An Antitumor Dual-Responsive Host-Guest Supramolecular Polymer Based on Hypoxia-Cleavable Azocalix[4]arene.

The exploitation of specific guests which can respond to external stimuli is the main approach for the construction of stimuli-responsive supramolecular polymers (SPs) based on host-guest interactions. Most functional guests, however, fail to manifest stimuli-responses. Herein, a hypoxia-responsive dimeric azocalixarene (D-SAC4A) with outstanding hosting properties was used as the macrocyclic building block for the preparation of host stimuli-responsive SPs. Since azocalixarenes can also be compatible with stimuli-responsive guests, an antitumor drug, camptothecin (CPT), was chosen and linked via a disulfide-containing linker to afford a glutathione (GSH)-responsive ditropic guest (D-CPT). A unique dual-responsive SP was obtained by 1 : 1 mixing of D-SAC4A and D-CPT in water, which further assembled into SP nanoparticles (DSPNs). DSPNs displayed outstanding stability against dilution and biological interferants, as well as precise CPT-release under GSH and hypoxia conditions. In vitro and in vivo experiments demonstrated the good biosafety and tumor-suppressive effects of DSPNs.

Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy.

BACKGROUND: Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs). RESULTS: In murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α4ß1 and αLß2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects. CONCLUSION: This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.

A general supramolecular adjuvant for pesticides based on host-guest recognition.

BACKGROUND: Pesticides are indispensable in agriculture and can effectively improve the yields and quality of crops. Due to their weak water solubility, most pesticides need to be dissolved by adding solubilizing adjuvants. In this work, based on molecular recognition of the macrocyclic host, we developed a novel supramolecular adjuvant, called sulfonated azocalix[4]arene (SAC4A), which significantly improves the water solubility of pesticides. RESULTS: SAC4A presents multiple advantages, including high water solubility, strong binding affinity, universality, and simple preparation. SAC4A showed an average binding constant value of 1.66 × 105 M-1 for 25 pesticides. Phase solubility results indicated that SAC4A increased the water solubility of pesticides by 80-1310 times. The herbicidal, fungicidal, and insecticidal activities of supramolecular formulations were found to be superior to those of technical pesticides, and the herbicidal effects were even better than those of commercial formulations. CONCLUSION: Overall results revealed the potential of SAC4A to improve the solubility and effectiveness of pesticides, providing a new development idea for the application of adjuvants in agriculture. © 2023 Society of Chemical Industry.

Dual hypoxia-responsive supramolecular complex for cancer target therapy.

The prognosis with pancreatic cancer is among the poorest of any human cancer. One of the important factors is the tumor hypoxia. Targeting tumor hypoxia is considered a desirable therapeutic option. However, it has not been translated into clinical success in the treatment of pancreatic cancer. With enhanced cytotoxicities against hypoxic pancreatic cancer cells, BE-43547A2 (BE) may serve as a promising template for hypoxia target strategy. Here, based on rational modification, a BE prodrug (NMP-BE) is encapsulated into sulfonated azocalix[5]arene (SAC5A) to generate a supramolecular dual hypoxia-responsive complex NMP-BE@SAC5A. Benefited from the selective load release within cancer cells, NMP-BE@SAC5A markedly suppresses tumor growth at low dose in pancreatic cancer cells xenograft murine model without developing systemic toxicity. This research presents a strategy for the modification of covalent compounds to achieve efficient delivery within tumors, a horizon for the realization of safe and reinforced hypoxia target therapy using a simple approach.

Noninvasive and Individual-Centered Monitoring of Uric Acid for Precaution of Hyperuricemia via Optical Supramolecular Sensing.

Characterized by an excessively increased uric acid (UA) level in serum, hyperuricemia induces gout and also poses a great threat to renal and cardiovascular systems. It is urgent and meaningful to perform early warning by noninvasive diagnosis, thus conducing to blockage of disease aggravation. Here, guanidinocalix[5]arene (GC5A) is successfully identified from the self-built macrocyclic library to specifically monitor UA from urine by the indicator displacement assay. UA is strongly bound to GC5A at micromolar-level, while simultaneously excluding fluorescein (Fl) from the GC5A·Fl complex in the "switch-on" mode. This method successfully differentiates patients with hyperuricemia from volunteers except for those with kidney dysfunction and targets a volunteer at high risk of hyperuricemia. In order to meet the trend from hospital-centered to individual-centered testing, visual detection of UA is studied through a smartphone equipped with a color-scanning feature, whose adaptability and feasibility are demonstrated in sensing UA from authentic urine, leading to a promising method in family-centered healthcare style. A high-throughput and visual detection method is provided here for alarming hyperuricemic by noninvasive diagnosis.

Supramolecular Radiosensitizer Based on Hypoxia-Responsive Macrocycle.

Radiotherapy (RT) has been viewed as one of the most effective and extensively applied curatives in clinical cancer therapy. However, the radioresistance of tumor severely discounts the radiotherapy outcomes. Here, an innovative supramolecular radiotherapy strategy, based on the complexation of a hypoxia-responsive macrocycle with small-molecule radiosensitizer, is reported. To exemplify this tactic, a carboxylated azocalix[4]arene (CAC4A) is devised as molecular container to quantitatively package tumor sensitizer banoxantrone dihydrochloride (AQ4N) through reversible host-guest interaction. Benefited from the selective reduction of azo functional groups under hypoxic microenvironment, the supramolecular prodrug CAC4A•AQ4N exhibits high tumor accumulation and efficient cellular internalization, thereby significantly amplifying radiation-mediated tumor destruction without appreciable systemic toxicity. More importantly, this supramolecular radiotherapy strategy achieves an ultrahigh sensitizer enhancement ratio (SER) value of 2.349, which is the supreme among currently reported noncovalent-based radiosensitization approach. Further development by applying different radiosensitizing drugs can make this supramolecular strategy become a general platform for boosting therapeutic effect in cancer radiotherapies, tremendously promising for clinical translation.

A hypoxia-responsive supramolecular formulation for imaging-guided photothermal therapy.

Photothermal agents (PTAs) based on organic small-molecule dyes emerge as promising theranostic strategy in imaging and photothermal therapy (PTT). However, hydrophobicity, photodegradation, and low signal-to-noise ratio impede their transformation from bench to bedside. In this study, a novel supramolecular PTT formulation by a stimuli-responsive macrocyclic host is prepared to overcome these obstacles of organic small-molecule PTAs. Methods: Sulfonated azocalix[4]arene (SAC4A) was synthesized as a hypoxia-responsive macrocyclic host. Taking IR780 as an example, the supramolecular nanoformulation IR780@SAC4A was constructed by grinding method, and its solubility, photostability, and photothermal conversion were evaluated. The hypoxia tumor-selective imaging and supramolecular PTT of IR780@SAC4A were further evaluated in vitro and in vivo. Results: IR780@SAC4A is capable of enhancing the solubility, photostability, and photothermal conversion of IR780 significantly, which achieve this supramolecular formulation with good imaging-guided PTT efficacy in vitro and in vivo. Conclusions: This study demonstrates that the supramolecular PTT strategy is a promising cancer theranostic method. Moreover, this supramolecular approach is applicative to construct kinds of supramolecular PTAs, opening a general avenue for extending smart PTT formulations.

A Supramolecular Antidote to Macromolecular Toxins Prepared through Coassembly of Macrocyclic Amphiphiles.

Poisoning is a leading cause of admission to medical emergency departments and intensive care units. Supramolecular detoxification, which involves injecting supramolecular receptors that bind with toxins to suppress their biological activity, is an emerging strategy for poisoning treatment; it has few requirements and a broad application scope. However, it is still a formidable challenge to design supramolecular therapeutic materials as an antidote to macromolecular toxins, because the large size, flexible conformation, and presence of multiple and diverse binding sites of biomacromolecules hinder their recognition. Herein, a supramolecular antidote to macromolecular toxins is developed through the coassembly of macrocyclic amphiphiles, relying on heteromultivalent recognition between the coassembled components and toxic macromolecules. The coassembly of amphiphilic cyclodextrin and calixarene strongly and selectively captures melittin, a toxin studied herein; this imparts various therapeutic effects such as inhibiting the interactions of melittin with cell membranes, alleviating melittin cytotoxicity and hemolytic toxicity, reducing the mortality rate of melittin-poisoned mice, and mitigating damage to major organs. The use of the proposed antidote overcomes the limitation of supramolecular detoxification applicability to only small-molecular toxins. The antidote can also detoxify other macromolecular toxins as long as selective and strong binding is achieved because of the coassembling tunability.

Macrocyclic-Amphiphile-Based Self-Assembled Nanoparticles for Ratiometric Delivery of Therapeutic Combinations to Tumors.

Combination chemotherapy refers to the use of multiple drugs to treat cancer. In this therapy, the optimal ratio of the drugs is essential to achieve drug synergism and the desired therapeutic effects. However, most delivery strategies are unable to precisely control the ratio of the drugs during the drug loading and delivery processes, resulting in inefficient synergy and unpredictable efficacy. Herein, a macrocyclic-amphiphile-based self-assembled nanoparticle (MASN) that achieves precise loading and ratiometric delivery of therapeutic combinations is presented. By integrating multiple macrocyclic cavities within a single nanoparticle, the MASN can load multiple drug molecules via the host-guest interaction, and the ratio of the drugs loaded can be predicted with their initial concentrations and characteristic binding affinity. Moreover, MASNs are readily degraded under a hypoxic microenvironment, allowing spontaneous release of the drugs upon reaching tumor tissues. With precise drug loading and controlled release mechanisms, MASNs achieve ratiometric delivery of multiple commercial drugs to tumors, thereby achieving optimal anti-tumor effects. Since the optimal drug ratio of a therapeutic combination can be quickly determined in vitro, MASNs can translate this optimal ratio to the therapeutic benefits in vivo, providing a potential platform for the rapid development of effective combination cancer therapies involving multiple drugs.

A General Hypoxia-Responsive Molecular Container for Tumor-Targeted Therapy.

Enhanced drug delivery can improve the therapeutic efficacy of drugs and help overcome side effects. However, many reported drug-delivery systems are too complex and irreproducible for practical use. In this work, the design of a hypoxia-responsive molecular container based on calixarene, called CAC4A, which presents a significant advance in practical, hypoxia-targeted drug-delivery, is reported. CAC4A enables a wide variety of clinical drugs to be quantitatively loaded to improve their solubility and stability, as well as enable the administration of reduced doses. Furthermore, as a result of its azo functional groups, which are sensitive to reduction within a hypoxic environment, it is possible to achieve tumor-targeted drug-release with reduced side effects. CAC4A fulfils all essential requirements for a drug-delivery system in addition to multiple advantages, including facile preparation, well-defined molecular weight, and structure, and universal applicability. Such features collectively enable supramolecular prodrugs to be formulated simply and reproducibly, with potential for bench-to-bedside translation. Moreover, CAC4A is amenable to other therapy modalities and can be facilely decorated with functional groups and hybridized with nanomaterials, providing ample possibilities for its role in future drug-delivery systems.

Supramolecular Tandem Assay for Pyridoxal-5'-phosphate by the Reporter Pair of Guanidinocalix[5]Arene and Fluorescein.

Guanidinocalix[5]arene and fluorescein reporter pair has been chosen to set up a supramolecular tandem assay principle based on the differential recognition of pyridoxal-5'-phosphate (the substrate of alkaline phosphatase, ALP), pyridoxal (the product of ALP) and phosphate (the product of ALP). This supramolecular tandem assay system offers an opportunity to monitor the activity of ALP in a label-free, continuous, and real-time manner. More importantly, a calibration curve can be given for selective and quantitative detection of pyridoxal-5'-phosphate (biomarker for several diseases).