Structure-Activity Relationship Studies Leading to the Discovery of Highly Water-Soluble and Biocompatible Acyclic Cucurbit[n]uril FY-3451 as a Universal Antagonist That Rapidly Reverses Neuromuscular Blocking Agents In Vivo.

The development of a reversal agent that can rapidly reverse clinically used nondepolarizing neuromuscular blocking agents (NMBAs) has long been a challenge. Here, we report the synthesis of a series of highly water-soluble acyclic cucurbit[n]urils (acCBs). Systematic structure-activity relationship studies reveal that introducing two propylidene units on the peripheral benzene rings not only remarkably improves the activity of the corresponding derivative acCB6 (FY 3451) in reversing the neuromuscular block of rocuronium, cisatracurium, vecuronium, and pancuronium, the four clinically used NMBAs, through stable inclusion, but also allows for high water-solubility as well as a maximum tolerated dose (2000 mg/kg on rats). In vivo experiments with rats show that, at the identical dose of 25 mg/kg, for rocuronium, vecuronium, and pancuronium, acCB6 can achieve a recovery time shorter than that of sugammadex for rocuronium and, at the dose of 100 mg/kg, realize comparably rapid reversal for cisatracurium.

Tracheoplasty should be proactively considered in the surgical strategy for treating the ring-sling complex.

OBJECTIVE: To examine the safety and effectiveness of proactive tracheoplasty for pediatric ring-sling complex. METHODS: We retrospectively collected data from 304 children who were diagnosed with a ring-sling complex and underwent surgery at 3 cardiac centers in China between January 2010 and June 2023. The children were categorized into 3 surgical groups: concurrent sling and tracheal surgery (group A; n = 258), staged sling and tracheal surgery (group B; n = 25), and sling-only surgery (group C; n = 21). We compared perioperative clinical characteristics, tracheal morphology changes, and outcomes across the 3 groups. RESULTS: The median age of the children was 1.2 years (interquartile range, [IQR], 0.7-1.9 years). The anomalous tracheobronchial arborization rates were higher in group A (52.5%) and group B (60.0%) compared to group C (15.0%). The preoperative narrow-wide ratio (NWR) was lower in groups A and B than in group C, with values of 0.44 (IQR, 0.35-0.52), 0.44 (IQR, 0.33-0.59), and 0.68 (IQR, 0.54-0.72), respectively (P < .001). Preoperative subcarina angles were similar among the groups (P = .54). After specific surgeries, the NWR and subcarina angle were improved significantly in groups A and B but not in group C. There were 7 in-hospital deaths and 2 postdischarge deaths. Respiratory symptoms improved in groups A and B, but 7 children in group C remained in respiratory dysfunction. Six children presented with residual stenosis of the left pulmonary artery. CONCLUSIONS: Concurrent sling and tracheal surgeries for children with the ring-sling complex are safe and effective and are especially preferable for those with NWR ≤0.6, long-segment or diffuse tracheal stenosis, anomalous tracheobronchial arborization, and pronounced respiratory symptoms.

Bispillar[5]arene-Based Slide-Ring Polyrotaxanation Enables Enhanced Toughness, Recyclability, Impact, and Puncture Resistance of Polyisoprene Elastomers.

A series of slide-ring polyrotaxanes (SRPs) have been constructed by the solvent-free blending of a ditopic pillar[5]arene (DP5A) and polyisoprene (PIP) after thermal annealing. Solid-state 13C NMR experiments supported the fact that the pillar[5]arene rings of DP5A were threaded by PIP chains to afford physically interlocked networks. Tensile tests revealed that 1% of DP5A can improve the elongation at break from 50 to 239%, the tensile modulus from 2.1 to 3.9 MPa, and the toughness from 0.35 to 4.5 MJ/m3. Impact and puncture resistance experiments show that the DP5A-doped materials exhibit remarkable enhancement of protective and impalement-resistant performance. The samples can be also recycled repeatedly due to their physical crosslinking nature. The important stress delocalization effects have been attributed to the pulley effect of DP5A in the SRP materials, which represents a supramolecular approach for improving the performance of PIP elastomers.

Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Modular Strategy for Constructing para-Cage[n]arenes, meta-Cage[n]arenes, and meta-Bimacrocyclic-Arenes.

Here, we present a versatile modular strategy for crafting novel covalent organic cages (para-cage[n]arenes and meta-cage[n]arenes, n = 3,4) and bimacrocycles (meta-bimacrocyclic-arenes) with stable backbones and modifiable rims. These structures can be synthesized from commercially available aromatic multialdehydes in a three-step process: quantitative bromination, Suzuki-Miyaura reaction (yielding over 60%), and a rapid one-pot Friedel-Crafts reaction with paraformaldehyde. Notably, the cage[n]arenes exhibit a well-defined prismatic shape, and the bimacrocyclic-arenes display both dimeric and monomeric configurations.

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo.

Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.

Macrocycles and Acyclic Cucurbit[n]urils as Pseudo[2]catenane Partners for Long-Acting Neuromuscular Blocks and Rapid Reversal In Vivo.

Long-acting neuromuscular blocks followed by rapid reversal may provide prolonged surgeries with improved conditions by omitting repetitive or continuous administration of the neuromuscular blocking agent (NMBA), eliminating residual neuromuscular block and minimizing postoperative recovery, which, however, is not clinically available. Here, we demonstrate that imidazolium-based macrocycles (IMCs) and acyclic cucurbit[n]urils (ACBs) can form such partners by functioning as long-acting NMBAs and rapid reversal agents through a pseudo[2]catenation mechanism based on stable complexation with Ka values of over 109 M-1. In vivo experiments with rats reveal that, at the dose of 2- and 3-fold ED90, one IMC attains a duration of action corresponding to 158 or 442 min for human adults, covering most of prolonged surgeries. The block can be reversed by one ACB with recovery time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, the clinically most widely used intermediate-acting NMBA.

Structural Conjugation Tuning in Covalent Organic Frameworks Boosts Charge Transfer and Photocatalysis Performances.

Structural conjugation greatly affects the optical and electronic properties of the COF photocatalyst. Herein, we show that 2D hydrazone COFs with either π-extended biphenyl (BPh-COF) or acetylene (AC-COF) frameworks demonstrated distinct charge transfer and photocatalytic performances. The two COFs show good crystallinity and decent porosity as their frameworks are enforced by intra/interlayers hydrogen bonding. However, computational and experimental data reveal that AC-COF managed broader visible-light absorption and narrower optical bandgaps and performed efficient photoinduced charge separation and transfer in comparison with BPh-COF, meaning that the ethynyl skeleton with enhanced planarity better improves the π-conjugation of the whole structure. As a result, AC-COF exhibited an ideal bandgap for rapid oxidative coupling of amines under visible-light irradiation. Furthermore, taking advantage of its better charge transfer properties, AC-COF demonstrated considerable enhanced product conversion and notable functional tolerance for metallaphotocatalytic C-O cross-coupling of a wide range of both aryl bromides and chlorides with alcohols. More importantly, besides being recoverable, AC-COF showcased the previously inaccessible etherification of dihaloarene. This report shows a facile approach for manipulating the structure-activity relationship and paves the way for the development of a COF photocatalyst for solar-to-chemical energy conversion.

Acyclic Cucurbit[n]urils: Effective Taste Masking Nanocontainers for Cationic Bitter Compounds.

New acyclic cucurbit[n]urils (ACBs) with eight carboxylate groups were synthesized. These hosts are highly soluble in water, and can form stable inclusion complexes with cationic bitter compounds. ACBs are confirmed to be non-toxic and biocompatible. Two-bottle preference (TBP) tests on mice show that all ACBs are tasteless to mammals. ACBs are discovered to mask the bitterness of berberine and denatonium benzoate, but not quinine hydrochloride, due to different binding modes.

Acyclic cucurbit[n]uril-based nanosponges significantly enhance the photodynamic therapeutic efficacy of temoporfin in vitro and in vivo.

Acyclic cucurbit[n]uril-based nanosponges are prepared based on supramolecular vesicle-templated cross-linking. The nanosponges are capable of encapsulating the clinically approved photodynamic therapeutic (PDT) drug temoporfin. When loaded with nanosponges, the PDT bioactivity of temoporfin is enhanced 7.5-fold for HeLa cancer cells and 20.8 fold for B16-F10 cancer cells, respectively. The reason for the significant improvement in PDT efficacy is confirmed to be an enhanced cell uptake by confocal laser scanning microscopy and flow cytometry. Animal studies show that nanosponges could dramatically increase the tumor suppression effect of temoporfin. In vitro and in vivo experiments demonstrate that nanosponges are nontoxic and biocompatible.

Pseudo[n]-pillar[5]arenes: Synthesis, Structures, and Host-Guest Binding Properties.

[1n]Paracyclophane has been known for nearly 40 years, but its derivatives and properties are understudied in comparison to those of other macrocyclic compounds. By the modification of pillar[5]arene, we successfully obtained five electron-rich pentagonal macrocycles (pseudo[n]-pillar[5]arenes, n = 1-4) with the decrease of substituted phenylenes one after another, achieving the partial derivatization of [15]paracyclophane skeleton at its phenylene sites. Pseudo[n]-pillar[5]arenes (P[n]P[5]s) served as a kind of macrocyclic host to form complexes with various guests, such as dinitriles, dihaloalkanes, and imidazolium salt, in a 1:1 host-guest stoichiometric ratio. The binding constants with the guest gradually reduce along the decrease of substituted phenylene segments from host P[1]P[5] to P[4]P[5]. It is worthy to note that P[n]P[5]s can adjust their conformations to the "pillar-like" shape effectively when binding with succinonitrile in the solid state.

Decasubstituted Pillar[5]arene Derivatives Containing L-Tryptophan and L-Phenylalanine Residues: Non-Covalent Binding and Release of Fluorescein from Nanoparticles.

Sensitive systems with controlled release of drugs or diagnostic markers are attractive for solving the problems of biomedicine and antitumor therapy. In this study, new decasubstituted pillar[5]arene derivatives containing L-Tryptophan and L-Phenylalanine residues have been synthesized as pH-responsive drug nanocarriers. Fluorescein dye (Fluo) was loaded into the pillar[5]arene associates and used as a spectroscopic probe to evaluate the release in buffered solutions with pH 4.5, 7.4, and 9.2. The nature of the substituents in the pillar[5]arene structure has a huge influence on the rate of delivering. When the dye was loaded into the associates based on pillar[5]arene derivatives containing L-Tryptophan, the Fluo release occurs in the neutral (pH = 7.4) and alkaline (pH = 9.2) buffered solutions. When the dye was loaded into the associates based on pillar[5]arene with L-Phenylalanine fragments, the absence of release was observed in every pH evaluated. This happens as the result of different packing of the dye in the structure of the associate. This fact was confirmed by different fluorescence mechanisms (aggregation-caused quenching and aggregation-induced emission) and association constants. It was shown that the macrocycle with L-Phenylalanine fragments binds the dye more efficiently (lgKa = 3.92). The experimental results indicate that the pillar[5]arene derivatives with amino acids fragments have a high potential to be used as a pH-responsive drug delivery devices, especially for promoting the intracellular delivering, due to its nanometric size.

Metallaphotocatalytic Amination of Aryl Chlorides Enabled by Highly Crystalline Acetylene-Based Hydrazone-Linked Covalent Organic Frameworks.

Amination of aryl chlorides by metallaphotocatalysis is highly desired but remains practically challenging. Meanwhile, relying on soluble noble-metal photocatalysts suffers from resource scarcity and structural instability which limit their practical application. Here in, a highly crystalline acetylene-based hydrazone-linked covalent organic framewok-1 (AC-COF-1) is reported that enables metallaphotocatalytic amination of aryl chlorides. The non-planar effect of hydrazone linkage and weak interlayer attraction of acetylene bond are minimized by intralayer hydrogen-bonding. As a result, the COF shows not only improved crystallinity and porosity, but also enhanced optical and electronic properties compared to a COF analog without hydrogen-bonding. Notably, dual AC-COF-1/Ni system affords CN coupling products from broad aryl chloride substrates in excellent yields (up to 99%) and good functional tolerance. Furthermore, AC-COF-1 is recoverable and reusable for seven times photocatalysis cycles. This report demonstrates simple approach to tune the structure-activity relationship in COFs at molecular level.

Host-guest binding of tetracationic cyclophanes to photodynamic agents inhibits posttreatment phototoxicity and maintains antitumour efficacy.

In the past two decades, photodynamic therapy (PDT) has become an effective method for the treatment of cancer. However, the posttreatment residue of photodynamic agents (PDAs) causes long-term skin phototoxicity. Here, we apply naphthalene-derived, box-like tetracationic cyclophanes, named NpBoxes, to bind to clinically used porphyrin-based PDAs to alleviate their posttreatment phototoxicity by reducing their free content in skin tissues and 1O2 quantum yield. We show that one of the cyclophanes, 2,6-NpBox, could include the PDAs to efficiently suppress their photosensitivity for the generation of reactive oxygen species. A tumour-bearing mouse model study revealed that, when Photofrin, the most widely used PDA in clinic, was administrated at a dose corresponding to the clinical one, 2,6-NpBox of the same dose could significantly suppress its posttreatment phototoxicity on the skin induced by simulated sunlight irradiation, without imposing a negative influence on its PDT efficacy.

Synthetic Topological Vacua of Yang-Mills Fields in Bose-Einstein Condensates.

Topological vacua are a family of degenerate ground states of Yang-Mills fields with zero field strength but nontrivial topological structures. They play a fundamental role in particle physics and quantum field theory, but have not yet been experimentally observed. Here we report the first theoretical proposal and experimental realization of synthetic topological vacua with a cloud of atomic Bose-Einstein condensates. Our setup provides a promising platform to demonstrate the fundamental concept that a vacuum, rather than being empty, has rich spatial structures. The Hamiltonian for the vacuum of topological number n=1 is synthesized and the related Hopf index is measured. The vacuum of topological number n=2 is also realized, and we find that vacua with different topological numbers have distinctive spin textures and Hopf links. Our Letter opens up opportunities for exploring topological vacua and related long-sought-after instantons in tabletop experiments.

Highly Water-Soluble Cucurbit[8]uril Derivative as a Broad-Spectrum Neuromuscular Block Reversal Agent.

Broad-spectrum agents for the reversal of residual curarization induced by neuromuscular blocking agents are of great significance. Here, we report a highly water-soluble cucurbit[8]uril (CB[8]) derivative as a broad-spectrum neuromuscular block reversal agent induced by both benzylisquinolinium and aminosteroid neuromuscular block agents by the supramolecular sequestration strategy. The UV/Vis competition titration assays suggest the high binding affinity of the CB[8] derivative toward both benzylisquinolinium-type cisatracurium besylate and aminosteroid-type rocuronium, vecuronium, and pancuronium, at the level of 107 M-1. In vivo studies demonstrate that the administration of the CB[8] derivative could significantly accelerate the recovery time compared to the placebo or neostigmine groups. The reversal activity of the CB[8] derivative is comparable to or higher than that of clinically approved sugammadex. Acute toxicity evaluations reveal that the CB[8]-derivative displays outstanding biocompatibility, with the maximum tolerance dose as high as 960 mg kg-1.

Supramolecular Organic Frameworks as Adsorbents for Efficient Removal of Excess Bilirubin in Hemoperfusion.

Excess bilirubin accumulates in the bodies of patients suffering from acute liver failure (ALF) to cause much irreversible damage and bring about serious clinical symptoms such as kernicterus, hepatic coma, or even death. Hemoperfusion is a widely used method for removing bilirubin from the blood, but clinically used adsorbents have unsatisfactory adsorption capacity and kinetics. In this study, we prepared four supramolecular organic framework microcrystals SOF-1-4 via slow evaporation of their aqueous solutions under infrared light. SOF-1-4 possess good regularity and excellent stability. We demonstrate that all the four SOFs could serve as adsorbents for bilirubin with fast adsorption kinetics within 20 min and ultrahigh adsorption capacity of 609.1 mg g-1, driven by electrostatic interaction and hydrophobicity. The superior adsorption performance of the SOFs outperformed most of the reported bilirubin adsorbents. Remarkably, SOF-3 could remove about 90% of bilirubin in the presence of 40 g L-1 BSA with a minimal loss of albumin and was thus further processed to a bead-shaped composite with a diameter of 2 mm with poly(ether sulfone) (PES). This PES-loaded SOF could efficiently adsorb bilirubin to the normal level from human plasma with an adsorption equilibrium concentration of 7.8 mg L-1 in 6 h through a dynamic hemoperfusion process. This work provides a new vitality for the development of novel bilirubin adsorbents for hemoperfusion therapy.

Flexible organic frameworks sequester neuromuscular blocking agents in vitro and reverse neuromuscular block in vivo.

Supramolecular sequestration and reversal of neuromuscular block (NMB) have great clinical applications. Water-soluble flexible organic frameworks (FOFs) cross-linked by disulfide bonds are designed and prepared. Different linker lengths are introduced to FOFs to give them varied pore sizes. FOFs are anionic nanoscale polymers and capable of encapsulating cationic neuromuscular blocking agents (NMBAs), including rocuronium (Roc), vecuronium (Vec), pancuronium (Panc) and cisatracurium (Cis). A host-guest study confirms that FOFs bind NMBAs in water. The multivalency interaction between FOFs and NMBAs is able to sequester NMBAs, and prevent them from escaping. These FOFs are non-toxic and biocompatible. Animal studies show that FOFs are effective for the reversal of NMB induced by Roc, Vec and Cis, which shorten the time to a train-of-four ratio of 0.9 by 2.6, 3.8 and 5.7-fold compared to a placebo, respectively.

Supramolecular Organic Frameworks: Exploring Water-Soluble, Regular Nanopores for Biomedical Applications.

In past decades, regular porous architectures have received a great amount of attention because of their versatile functions and applications derived from their efficient adsorption of various guests. However, most reported porous architectures exist only in the solid state. Therefore, their applications as biomaterials may face several challenges, such as phase separation, slow degradation, and long-term accumulation in the body. This Account summarizes our efforts with respect to the development and biomedical applications of water-soluble 3D diamondoid supramolecular organic frameworks (dSOFs), a family of supramolecular polymers that possess intrinsic regular nanoscale porosity.dSOFs have been constructed from tetratopic components and cucurbit[8]uril (CB[8]) through hydrophobically driven encapsulation by CB[8] for intermolecular dimers formed by peripheral aromatic subunits of the tetratopic components in water. All dSOFs exhibit porosity regularity or periodicity in aqueous solution, which is confirmed by solution-phase synchrotron SAXS and XRD experiments. Dynamic light scattering (DLS) reveals that their sizes range from 50 to 150 nm, depending on the concentrations of the components. As nonequilibrium supramolecular architectures, dSOFs can maintain their nanoscale sizes at micromolar concentrations for dozens of hours. Their diamondoid pores have aperture sizes ranging from 2.1 to 3.6 nm, whereas their water solubility and porosity regularity allow them to rapidly include discrete guests driven by ion-pair electrostatic attraction, hydrophobicity, or a combination of the two interactions. The guests may be small molecule or large macromolecular drugs, photodynamic agents (PDAs), or DNA.The rapid inclusion of bioactive guests into dSOFs has led to two important biofunctions. The first is to function as antidotes through including residual drugs. For heparins, the inclusion results in full neutralization of their anticoagulant activity. For clinically used porphyrin PDAs, the inclusion can alleviate their long-term posttreatment phototoxicity but does not reduce their photodynamic efficacy. The second is to function as in situ loading carriers for the intracellular delivery of antitumor drugs or DNA. Their nanoscale sizes bring out their ability to overcome the multidrug resistance of tumor cells, which leads to a remarkable enhancement of the bioactivity of the included drugs. By conjugating aldoxorubicin to tetrahedral components, albumin-mimicking prodrugs have also been constructed, which conspicuously improves the efficacy of aldoxorubicin toward multi-drug-resistant tumors through the delivery of the frameworks. As new supramolecular drugs and carriers, dSOFs are generally biocompatible. Thus, further efforts might lead to medical benefits in the future.

Porous organic polymer overcomes the post-treatment phototoxicity of photodynamic agents and maintains their antitumor efficiency.

Since 1995, photodynamic therapy (PDT) has been utilized as an effective method for cancer treatment. However, the residues of photosensitizers in the normal tissues after PDT can be activated by sunlight to cause severe skin phototoxicity, for which currently there are no clinical solutions. As a result, post-PDT patients need to remain out of sunlight for up to five weeks, which produces great living and mental burdens for patients. Herein, we report that a biocompatible porous organic polymer (POP) with average 3.1 nm porosity is able to suppress the skin phototoxicity of clinically used porphyrin-based photodynamic agents (PDAs), including Photofrin, Talaporfin and Hiporfin, through an adsorption-elimination mechanism. Fluorescence titration and dialysis experiments show that POP can adsorb and retain the PDAs at a micromolar concentration. In vivo experiments demonstrate that POP can significantly suppress the skin phototoxicity caused by all the three PDAs without reducing their PDT efficacy. STATEMENT OF SIGNIFICANCE: Up to now, no efficient clinical treatment for the inhibition of post-PDT phototoxicity of clinically used porphyrin-based PDAs is available. In the manuscript, a water-soluble cationic porous organic polymer has been revealed to include three clinically used PDAs. In vivo experiments show that this inclusion remarkably reduces the content of PDAs in mouse skins, leading to significant alleviation of their post-PDT phototoxicity without no negative effect on their PDT efficacy. Thus, this work provides a strategy for overcoming the drawback of clinically used photodynamic agents.