Light-Operated Transient Unilateral Adhesive Hydrogel for Comprehensive Prevention of Postoperative Adhesions.

Dislocation of anti-adhesion materials, non-specific tissue adhesion, and the induction of secondary fibrinolysis disorders are the main challenges faced by postoperative anti-adhesion materials. Herein, a self-leveling transient unilateral adhesive hydrogel is custom-designed to conquer these challenges with a theoretically calculated and dual-step tailored gellan gum (GG) as the sole agent. First, the maximum gelation temperature of GG is lowered from 42-25 °C through controlled perturbation of intra- and inter-molecular hydrogen bonds, which is achieved by employing the methacrylic anhydride as a "hydrogen bond's perturbator" to form methacrylate GG (MeGG). Second, the "self-leveling" injectability and wound shape adaptably are endowed by the formation of borate-diol complexed MeGG (BMeGG). Finally, the transient unilateral tissue-adhesive hydrogel (BMeGG-H) barrier is prepared through photo-controlled cross-linking of reactive alkenyl groups. This degradable hydrogel demonstrates favorable rheological properties, light-controlled unilateral adhesion properties, biocompatibility, anti-fibrin adhesion, and anti-cell adhesion properties in vitro. Comprehensive regulation of the fibrinolysis balance toward non-adhesion is conformed in a rat model after intra-abdominal surgery via anti-autoinflammatory response, intestinal wall integrity repair, and Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) balance adjustment. Notably, the 14th day anti-adhesion effective rate is 100%, indicating its significant potential in clinical applications for postoperative anti-adhesion.

Ginsenoside CK induces apoptosis in triple-negative breast cancer cells by targeting glutamine metabolism.

Breast cancer (BC) has replaced lung cancer as the most common cancer worldwide. Ginsenoside CK (CK) can effectively inhibit triple-negative breast cancer (TNBC), the occurrence and development of which are associated with glutamine addiction. However, the connection between CK and glutamine metabolism in TNBC proliferation and the mechanism of cell death induction remains unclear. Here, we found that high glutamine-addicted TNBC cells were particularly sensitive to CK treatment. CK exerted antitumour activity against TNBC by suppressing glutamine consumption and glutamate production via downregulation of glutaminase 1 (GLS1) expression. CK treatment further decreased cellular ATP production, reduced the utilisation of amino acids associated with glutamine metabolism, and induced glutathione (GSH) depletion and reactive oxygen species (ROS) accumulation, consequently triggering apoptosis in TNBC. Furthermore, CK decreased GLS1 expression in SUM159 xenograft mouse mammary tumours and significantly inhibited tumour growth with few side effects. Together, our data provide a powerful theoretical basis for the application of CK as a glutamine metabolic inhibitor in TNBC treatment.

Ginsenoside Rh4 Suppresses Metastasis of Gastric Cancer via SIX1-Dependent TGF-ß/Smad2/3 Signaling Pathway.

Gastric cancer (GC) is the leading causes of cancer-related death worldwide. Surgery remains the cornerstone of gastric cancer treatment, and new strategies with adjuvant chemotherapy are currently gaining more and more acceptance. Ginsenoside Rh4 has excellent antitumor activity. Conversely, the mechanisms involved in treatment of GC are not completely understood. In this study, we certified that Rh4 showed strong anti-GC efficiency in vitro and in vivo. MTT and colony formation assays were performed to exhibit that Rh4 significantly inhibited cellular proliferation and colony formation. Results from the wound healing assay, transwell assays, and Western blotting indicated that Rh4 restrained GC cell migration and invasion by reversing epithelial-mesenchymal transition (EMT). Further validation by proteomic screening, co-treatment with disitertide, and SIX1 signal silencing revealed that SIX1, a target of Rh4, induced EMT by activating the TGF-ß/Smad2/3 signaling pathway. In summary, our discoveries demonstrated the essential basis of the anti-GC metastatic effects of Rh4 via suppressing the SIX1-TGF-ß/Smad2/3 signaling axis, which delivers a new idea for the clinical treatment of GC.

A physicochemical double cross-linked multifunctional hydrogel for dynamic burn wound healing: shape adaptability, injectable self-healing property and enhanced adhesion.

Burn wounds are one of the most destructive skin traumas that cause more than 180000 deaths each year. Patients with large, irregular burn wounds suffer from slow healing. Dynamic burn wounds have special requirements for hydrogel dressing due to their high frequency movement. To focus on dynamic burn wounds, we designed a novel double cross-linked hydrogel prepared by Schiff base and catechol-Fe3+ chelation bond. The unique double cross-linked structure of the hydrogel resulted in better physicochemical properties and enhanced efficacy. The enhanced physicochemical properties, such as faster gelation time (52 ± 2 s), stronger mechanical property (535 kPa of G'), enhanced adhesive strength (19.3 kPa) and better self-healing property, made the hydrogel suitable for dynamic wounds. The excellent shape adaptability (97.1 ± 1.3% of recovery) made the hydrogel suitable for wounds with irregular shapes. The hydrogel exhibited not only biodegradability during the wound healing process but also superior inherent antibacterial activity (100% killing ratio) and hemostatic property. The results showed that the hydrogel shortened the healing time of burn wounds to 13 days, and accelerated the reconstruction of skin structure and function. This double cross-linked multifunctional hydrogel is a promising candidate as a dynamic burn wound dressing.

Highly Penetrable and On-Demand Oxygen Release with Tumor Activity Composite Nanosystem for Photothermal/Photodynamic Synergetic Therapy.

A deep penetrating and pH-responsive composite nanosystem was strategically developed to improve the efficacy of synergetic photothermal/photodynamic therapy (PTT/PDT) against hypoxic tumor. The designed nanosystem ([PHC]PP@HA NPs) was constructed by coloading hemoglobin (Hb) and chlorin e6 on polydopamine to build small-sized PHC NPs, which were encapsulated inside the polymer micelles (poly(ethylene glycol)-poly(ethylenimine)) and then capped with functionalized hyaluronic acid. The pH-responsive feature made [PHC]PP@HA NPs retain an initial size of ∼140 nm in blood circulation but rapidly release small PHC NPs (∼10 nm) with a high tumor-penetrating ability in the tumor microenvironment. The in vitro penetration experiment showed that the penetration depth of PHC NPs in the multicellular tumor spheroids exceeded 110 µm. The [PHC]PP@HA NPs exhibited excellent biocompatibility, deep tumor permeability, high photothermal conversion efficiency (47.09%), and low combination index (0.59) under hypoxic conditions. Notably, the nanosystem can freely adjust the release of oxygen and damaging PHC NPs in an on-demand manner on the basis of the feedback of tumor activity. This feedback tumor therapy significantly improved the synergistic effect of PTT/PDT and reduced its toxic side effects. The in vivo antitumor results showed that the tumor inhibition rate of [PHC]PP@HA NPs with an on-demand oxygen supply of Hb was ∼100%, which was much better than those of PTT alone and Hb-free nanoparticles ([PC]PP@HA NPs). Consequently, the [PHC]PP@HA NP-mediated PTT/PDT guided by feedback tumor therapy achieved an efficient tumor ablation with an extremely low tumor recurrence rate (8.3%) 60 d later, indicating the versatile potential of PTT/PDT.

An Enzyme-Responsive "Turn-on" Fluorescence Polymeric Superamphiphile as a Potential Visualizable Phosphate Prodrug Delivery Vehicle.

The development of inexpensive and highly efficient enzyme-responsive polymers has significantly contributed to targeted drug delivery systems. Here, a superamphiphile with a capability of fluorescent dissociation sensing is designed. It is constructed with negatively charged adenosine 5'-triphosphate (ATP) and negatively charged fluorescein diphosphate (FDP), which are used as fluorescence detection, and a cationic diblock copolymer methoxy-poly(ethylene glycol)113 -b-poly(2-dimethyl-aminoethyl methacrylate)70 . Upon addition of calf intestinal alkaline phosphatase, the superamphiphile disintegrates, presumably due to the enzymatic hydrolysis of ATP. This process is accompanied by an increase in the fluorescence emission intensity of fluorescein owing to the hydrolysis of FDP. The in vitro application of the superamphiphile is also proven. Thus, the "turn-on" fluorescence of the superamphiphile serves as a real-time module for detection of the disintegration of superamphiphile.

Versatile hyaluronic acid modified AQ4N-Cu(II)-gossypol infinite coordination polymer nanoparticles: Multiple tumor targeting, highly efficient synergistic chemotherapy, and real-time self-monitoring.

A novel strategy for the preparation of infinite coordination polymer nanoparticles (ICPs) based nanomedicines was developed, with which hyaluronic acid modified AQ4N-Cu(II)-gossypol nanoparticles (HA@AQ4N-Cu(II)-gossypol NPs) were obtained. This is a highly efficient nanomedicine, in which gossypol serves as a chemotherapeutic agent and a self-carrier material; Cu(II) serves as the connecting point and anti-tumor enhancer; AQ4N not only serves as a chemotherapeutic agent and self-carrier material, but also as the self-monitor based on its inherent fluorescence. HA@AQ4N-Cu(II)-gossypol NPs possessed a spherical shape with a dynamic size of 88.7 ± 7.4 nm, and the total drug-loading content and drug encapsulation efficiency are 77.41% and 100%, respectively. This nanomedicine has a multiple tumor-targeting ability caused by HA-receptor mediation and pH-responsive drug release. A significantly low combination index (0.097) of AQ4N and gossypol is ascertained. In vivo experiments indicate that it accumulates and significantly releases drugs at the tumor region. With the use of only one-fiftieth of AQ4N and half of gossypol of the generally administered dose, they can achieve significantly high anti-tumor efficiency with negligible side effects. Importantly, the switching-type changed fluorescence of AQ4N can be used for in vivo real-time self-monitoring of the drug release and distribution, which allows us to adjust the administration dose and time for different tumor types and stages for individual therapy.