). Similar cytotoxicity of CPTSSCB and pristine CPT indicates that the CPT fragment in CPTSSCB can be effectively released to show its antitumor bioactivity. To confirm the release of CPT through the cleavage of the disulfide bond, a self-inclusion conjugate that cannot be cleaved, named CPTEGCB (Figure 3b), was used as a control. Due to the absence of the disulfide bond, the CPT fragment in CPTEGCB was stably encapsulated in the cavity of CB[7] by self-inclusion, thus demonstrating low cytotoxicity. As shown in Figure 3a, the cell viability of HCT116 was higher than 90% in the concentration range of 1.0 nM∼1.0 μM, and the IC50 of CPTEGCB is higher than 10 μM. Therefore, the cleavable self-inclusion conjugate exhibited high antitumor bioactivity on the basis of tumor microenvironment-triggered drug release. Figure 3 | (a) Cell viability of CPT, CPTSSCB, and CPTEGCB for HCT116 cells after incubating 48 h; (b) chemical structure of CPTEGCB. Download figure Download PowerPoint We wondered whether the high antitumor bioactivity of the cleavable self-inclusion conjugate could be exhibited in vivo. To answer this question, Hela tumor xenograft model experiments were conducted on nude mice, and the therapeutic effect of CPTSSCB was estimated according to their tumor size and body weight. As shown in Figure 4a, the tumor growth inhibition rate of CPTSSCB was as high as 76.2%, exhibiting significant treatment outcomes. While CPT shows a limited inhibition rate of tumor growth, this could be attributed to its instability in blood circulation and poor water solubility. The control compound CPTEGCB also did not exhibit remarkable inhibition for tumor growth, indicating that the introduction of a cleavable bond is necessary for drug release. In addition, as shown in Figure 4b, the negligible relative body weight loss of mice in the CPTSSCB group was observed, demonstrating its safety and good biocompatibility for mice. To further understand the higher tumor growth inhibition rate of CPTSSCB, the in vivo blood elimination kinetics of CPTSSCB and CPT have been studied on SD rats. As shown in Supporting Information Figure S15, the rats that intravenously administrated CPTSSCB demonstrated significantly higher CPT concentration in plasma than neat CPT group. The area under the curve in plasma was 3.94 μg/mL·h for CPTSSCB group, which was 5.25-fold higher than that of CPT group. Therefore, this could be a possible reason for the better anti-tumor activity of CPTSSCB than CPT in the animal experiments. The above results confirm that the cleavable self-inclusion conjugate not only ensures the safety of CPT, but it also remarkably improves the in vivo antitumor bioactivity. Figure 4 | (a) Relative tumor volume and (b) relative body weight of nude mice with Hela tumor xenografts during treatment with prescribed formulations (n = 3, tail vein injection, in terms of CPT concentration with 2.5 mg/kg, 7 times in 2 weeks). Download figure Download PowerPoint Conclusion We have constructed a cleavable self-inclusion host-drug conjugate CPTSSCB and successfully demonstrated its good biocompatibility as well as enhanced antitumor bioactivity. The significant advantages of CPTSSCB result from its nearly 100% encapsulation efficiency even under sub-μM, which improves the water solubility and stability of CPT. What is more, the cleavage of CPTSSCB under the reductive tumor microenvironment transforms the self-inclusion manner into binary host–guest complexation, triggering complete drug release owing to the concentration-dependent complexation. We envision that this self-inclusion supramolecular strategy can be applied to many other kinds of antitumor drugs as well as host molecules. It is highly anticipated that this line of research will open new horizons for supramolecular drug delivery systems operating under diluted and competitive conditions. Supporting Information Supporting Information is available and includes experimental details about synthetic methods and characterizations of PXTM, CPTSSCB, and CPTEGCB; the binding constant of self-inclusion; interaction between HSA and CPT, [email protected][7], and CPTSSCB; drug release by GSH; cytotoxicity of self-inclusion supramolecular drug to Hela cells and NCM460 cells; some diffusion coefficients and CCS of model molecules; and in vivo blood elimination kinetics of CPT and CPTSSCB. Disclosures Animal care and handling procedures were in agreement with the guidelines evaluated and approved by the Institutional Animal Care and Use Committee (IACUC) of the Laboratory Animal Research Center, Tsinghua University. Study protocols involving animals were approved by the IACUC of the Laboratory Animal Research Center, Tsinghua University (2022-299). Conflict of Interest There is no conflict of interest to report. Funding Information This work was financially supported by the Ministry of Science and Technology of China (grant no. 2018YFA0208900), the National Natural Science Foundation of China (grant no. 21821001), and the Strategic Priority Research Program of Chinese Academy of Sciences (grant no. XDB36000000). Acknowledgments The authors are grateful to Chen Zhou (Institute of Chemistry, Chinese Academy of Sciences) for his help with HPLC experiments, Dr. Shaolong Qi (Tsinghua University) for his help with animal experiments, and Dr. Guocan Yu (Tsinghua University) for helpful discussions. Some NMR experiments were carried out at the BioNMR facility, Tsinghua University Branch of China National Center for Protein Sciences (Beijing). We also thank Dr. Ning Xu for assistance in NMR data collection.

The introduction of non-covalent bonds is effective for achieving self-healing properties because they can be controlled reversibly. One approach to introduce these bonds into supramolecular materials is use of host-guest interactions. This feature article summarizes the development of supramolecular materials constructed by non-covalent cross-linking through several approaches, such as host-guest interactions between host polymers and guest polymers, 1 : 2-type host-guest interactions, and host-guest interactions from the polymerization of host-guest inclusion complexes. Host-guest interactions show self-healing functions while also enabling stimuli-responsiveness (redox, pH, and temperature). The self-healing function of supramolecular materials is achieved by stress dispersion arising from host-guest interactions when stress is applied. Reversible bonds based on host-guest interactions have tremendous potential to expand the variety of functional materials.

Amplification of asymmetry (chiral amplification) isone of thedistinctive phenomena of dynamic helical polymers whose helical senseexcess is significantly enhanced with a small amount of chiral unitsthrough the strong cooperative interactions among the monomer units.The Ising model for the amplification of asymmetry in the dynamichelical copolymers bearing the chiral side chains has been well-established.However, the theoretical models have not yet been developed for theamplification of asymmetry in the dynamic helical polymers inducedby noncovalent intermolecular (host–guest) interactions ofthe achiral side chains with the chiral/chiral (majority rule effect)and chiral/achiral (sergeants and soldiers effect) guest molecules.In this work, we propose the theoretical models for two types of 1:1host–guest interactions: the majority rule effect type 1:1host–guest interaction (MRHG) and sergeants and soldiers effecttype 1:1 host–guest interaction (SSHG) models, in which eachtwisting unit of the dynamic helical polymers is assumed to interactwith one guest molecule. The excess energy of the helical reversalstate (ΔGr), per unit energy favoringone helical state over the other (2ΔGh), and enantioselectivity (α) can be effectively determinedusing the MRHG model. Moreover, it was revealed that the chiral solvationmodel reported by Green, Morawetz, and co-workers is a particularsolution of the SSHG model.

The construction of distorted or irregular coordination polyhedrons with specific shapes and functionalities is highly challenging. Here, we demonstrate a viable strategy for attaining a severely d...

Host–Guest chemistry based on solid-state pillar[n]arenes

The physical nature of host-guest (HG) interactions occurring between molecular triangles and linear anions was explored using density functional theory (DFT) calculations combined with energy decomposition analyses (EDA), nuclear independent chemical shift (NICS), and non-covalent interaction index (NCI). We demonstrate that: (i) in addition to the host being significantly rigid, the strain energies are not negligible, especially for host 2; (ii) halogen anions interact mainly by electrostatic forces (ΔEelst > ΔE > ΔEdisp), meanwhile; (iii) trihalogen anions interact mostly by dispersion forces (ΔEdisp > ΔEelst≈ΔE). The NICS and NCI calculations corroborate the idea that HG interactions are considerably mediated through dispersion terms, and also indicate an antiaromatic character inside the host walls.

Compared with conventional drug delivery systems (DDSs), DDSs based on host-guest interactions possess unique advantages, such as high selectivity, tunable binding ability, and controllable release of drugs. It is important to study the host-guest interactions between the carrier and drug under physiological conditions for constructing DDSs. In this work, we have studied the host-guest interaction between cucurbit[7]uril (CB[7]) and oxaliplatin (OxPt), a clinical antitumor drug, in the cell culture medium. The results show that amino acids such as phenylalanine in the 1640 culture medium can partially occupy the cavity of CB[7], which leads to the decrease of enthalpy changes of the host-guest interaction between OxPt and CB[7]. In addition, inorganic salts such as NaCl in the medium reduce the enthalpy change and increase the entropy change of the binding because of the preorganization of the portal of CB[7] and sodium cation. As a result, the binding constant of CB[7] with OxPt in the 1640 culture medium is 1/20 of that in pure water. When CB[7] is modified at the terminal of star-type PEG to construct the star-PEGylated CB[7], it is shown that the molecular weight and topological structure of the PEG polymer backbone exhibit little effect on the host-guest interactions between CB[7] and OxPt. This study enriches the host-guest chemistry of cucurbiturils and may provide guidance for constructing novel DDSs based on host-guest interactions with high loading and releasing efficiency.

CONSPECTUS: All living organisms and soft matter are intrinsically responsive and adaptive to external stimuli. Inspired by this fact, tremendous effort aiming to emulate subtle responsive features exhibited by nature has spurred the invention of a diverse range of responsive polymeric materials. Conventional stimuli-responsive polymers are constructed via covalent bonds and can undergo reversible or irreversible changes in chemical structures, physicochemical properties, or both in response to a variety of external stimuli. They have been imparted with a variety of emerging applications including drug and gene delivery, optical sensing and imaging, diagnostics and therapies, smart coatings and textiles, and tissue engineering. On the other hand, in comparison with molecular chemistry held by covalent bonds, supramolecular chemistry built on weak and reversible noncovalent interactions has emerged as a powerful and versatile strategy for materials fabrication due to its facile accessibility, extraordinary reversibility and adaptivity, and potent applications in diverse fields. Typically involving more than one type of noncovalent interactions (e.g., hydrogen bonding, metal coordination, hydrophobic association, electrostatic interactions, van der Waals forces, and π-π stacking), host-guest recognition refers to the formation of supramolecular inclusion complexes between two or more entities connected together in a highly controlled and cooperative manner. The inherently reversible and adaptive nature of host-guest molecular recognition chemistry, stemming from multiple noncovalent interactions, has opened up a new platform to construct novel types of stimuli-responsive materials. The introduction of host-guest chemistry not only enriches the realm of responsive materials but also confers them with promising new applications. Most intriguingly, the integration of responsive polymer building blocks with host-guest recognition motifs will endow the former with further broadened responsiveness to external stimuli and accordingly more sophisticated functions. In this Account, we summarize recent progress in the field of responsive polymeric materials containing host-guest recognition motifs with selected examples and highlight their versatile functional applications, whereas small molecule-oriented host-guest supramolecular systems are excluded. We demonstrate how the introduction of host-guest chemistry into conventional polymer systems can modulate their responsive modes to external stimuli. Moreover, the responsive specificity and selectivity of polymeric systems can also be inherited from the host-guest recognition motifs, and these features provide extra advantages in terms of function integration. The following discussions are categorized in terms of design and functions, namely, host-guest chemistry toward the fabrication of responsive polymers and assemblies, optical sensing and imaging, drug and gene delivery, and self-healing materials. A concluding remark on future developments is also presented. We wish this prosperous field would incur more original and evolutionary ideas and benefit fundamental research and our daily life in a more convenient way.

SummaryThe precise sequence control of polymer chain is an important research topic of polymer chemistry. Although some methods such as iterative synthesis and supramolecular polymerization have been developed to fabricate sequence-controllable polymer, it is still a great challenge to consecutively prepare multiple supramolecular polymers with different sequence structures. In this work, through the reasonable utilization of assembly motifs, we integrated multiple host-guest recognitions and metal coordination interactions to prepare different sequence-controlled supramolecular polymers by a multistep assembly strategy. This research provides inspiration for the design and preparation of supramolecular polymers with different sequence structures.