Crown-ether threaded covalent organic polyrotaxane framework (COPF) towards synergistic crown/Zn2+/photothermal/photodynamic antibacterial and infected wound healing therapy.

Controllable preparation of materials with new structure has always been the top priority of polymer materials science research. Here, the supramolecular binding strategy is adopted to develop covalent organic frameworks (COFs) with novel structures and functions. Based on this, a two-dimensional crown-ether ring threaded covalent organic framework (COF), denoted as Crown-COPF with intrinsic photothermal (PTT) and photodynamic (PDT) therapeutic capacity, was facilely developed using crown-ether threaded rotaxane and porphyrin as building blocks. Crown-COPF with discrete mechanically interlocked blocks in the open pore could be used as a molecular machine, in which crown-ether served as the wheel sliding along the axle under the laser stimulation. As a result, Crown-COPF combining with the bactericidal power of crown ether displayed a significant photothermal and photodynamic antibacterial activity towards both the Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus), far exceeding the traditional Crown-free COF. Noteworthily, the bactericidal performance could be further enhanced via impregnation of Zn2+ ions (Crown-COPF-Zn) flexible coordinated with the multiple coordination sites (crown-ether, bipyridine, and porphyrin), which not only endow the positive charge with the skeleton, enhancing its ability to bind to the bacterial membrane, but also introduce the bactericidal ability of zinc ions. Notably, in vivo experiments on mice with back infections indicates Crown-COPF-Zn with self-adaptive multinuclear zinc center, could effectively promote the repairing of wounds. This study paves a new avenue for the effectively preparation of porous polymers with brand new structure, which provides opportunities for COF and mechanically interlocked polymers (MIPs) research and applications.

PEG-modified carbon-based nanoparticles as tumor-targeted drug delivery system reducing doxorubicin-induced cardiotoxicity.

Herein, a doxorubicin-loaded carbon-based drug delivery system, denoted as PC-DOX, composed of pH-responsive imine bond was developed for the tumor-targeted treatment. PC-DOX with a uniform particle size around 180 nm was synthesized by coating of as-synthesized hollow carbon-based nanoparticles (NPs) with dialdehyde PEG, which was used as carrier to attach DOX covalently through dynamic covalent bond. The unique structure endowed the advantages of specific tumor targeting and tumor microenvironment (TME) specific drug delivery capacity with PC-DOX. For the one hand, the tumor targeting caused by the enhanced permeability and retention (EPR) effect could significantly improve the tumor cellular uptake. For the other hand, the pH-responsiveness could realize the effective DOX accumulation in tumor tissues, avoiding the unwanted side effect to the normal tissues. As a result, PC-DOX with high DOX loading capacity (70.12%) and excellent biocompatibility, concurrently, presented a significant anti-tumor effect at a low mass concentration (DOX equivalent dose: 20 µg/mL). Another attractive characteristic of PC-DOX was the remarkable protective effect towards DOX-induced cardiotoxicity, which could be clearly observed from in vitro cellular, and animal assays. Compared with free DOX, the cardiomyocyte viability increased by average 30.58%, and the heart function was also significantly improved. This novel drug delivery nanoplatform provides a new method for the future clinical application of DOX in the cancer's therapeutics.

A diselenium-bridged covalent organic framework with pH/GSH/photo-triple-responsiveness for highly controlled drug release toward joint chemo/photothermal/chemodynamic cancer therapy.

Here, a novel joint chemo/photothermal/chemodynamic therapy was developed using a pH/GSH/photo triple-responsive 2D-covalent organic framework (COF) drug carriers for passive target treatment of tumors with extraordinarily high efficiency. The well-designed COF (DiSe-Por) with simultaneous dynamic diselenium and imine bonds, synthesized by the copolymerization of 4,4'-diselanediyldibenzaldehyde (DiSe) with 5,10,15,20-(tetra-4-aminophenyl)-porphyrin (Por) via Schiff base chemistry, which was applied as the host for effective encapsulation and highly controlled release of anticancer drug (DOX), was stable under normal physiological settings and can effectively accumulate in tumor sites. After being internalized into the tumor cells, the unique microenvironment i.e., acidic pH and overexpressed GSH, triggered substantial degradation of DiSe-Por-DOX, promoting DOX release to kill the cancer cells. Meanwhile, the breaking of Se-Se bonds boosted the generation of intracellular ROS, disturbing the redox balance of tumor cells. The highly extended 2D structure endowed the drug delivery system with significant photothermal performance. The rise of temperature with external laser irradiation (808 nm) further promoted drug release. Additionally, the phototherapy effect was further augmented after the loading of DOX, guaranteeing an almost complete drug release to tumor tissue. As a result, the triple-responsive drug delivery system achieved a synergistic amplified therapeutic efficacy with a growth inhibitory rate of approximately 93.5% for the tumor xenografted in nude mice. Moreover, the body metabolizable and clearable DiSe-Por-DOX presented negligible toxicities toward major organs in vivo. All these characteristics verified the great potential of DiSe-Por-DOX nanosheets for multi-modality tumor treatment, accelerating the application range of COFs in biomedical fields.

Inactivation of P2YR12 contributes to isoflurane-induced neuronal injury by altering TLR-4/BDNF/TNF-α.

The present investigation evaluated the effect of inhibiting the P2Y12 gene on anaesthetic-induced neuronal injury in a rat model. Neuronal injury was induced by exposing the animals for 6 h to 30% oxygen containing 0.75% isoflurane and 1.2 mg/kg prasugrel (a P2Y12 inhibitor) p.o. for 14 days. Cognitive function was determined by the Morris water maze, and the neurological severity score was determined. Enzyme-linked immunosorbent assay was used to estimate the level of oxidative stress and mediators of inflammation in brain tissues of isoflurane-induced neuronal injury rats. Apoptosis of neuronal cells was estimated by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot assays. Real time-polymerase chain reaction was performed to estimate the expression levels of several proteins. The data revealed that inhibiting the P2Y12 gene ameliorated changes in the modified neurological severity score and cognitive function in neuronal injury rats. Moreover the levels of proinflammatory mediators, oxidative stress, and cyclic AMP, and the number of TUNEL-positive cells, decreased significantly (p < 0.01) in the prasugrel-treated group compared to the negative control group. In addition, apoptosis of neuronal cells decreased in the prasugrel-treated group, as it ameliorated expression of the PI3K, Bcl-2, Bad, and Akt proteins in the isoflurane-induced neuronal injury rats. Expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) proteins was enhanced, whereas the Toll-like receptor-4 (TLR-4) and nuclear factor κB (NF-κB) proteins decreased in the brain tissues of the prasugrel-treated group compared to the negative control group of rats. These results suggest that inhibiting the P2YR12 gene protects against neuronal injury in isoflurane-induced neuronal injury rats. Inhibiting the P2YR12 gene ameliorated neuronal apoptosis by regulating the BDNF/TLR-4/TNF-α pathway.