Supramolecularly Engineered Conjugate of Bacteria and Cell Membrane-Coated Magnetic Nanoparticles for Enhanced Ferroptosis and Immunotherapy of Tumors.

Although various ferroptosis inducers including magnetic nanoparticles (Fe3 O4 ) and iron-organic frameworks have been applied in cancer treatment, the mild immunogenicity, low targeting efficiency to the tumor, and poor tissue penetration have limited the therapeutic efficacy. Herein, a supramolecularly engineered conjugate between living bacteria (facultative anaerobic Salmonella typhimurium VNP20009, VNP) and cancer cell membranes-coated Fe3 O4 nanoparticles is developed for improving targeted delivery of Fe3 O4 nanoparticles into the tumor tissue and for synergistic ferroptosis and immunotherapy of tumor. The enhanced ferroptosis induced by both Fe3 O4 nanoparticles and the loaded ferroptosis inducing agent (sulfasalazine (SAS)) effectively inhibits tumor growth and generates immune response via immunogenic cell death (ICD). The colonization of VNP in tumors also induces adaptive immune responses and further promotes ferroptosis. Fundamentally, the supramolecular conjugate of VNP and cell membranes-coated Fe3 O4 can potentiate the therapeutic capability of each other through mutually magnifying the ferroptosis and immunotherapy, resulting in significantly enhanced antitumor effects.

Platelet-mimicking supramolecular nanomedicine with precisely integrated prodrugs for cascade amplification of synergistic chemotherapy.

Camptothecin (CPT) and cisplatin (Pt) have shown synergistic effects on a variety of cancers during preclinical and clinical studies. However, the ratio of the two drugs often could not be precisely regulated in different delivery systems, which hinders the desired synergistic effect. In addition, the low delivery efficiency of the two drugs to the tumor further impedes the ideal therapeutic outcomes. Herein, we report that a platelet-mimicking supramolecular nanomedicine (SN) could precisely control of the ratio of CPT and Pt with a high tumor accumulation rate for cascade amplification of synergistic chemotherapy. The SN was fabricated via the host-guest interaction between cucurbit[7]uril conjugated hyaluronic acid (HA-CB[7]) and adamantane (ADA) respectively functionalized CPT- and Pt-based prodrugs. The ratio of CPT and Pt in the SN could be facilely regulated by simply controlling the loading ratio, based on the strong binding affinity between CB[7] and ADA, and SN60 with 60% CPT and 40% Pt showed the highest synergistic effects on 4T1 cells. To improve the tumor accumulation efficiency of SN, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a tumor vasculature-disruptive agent) was loaded into the optimized SN and then coated with platelet membrane to yield platelet-mimicking supramolecular nanomedicine (D@SN-P). D@SN-P could first passively accumulate in tumors owing to the enhanced permeability and retention (EPR) effect after intravenous administration. The initially release of DMXAA from D@SN-P could induce tumor vascular disruption, and the resultant epithelial collagen exposure around the disrupted tumor vasculature provided a target for further recruitment of platelet-mimicking SN, leading to cascade amplification of tumor accumulation with synergistic chemotherapy. Hence, this platelet-mimicking supramolecular nanomedicine presents a universal supramolecular strategy to finely regulate the ratio of loaded pro-drugs, and improve the accumulation efficiency to amplify chemotherapy via platelet-mimics.

Microalgae Microneedle Supplies Oxygen for Antiphotoaging Treatment.

UV exposure often triggers photoaging of the skin. Pharmacological treatment suffers from severe side effects as well as poor efficacy because of insufficient skin penetration. Dissolved oxygen has been previously shown to reverse photoaged skin; however, the treatment is often limited by the availability of equipment (e.g., high-pressure oxygen). Poor oxygen diffusion into the skin has also limited its therapeutic efficacy. Herein, we developed a microneedle patch to deliver living microalgae to the deeper layers of the skin for efficient oxygenation and reversal of photoaging. The continuous release of oxygen from microalgae in the skin through photosynthesis reversed the inflammatory microenvironment and reduced reactive oxygen species levels in the photodamaged skin, leading to collagen regeneration and reduced wrinkles. This study provides not only a means for highly efficient skin oxygenation and reversal of photoaging but also an important theoretical basis for the clinical treatment of photoaging.

Drug-free tumor therapy via spermine-responsive intracellular biomineralization.

Chemotherapy based on molecular drugs remains the most frequently used approach for the therapy of tumors, however their poor specificity, severe side effects and tumor resistance often seriously hinder their applications. It is therefore desirable to develop a new, alternative therapeutic strategy for tumor treatment without traditional chemotherapeutic drugs. Herein, we report a drug-free tumor therapy approach involving spermine (SPM)-responsive intracellular biomineralization in tumor cells. In this work, we designed calcium carbonate (CaCO3) nanoparticles capped with folic acid and supramolecular peptides, which could target tumor cells and rapidly self-aggregate into micron-sized CaCO3 aggregates in SPM-overexpressed tumor cells. Due to the extended intracellular retention, CaCO3 aggregates could induce intracellular biomineralization and Ca2+ overload of tumor cell, leading to mitochondrial damage and cellular apoptosis, resulting in effective inhibition of tumor growth without serious side effects otherwise seen in conventional chemotherapy.

Hyaluronic acid-based supramolecular nanomedicine with optimized ratio of oxaliplatin/chlorin e6 for combined chemotherapy and O2-economized photodynamic therapy.

Dual- or multi-modality combination therapy has become one of the most effective strategies to overcome drug resistance in cancer therapy, and the optimized ratio of the therapeutic agents working on the tumor greatly affects the therapeutic outcomes. However, the absence of a facile method to optimize the ratio of therapeutic agents in nanomedicine has, at least in part, impaired the clinical potential of combination therapy. Herein, a new cucurbit[7]uril (CB[7])-conjugated hyaluronic acid (HA) based nanomedicine was developed, in which both chlorin e6 (Ce6) and oxaliplatin (OX) were co-loaded non-covalently at an optimized ratio via facile host-guest complexation, for optimal, combined photodynamic therapy (PDT)/chemotherapy. To maximize the therapeutic efficacy, a mitochondrial respiration inhibitor, atovaquone (Ato), was also loaded into the nanomedicine to limit consumption of oxygen by the solid tumor, sparing oxygen for more efficient PDT. Additionally, HA on the surface of nanomedicine allowed targeted delivery to cancer cells with over-expressed CD44 receptors (such as CT26 cell lines). Thus, this supramolecular nanomedicine platform with an optimal ratio of photosensitizer and chemotherapeutic agent not only provides an important new tool for enhanced PDT/chemotherapy of solid tumors, but also offers a CB[7]-based host-guest complexation strategy to facilely optimize the ratio of therapeutic agents for multi-modality nanomedicine. STATEMENT OF SIGNIFICANCE: Chemotherapy remains the most common modality for cancer treatment in clinical practice. Combination therapy by co-delivery of two or more therapeutic agents has been recognized as one of the most effective strategies to improve therapeutic outcome of cancer treatment. However, the ratio of loaded drugs could not be facilely optimized, which may greatly affect the combination efficiency and overall therapeutic outcome. Herein, we developed a hyaluronic acid based supramolecular nanomedicine with facile method to optimize the ratio of two therapeutic agents for improved therapeutic outcome. This supramolecular nanomedicine not only provides an important new tool for enhanced photodynamic therapy/chemotherapy of solid tumors, but also offers insights in using macrocyclic molecule-based host-guest complexation to facilely optimize the ratio of therapeutic agents in multi-modality nanomedicine.

Hyaluronic acid-based supramolecular medicine with polyamines sequestration capability for cooperative anti-psoriasis.

Psoriasis seriously harms physical and mental health of patients. Hyaluronic acid (HA)-based topical formulation can increase drug concentration in psoriatic skin via CD44-assisted targeting. Herein, we developed a supramolecular medicine composed of curcumin-loaded HA-cucurbit[7]uril (HA-CB[7]@Cur), which could efficiently sequester polyamines (PAs) via host-guest interactions of CB[7] and PAs to suppress RNA-PAs immunocomplex formation. Meanwhile, anti-psoriasis drug Cur could be released from HA-CB[7]@Cur by PAs. With phenotypical disease evaluation, psoriasis area measurements and severity index scoring, and histological characterizations, we demonstrate topical administration of Carbopol gel formulation of HA-CB[7]@Cur on psoriasis-like skin in mice exhibited an enhanced anti-psoriasis activity, in comparison with gel of free Cur or HA-CB[7]. Cytokine expression analysis in psoriatic skin also supported the observed therapeutic outcomes. We provide a novel and effective supramolecular strategy to realize cooperative anti-psoriasis via controlled release of curcumin and PAs sequestration, which can be potentially expanded to treat other PA-involved skin inflammatory diseases.

Supramolecularly functionalized platelets for rapid control of hemorrhage.

Excessive bleeding has always been of great medical challenge, particularly in trauma and surgery. Due to the fast clearance of medicine and complex hemodynamics during hemorrhage, it is often difficult to achieve rapid and effective hemostasis on irregularly shaped, noncompressible visceral bleeding wounds. Herein, we report a hemostatic derived from supramolecularly functionalized platelets (SPLTs), showing rapid hemorrhage controlling effects via efficiently targeting injured vessels and in-situ aggregation. Von Willebrand factor-binding peptide (VBP) modified hyaluronic acid (HA-VBP) decorated platelets (PLTs) were fabricated via supramolecular host-guest interactions between cucurbit[7]uril (CB[7], a host molecule) modified on HA-VBP (HA-CB[7]-VBP) and adamantane (ADA, a guest molecule) anchored on the surface of PLTs (ADA-PLTs). The SPLTs demonstrated approximately 10-fold improvements than the native PLTs in the targeting efficiency into the injured vessels in mice upon intravenous injection. More significantly, the total bleeding time and bleeding volume were dramatically reduced down to less than 1/4 and 1/10 of the control group, respectively, in both external and internal major bleeding mice models. This SPLTs provide a facile yet effective approach for rapid control of major hemorrhage and offers important new insights to the design and development PLTs-based hemostatics. STATEMENT OF SIGNIFICANCE: Hemorrhage is one of the greatest threats to humans in trauma and surgery. To reduce bleeding volume and time, transfusion of hematological products such as platelets (PLTs)-rich plasma is one of the most commonly used therapeutics, but with low targeting and hemostatic efficiency. Thus, engineered PLTs with expanded structural repertoire and functionalities are in urgent clinical needs. Herein, we developed supramolecularly functionalized PLTs (SPLTs), prepared with a mild and facile approach, for rapid control of hemorrhage with significantly enhanced targeting efficiency. The SPLTs not only provide a facile approach for rapid control of major hemorrhage, but also offer important new insights into the development PLTs-based hemostatics.

Spermine-Responsive Intracellular Self-Aggregation of Gold Nanocages for Enhanced Chemotherapy and Photothermal Therapy of Breast Cancer.

Improving the precise accumulation and retention of nanomedicines in tumor cells is one of the keys to effective therapy of tumors. Herein, supramolecular peptides capped Au nanocages (AuNCs) that may self-aggregate into micron-sized clusters intracellularly in response to spermine (SPM), leading to specific accumulation and retention of AuNCs in SPM-overexpressed tumor cells, are developed. In this design, polydopamine (PDA) is in situ coated on the surface of AuNCs with doxorubicin (DOX) encapsulated. A small peptide, Phe-Phe-Val-Leu-Lys (FFVLK), is conjugated with PDA via esterification, and cucurbit[7]uril (CB[7]) is threaded onto the N-terminal Phe via host-guest interactions. Once the supramolecular peptide (CB[7]-FFVLK) capped AuNCs are internalized in SPM-overexpressed breast cancer cells, CB[7] can be competitively removed from FFVLK by SPM, due to the much higher binding affinity between CB[7] and SPM than that between CB[7] and Phe, leading to exposure of free FFVLK, which can subsequently self-assemble and induce the aggregation of AuNCs to micron-sized clusters, resulting in the significantly enhanced accumulation and retention of DOX-loaded AuNCs in tumor cells. Under NIR laser irradiation, the enhanced photothermal conversion of AuNCs aggregates, together with photothermia-induced release of DOX leads to synergistic photothermal therapy and chemotherapy against breast cancer.

Supramolecular biomaterials for bio-imaging and imaging-guided therapy.

Benefiting from their unique advantages, including reversibly switchable structures, good biocompatibility, facile functionalization, and sensitive response to biological stimuli, supramolecular biomaterials have been widely applied in biomedicine. In this review, the representative achievements and trends in the design of supramolecular biomaterials (mainly those derived from biomacromolecules) with specific macromolecules including peptides, deoxyribonucleic acid, and polysaccharides, as well as their applications in bio-imaging and imaging-guided therapy are summarized. This review will serve as an important summary and "go for" reference for explorations of the applications of supramolecular biomaterials in bio-imaging and image-guided therapy, and will promote the development of supramolecular chemistry as an emerging interdisciplinary research area.

Hyaluronic acid-based nanogels derived from multicomponent self-assembly for imaging-guided chemo-photodynamic cancer therapy.

Multifunctional theranostic nanoplatforms integrated of imaging function, multi-modality therapy, stimuli-responsiveness, and targeted delivery are of highly desirable attributes in achieving precise medicine. However, preparation of multifunctional nanoplatforms often involves laborious, multiple steps and inevitably utilizes low-biocompatible or non-functional components. Herein we report a facile, one-step self-assembly strategy to fabricate hyaluronic acid (HA)-based multifunctional tumor theranostic nanoplatform by employing magnetic resonance imaging (MRI) agent Mn2+ as a reversible crosslink agent for histidine-grafted HA, along with simultaneously loading chemotherapeutic agent doxorubicin hydrochloride (DOX) and photodynamic therapy agent chlorin e6, to realize MRI-guided targeted chemo-photodynamic cancer therapy. The targeted delivery and stimuli-responsive payload release were demonstrated in vitro and in vivo. Furthermore, the combined chemo-photodynamic therapy of the nanoassembly dramatically improved the cancer therapeutic outcome, in comparison with that of free DOX and nanoplatform solely loaded DOX in a melanoma bearing mice. Our one step assemble strategy is of great potential in clinic transformation.

Supramolecular nanomedicine derived from cucurbit[7]uril-conjugated nano-graphene oxide for multi-modality cancer therapy.

Nano-graphene oxide (NGO) has attracted increasing attention as an advanced drug delivery system. However, the current surface functionalization and drug-loading of NGO either rely on π-π stacking that is limited to aromatic molecules, or covalent conjugation that requires tedious synthesis. Herein, we developed the first cucurbit[7]uril (CB[7])-conjugated NGO (NGO-CB[7]) that allows non-covalent, modular surface functionalization and drug loading via not only traditional π-π stacking interactions between the NGO surface and functional molecules, but also strong host-guest interactions between CB[7] and guest payloads or adamantane (ADA)-tagged functional molecules, for more versatile biomedical applications. To this end, chlorin e6 (Ce6, a photosensitizer), banoxantrone dihydrochloride (AQ4N, a hypoxia-responsive prodrug) and oxaliplatin (OX, a guest of CB[7]) were co-loaded onto NGO-CB[7] via π-π stacking and host-guest interactions, respectively. Subsequently, ADA-tagged hyaluronic acid (ADA-HA) wrapped NGO-CB[7] non-covalently via CB[7]-ADA host-guest interactions to improve the physiological stability and overall biocompatibility of this supramolecular nanosystem, and to enable targeted delivery into cancer cells with CD44 receptors overexpressed. Remarkably, this supramolecular nanomedicine exhibited significant antitumor efficacy via combined photothermal/photodynamic therapy (PTT/PDT) from NGO/Ce6, as well as dual chemotherapy from OX and AQ4N (activated by PDT-enhanced hypoxia), in vitro and in vivo. This study not only offers a new supramolecular inorganic/organic hybrid nanosystem for multi-modality cancer therapy, but may also provide important new insights into noncovalent functionalization of other carbon nanomaterials and inorganic nanomaterials leading to multifunctional drug delivery systems.

Excessive Internet and game use among children with different household registration in Shanghai / 中国学校卫生

Objective@#To explore the status and related factors of excessive Internet and game use among primary and junior high school students with different household registration in Shanghai, and to provide a reference for creating healthy digital media usage family environment among children.@*Methods@#A questionnaire survey was conducted among 2 324 students and their parents from 4 primary schools, 4 middle schools in Shanghai. The sociodemographic characteristics, Internet Addiction Test, Game addiction scale and Family APGAR Index were investigated.@*Results@#Excessive internet use rate and the excessive game use rate was 16.1% and 9.4%, respectively. Low family economic status( OR =2.07), motivation type of Internet use to maintain emotional arousal ( OR =5.44) or to satisfy social function( OR =8.72), peer all the time gaming use( OR =2.21), peer gaming invitation( OR =1.85, 2.56, 2.53), family dysfunction above moderate( OR =2.62, 2.68) were positively associated with excessive internet use( P <0.05). Lack of confidence in their studies( OR =2.11, 4.14), motivation type of Internet use to maintain emotional arousal( OR = 4.82 ) or to satisfy social function( OR =6.09), peer often( OR =2.84) or all the time gaming use( OR =3.92), family dysfunction above moderate( OR =2.57, 2.16) were associated with excessive game use( P <0.05).@*Conclusion@#There is no significant difference in the excessive Internet and game use among children with different household registration.It is suggested that should attach importance to peer influence and family function, advocate schools and families to create a good environment for children s digital media use, and promote children s healthy development.

Oral Colon-Targeted Konjac Glucomannan Hydrogel Constructed through Noncovalent Cross-Linking by Cucurbit[8]uril for Ulcerative Colitis Therapy.

Orally administered colon-targeted formulations of drugs are of great importance in managing diseases in the colon. However, it is often challenging to maintain the integrity of such formulations during delivery, particularly in the gastric environment, which may lead to premature drug release before reaching the targeted colon. Herein, an oral colon-targeted drug delivery hydrogel (OCDDH) was developed through cucurbit[8]uril (CB[8])-mediated noncovalent cross-linking of phenylalanine (Phe)-modified Konjac glucomannan (KGM), in which berberine (BBR), a natural anti-inflammatory product originating from Chinese medicine, was loaded into the hydrogel matrix. With the strong host-guest complexation mediated cross-linking and the inherent reversibility of such interactions, KGM-Phe@CB[8] hydrogel exhibited a readily tunable degree of cross-linking and an excellent self-healing capability, and therefore the hydrogel retained ultrahigh stability in the gastric environment, which is important for orally administered formulations to target the colon. In the colon, KGM may get degraded by colon-specific enzymes, ß-mannanase or ß-glucosidase, resulting in burst release of the loaded cargoes on site. The structure and specific payload release of the hydrogel, with and without BBR, have been fully characterized in vitro, and the therapeutic effect of BBR-loaded KGM-Phe@CB[8] hydrogel was evaluated against dextran sulfate sodium (DSS) induced ulcerative colitis (UC) in a mouse model. Very interestingly, the BBR-loaded KGM-Phe@CB[8] hydrogel exhibited significantly improved therapeutic efficacy in treating colitis, without causing any systemic toxicity, when compared with free BBR. This strategy may pave a new way in the development of advanced supramolecular OCDDH.

Host-Guest Interactions Initiated Supramolecular Chitosan Nanogels for Selective Intracellular Drug Delivery.

Polysaccharide-based nanogels have drawn considerable interest in pharmaceutics because of their superior biocompatibility and potential responsiveness to external stimuli, enabling specific drug release. During the fabrication of nanogels, however, covalent cross-linking often involves less friendly cross-linkers and traditionally employed noncovalent cross-linking often relies on weak interactions that may lead to premature payload release. Herein, we report host-guest chemistry-driven supramolecular chitosan nanogels (CNGs) that are responsive to either endogenous or exogenous stimuli, thus allowing selective drug release in specific cancer cells or disease sites. In an aqueous solution, two phenylalanine (Phe) units of Phe-grafted chitosan (CS-Phe) were encapsulated into one cavity of cucurbit[8]uril (CB[8]), driving cross-linking of CS-Phe and formation of CNGs. Doxorubicin hydrochloride (DOX), a chemotherapeutic agent, was entrapped in the matrix of CNGs during the formation of nanogels to yield DOX-CNGs with an excellent drug loading efficiency. The morphology and size of CNGs were fully assessed by transmission electron microscopy and dynamic light scattering. The encapsulated DOX was selectively liberated in the presence of competitive guests of CB[8], such as endogenous spermine (SPM) that is overexpressed by certain types of cancer cells or exogenous amantadine (ADA) that may be added into cells or tissues that require targeted treatment, either of which may replace Phe from the cavity of CB[8] resulting in the breakdown of the nanogels and payload release. The CNGs were efficiently internalized by cells, and the DOX-CNGs exhibited specific, potent activity against cancerous cells such as A549 cell line that is well known for SPM overexpression. This study reports that the first stimuli (competitive guest)-responsive host-guest interactions initiated supramolecular CNGs with excellent biocompatibility and selective therapeutic efficacy against cancer cells. It may provide new insights into the design and fabrication of novel stimuli-responsive payload delivery systems.

Dual stimuli-responsive bispillar[5]arene-based nanoparticles for precisely selective drug delivery in cancer cells.

Paclitaxel-loaded nanoparticles based on a bispillar[5]arene compound were successfully developed using a microemulsion method for the first time. The nanoparticles exhibited dual stimuli-responsiveness towards both spermine and glutathione, allowing precisely selective drug release in lung cancer cells that overexpress both stimuli.

Macrocycle-wrapped polyethylenimine for gene delivery with reduced cytotoxicity.

Due to its outstanding capability to facilitate DNA condensation, transportation and endosomal escape, polyethylenimine (PEI) has been frequently studied for gene delivery. However, its molecular weight (M.W.) dependent transfection efficiency and cytotoxicity has severely limited its clinical application. To resolve this dilemma, a supramolecular strategy was developed for the first time, in which PEI with large M.W. (branched, 25 kDa) that has a satisfactory transfection efficiency, yet high non-specific cytotoxicity for gene delivery was wrapped with macrocyclic cucurbit[7]uril (CB[7]). The successful wrapping of the PEI by the macrocyclic CB[7] was proved by 1H NMR spectroscopy and supported by isothermal titration calorimetry (ITC). The plasmid DNA (pDNA) condensability of PEI was not affected by the supramolecular coating as evidenced from the agarose gel electrophoresis assay. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results demonstrated that the particle size, zeta potential, and morphology of the self-assemblies of PEI/pDNA and PEI/CB[7]/pDNA were comparable. As a consequence of the supramolecular wrapping, the cytotoxicity of PEI was significantly constrained as demonstrated by MTT assay, apoptosis assay, and a hemolysis study. In particular, both the cellular uptake and the gene transfection efficiency results suggest that the supramolecular wrapping of PEI by CB[7] exhibits negligible effects on PEI, thus functioning as an effective non-viral gene delivery vector. This novel supramolecular-wrapping strategy provides new insights for facile alleviation of the non-specific toxicity of PEI and potentially other polycationic gene vectors without compromising their transfection efficiency.

Highly Biocompatible Chlorin e6-Loaded Chitosan Nanoparticles for Improved Photodynamic Cancer Therapy.

The photosensitizer Chlorin e6 (Ce6) has been frequently employed for photodynamic therapy (PDT) of cancer; however, its nonspecific toxicity has limited its clinical applications. In this study, we prepared chitosan nanoparticles (CNPs), with a mean diameter of approximately 130 nm, by a nonsolvent-aided counterion complexation method in an aqueous solution, into which Ce6 could be physically entrapped during the preparation process. These CNPs and Ce6-loaded CNPs (CNPs-Ce6) were fully characterized by UV-vis, photoluminescence, and Fourier transform infrared spectroscopic analysis, as well as dynamic light scattering and transmission electron microscopy measurements. More importantly, the biocompatibility of the otherwise toxic Ce6 was significantly improved upon its loading into the CNPs, as demonstrated by both confocal laser scanning microscopy analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Furthermore, the PDT efficiency of Ce6-loaded CNPs was dramatically enhanced, in comparison with that of the free Ce6, as shown by both MTT and flow cytometry assays. This discovery provides a novel strategy for improving the biocompatibility and therapeutic efficacy of PDT agents by using a natural, biocompatible polysaccharide carrier.

An eco-friendly in situ activatable antibiotic via cucurbit[8]uril-mediated supramolecular crosslinking of branched polyethylenimine.

We report an unprecedented, eco-friendly, in situ activatable model antibiotic, phenylalanyl-polyethylenimine (PhePEI), to potentially diminish antibiotic pollution of the environment and associated antibiotic resistance. The inactive PhePEI can be reversibly activated upon supramolecular crosslinking by cucurbit[8]uril, conferring potent antibacterial activity.

Encapsulation of AGE-Breaker Alagebrium by Cucurbit[7]uril Improved the Stability of Both Its Carbonyl α-Hydrogen and Thiazolium C2-Hydrogen.

As determined by both 1 H NMR and UV/Vis spectroscopic titration, ESI-MS, isothermal titration calorimetry, and DFT molecular modeling, advanced glycation end products (AGE) breaker alagebrium (ALA) formed 1:1 guest-host inclusion complexes with cucurbit[7]uril (CB[7]), with a binding affinity, Ka , in the order of magnitude of 105 m-1 , thermodynamically driven by both enthalpy (ΔH=-6.79 kcal mol-1 ) and entropy (TΔS=1.21 kcal mol-1 ). For the first time, a dramatic inhibition of keto-enol tautomerism of the carbonyl α-hydrogen of ALA has been observed, as evidenced by over an order of magnitude decrease of both the first step rate constant, k1 , and the second step rate constant, k2 , during hydrogen/deuterium exchange in D2 O. Meanwhile, as expected, the reactivity of C2-hydrogen was also inhibited significantly, with an upshift of 2.09 pKa units. This discovery will not only provide an emerging host molecule to modulate keto-enol tautomerism, but also potentially lead to a novel supramolecular formulation of AGE-breaker ALA for improved stability and therapeutic efficacy.