Length and rigidity of the spacer impact on aldose reductase inhibition of the 5F-like ARIs in a dual-occupied mode.

The primary objective of this study was to investigate the structure-activity relationship of a new series of 5F-like Aldose Reductase Inhibitors (ARIs) using in silico docking method. In this perspective, 6 novel ARIs have been designed and synthesized. Evaluation of the inhibition of these compounds to ALR2 was carried on with epalrestat and 5F as the references. It was found that the spacer of 5F-like ARIs has a great influence on their inhibitory activity. Rigid spacer with length equal to 3 âˆ¼ 4 carbon alkyl chain brings about better inhibitory activity. Among them, compound 4b was verified as the most active ARIs, where its IC50 value was 16.8 ± 1.3 nM. Furthermore, in silico docking studies using AutoDock 4.2 as well as molecular simulation using GROMACS 2022.1 showed that 5F-like ARIs adopt a dual-occupation mode. The interaction energy (-25 to -74 kcal/mol), as well as MM-GBSA binding free energy (-37 to -65 kcal/mol) was positively correlated with their ALR2 inhibition constant (2000 to 16.8 nM). Docking interaction explained well the structure-activity relationship. A pharmacophore model has been set up for 5F-like ARIs thereafter. This model indicates that as an effective ARI, the entity should have four characteristics: an aromatic center, two hydrogen bond donors, and one hydrogen bond acceptor. By the way, all the 5F-like ARIs reported here are good to mild antioxidant with EC50 value between 13.6 ± 1.2 and 71.1 ± 3.2 µM. All our data direct the further development of more optimal ARIs for the treatment of diabetic complication in the future.

Enhanced antioxidation capacity endowed to a mixed type aldose reductase inhibitor leads to a promising anti-diabetic complications agent.

A series of 5f-based new compounds has been designed and synthesized. In vitro screening demonstrated that the binding affinity and selectivity on aldose reductase (AR) were positively correlated with its antioxidation capacity. Compound 6d was verified the most active candidate, where its IC50, selective index (SI), and EC50 value was 22.3 ± 1.6 nM, 236.2, and 8.7 µM respectively. 6d was confirmed as both an excellent antioxidant and aldose reductase inhibitor (ARI). It was identified as a mixed type ARI with Ki and Kis values of 23.94 and 1.20 nM. When evaluated by a high-glucose impaired chicken embryo model, it was found that 6d attenuated the incidence of neural tube defect (NTD) and death rate in a dose-dependent manner. It significantly improved the hyperglycemia-induced abnormalities of body weight and morphology of chicken embryos. 6d reversed the hyperglycemia-raised AR activity, sorbitol accumulation, reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It restored the high-glucose-reduced Pax3 protein expression. At the same dose (0.5 µM), 6d showed better effects than 5f in all the above detections. By the way, 6d did not affect hyperglycemia-elevated aldehyde reductase (ALR1) activity. This evidence together with its kinetic properties, implicated that 6d is a high selective ARI without the suspicion of promiscuity. 6d was proved here an effective agent to treat diabetic peripheral neuropathy (DPN). Whether 6d has potential to treat other types of diabetic complications (DC) needs to be further investigation.

A multifunctional upconverting nanoparticle incorporated polycationic hydrogel for near-infrared triggered and synergistic treatment of drug-resistant bacteria.

Recently, antibiotic drug-resistant therapies have become very important due to the emergence of antibiotic-resistant bacterial strains. The development of novel antibacterial materials has received significant attention. Here, quaternized chitosan hydrogels incorporated with NaYF4:Er/Yb/Mn@photosensitizer-doped silica (UCNPs/MB) were synthesized for effective killing of both gram-positive oxacillin-resistant S. aureus (DR-S. aureus) and gram-negative kanamyclin-resistant E. coli (DR-E. coli) bacteria upon near-infrared (NIR) laser irradiation. In this system, the cationic macroporous nature of the hydrogel acts as a molecular 'anion sponge', which sucks the outer part of the anionic microbe membrane into the gel interior voids and causes microbe membrane disruption. By incorporating UCNPs/MB-doped silica into the hydrogel, we have combined photodynamic therapy (PDT) with quaternized chitosan to obtain a high therapeutic index via a synergistic effect. In vitro experiments have demonstrated that our system had excellent antibacterial efficiency to both DR-S. aureus and DR-E. coli bacteria. More importantly, our new synergistic treatment modality provided an excellent therapy platform for drug-resistant bacteria, which could improve antimicrobial efficiency.

Upconverting nanoparticles with a mesoporous TiO2 shell for near-infrared-triggered drug delivery and synergistic targeted cancer therapy.

Malignant tumors remain a major health burden throughout the world and effective therapeutic strategies are urgently needed. Herein, we report the synthesis of upconverting nanoparticles with a mesoporous TiO2 (mTiO2) shell for near-infrared (NIR)-triggered drug delivery and synergistic targeted cancer therapy. The NaGdF4:Yb,Tm could convert NIR light to UV light, which activated the mTiO2 to produce reactive oxygen species for photodynamic therapy (PDT). Due to the large surface area and porous structure, the mTiO2 shell endowed the nanoplatform with another functionality of anticancer drug loading for chemotherapy. The hyaluronic acid modified on the surface not only promised controlled drug release but also conferred targeted ability of the system toward cluster determinant 44 overexpressed cancer cells. More importantly, cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of breast carcinoma cells compared with that of single chemotherapy or PDT.

DNA-mediated biomineralization of rare-earth nanoparticles for simultaneous imaging and stimuli-responsive drug delivery.

A DNA-guided method for surface engineering of NaGdF4:Ce/Tb hybrid nanoparticle has been proposed. In this study, the DNA molecules that retained after one-pot NaGdF4:Ce/Tb synthesis is directly utilized as biotemplate for CaP heterogeneous nucleation, thus the dual-purpose function of DNA is realized in the current study which could afford a new type of pH-responsive theranostic platform to enhance the therapeutic efficiency while minimizing side effects. The introduction of another layer of aptamer molecules on CaP facilitated cellular uptake of the resulting nanocomposite into specific target cells via receptor-mediated endocytosis. After been taken by the target tumor cells, the NaGdF4:Ce/Tb@CaP was found to be mostly accumulated in lysosome, which facilitated the dissolving of CaP coatings as non-toxic ions to initiate drug release and efficient cancer cell destruction. We envision that the hybrid nanocarrier may serve as practical and multifunctional probe for cancer therapy and the presented synthesis approach here may also benefit the preparation of many other types of multifunctional inorganic-biomolecular hybrid nanostructures based on the DNA nanotechnology.

Multifunctional upconverting nanoparticles for near-infrared triggered and synergistic antibacterial resistance therapy.

To integrate photodynamic therapy with photothermal therapy for improved multidrug-resistant bacteria therapy, we have constructed a novel multifunctional core/satellite nanostructure by decorating CuS nanoparticles onto the surface of NaYF4:Mn/Yb/Er@photosensitizer doped SiO2. This system exhibited a superior antibacterial activity towards drug-resistant Staphylococcus aureus and Escherichia coli.

DNA-mediated construction of hollow upconversion nanoparticles for protein harvesting and near-infrared light triggered release.

A simple DNA-mediated solvothermal method has been developed for the construction of well-defined hollow UNPs that can be used for a new paradigm to realize NIR light-controlled non-invasive protein release. In vitro studies show that the UNPs are capable of the transportation of enzyme into living cells. Intracellular NIR triggers the release of enzymes with high spatial and temporal precision and the released enzyme also retains its biological activity.

One-step nucleotide-programmed growth of porous upconversion nanoparticles: application to cell labeling and drug delivery.

A simple and "green" strategy has been reported for the first time to fabricate upconversion nanoparticles (UCNPs) by utilizing nucleotides as bio-templates. The influence of the functionalities present on the nucleotide on the production of nanoparticles was investigated in detail. Through the effects of nucleotides, the obtained nanoparticles possessed a porous structure. The use of the as-prepared UCNPs for cell imaging, drug delivery and versatile therapy applications were demonstrated. In view of the bright up-conversion luminescence as well as the excellent biocompatibility, and the good colloidal stability of the as-prepared UCNPs, we envision that our synthesis protocol might advance both the fields of UCNPs and biomolecule-based nanotechnology for future studies.

Reduced graphene oxide upconversion nanoparticle hybrid for electrochemiluminescent sensing of a prognostic indicator in early-stage cancer.

Upconversion nanoparticles (UCNPs) have been proposed as a promising new class of biological luminescent labels because of their weak auto-fluorescence background, strong penetration ability under near-infrared (NIR) radiation, resistance to photobleaching, and low toxicity. Although UCNPs hold great promise in nanotechnology and nanomedicine, their applications in ECL fields still remain unexplored. Herein, a label-free, ultra-sensitive and selective electrochemiluminescence (ECL) assay is developed for detection of cyclin A2 by using highly efficient ECL graphene-upconversion hybrid. Being an important member of the cyclin family, cyclin A2 is involved in the initiation of DNA replication, transcription and cell cycle reg-ulation through the association of cyclin-dependent kinases (CDK). Cyclin A2 is a prognostic indicator in early-stage cancers and a target for treatment of different types of cancers. However, the expression level of cyclin A2 is quite low, direct detection of cyclin A2 in crude cancer cell extracts is challenging and important for both clinical diagnosis of cancer in the early stage and the treatment. By chemically grafting cyclin A2 detection specific probe, a PEGlyted hexapeptide, to graphene-upconversion hybrid, the constructed ECL biosensor displays a superior performance for cyclin A2 , which can not only detect cyclin A2 directly in cancer cell extracts, but also discriminate between normal cells and cancer cells. More importantly, the ECL biosensor has different responses between clinical used anticancer drug-treated and non-treated cancer cells, which demonstrates that the sensor can be potentially used for drug screening, and for evaluation of therapeutic treatments in early-stage cancers.

Combination delivery of antigens and CpG by lanthanides-based core-shell nanoparticles for enhanced immune response and dual-mode imaging.

Europium-doped GdPO4 hollow spheres/polymer core-shell nanoparticles are functionalized with ovalbumin (OVA) as a model antigen and an oligonucleotide (CpG) that stimulates the immune response. These functionalized core-shell nanoparticles are used as vaccines, where they enable efficient delivery of an antigen to target sites, tracking of the vaccines using non-invasive clinical imaging technology.

Bioresponsive hyaluronic acid-capped mesoporous silica nanoparticles for targeted drug delivery.

In this paper, we present a facile strategy to synthesize hyaluronic acid (HA) conjugated mesoporous silica nanoparticles (MSP) for targeted enzyme responsive drug delivery, in which the anchored HA polysaccharides not only act as capping agents but also as targeting ligands without the need of additional modification. The nanoconjugates possess many attractive features including chemical simplicity, high colloidal stability, good biocompatibility, cell-targeting ability, and precise cargo release, making them promising agents for biomedical applications. As a proof-of-concept demonstration, the nanoconjugates are shown to release cargoes from the interior pores of MSPs upon HA degradation in response to hyaluronidase-1 (Hyal-1). Moreover, after receptor-mediated endocytosis into cancer cells, the anchored HA was degraded into small fragments, facilitating the release of drugs to kill the cancer cells. Overall, we envision that this system might open the door to a new generation of carrier system for site-selective, controlled-release delivery of anticancer drugs.

Biomineralization inspired surface engineering of nanocarriers for pH-responsive, targeted drug delivery.

Recent insight into the molecular mechanisms of natural biomineralization has enabled biomimetic synthesis of functional organic-inorganic hybrid materials under mild reaction conditions. Here, we describe a novel method to construct organic-inorganic hybrid on mesoporous silica nanoparticles by utilizing electrostatically absorbed hyaluronic acid (HA) as a reaction site for deposition of calcium phosphate (CaP) minerals. The addition of another layer of HA on the CaP surfaces not only stabilizes the nanocomposites but also confers target ability toward CD44 overexpressed cancer cells. The nanomaterials enable controlled release of loaded anticancer drugs in acidic subcellular environments after receptor mediated endocytosis. More importantly, our study demonstrated that the cancer targeting nanomaterials dramatically enhanced cellular uptake and cytotoxicity toward breast carcinoma cells. These results thus open new opportunities for biomineralization guided nanostructure assemblies with great potential for biomedical applications.

Aptamer-capped multifunctional mesoporous strontium hydroxyapatite nanovehicle for cancer-cell-responsive drug delivery and imaging.

A novel cancer-cells-triggered controlled-release gadolinium-doped luminescent and mesoporous strontium hydroxyapatite nanorods (designated as Gd:SrHap nanorods) system using cell-type-specific aptamers as caps has been constructed. Aptamers behave as a dual-functional molecule that acts as not only a lid but also a targeted molecular that can be used in an effective way for therapeutically special cancer cells. After incubated with cancer cells, for example, MCF-7 cells, the doxorubicin-loaded and aptamer-capped Gd:SrHap nanorods (designated as Gd:SrHap-Dox-aptamer) can be internalized into MCF-7 cells, resulting in the pore opening and drug releasing. Furthermore, the high biocompatibility and biodegradability Gd:SrHap nanorods with blue autofluorescence and paramagnetism could serve as a good contrast agent of targeting fluorescence and magnetic resonance imaging. We envision that this Gd:SrHap system could play a significant role in developing new generations of site-selective, controlled-release delivery and interactive sensory nanodevices.

Photosensitizer-incorporated G-quadruplex DNA-functionalized magnetofluorescent nanoparticles for targeted magnetic resonance/fluorescence multimodal imaging and subsequent photodynamic therapy of cancer.

A smart heteronanostructure has been constructed for targeted photodynamic therapy and magnetic fluorescent imaging of cancer cells using photosensitizer-incorporated G-quadruplex DNA functionalized magnetic nanoparticles.

Facile in situ fabrication of graphene-upconversion hybrid materials with amplified electrogenerated chemiluminescence.

A simple and general synthetic approach for one-step creation of graphene-upconversion nanocomposite by an in situ hydrothermal method has been developed. Using graphene oxide (GO) as a precursor reagent, the reduction of GO and the deposition of NaYF(4)/Yb,Er on graphene occur simultaneously. The electrogenerated chemiluminescent intensity of NaYF(4)/Yb,Er is significantly amplified by graphene due to its wonderful conductivity, extraordinary electron transport properties and large specific surface area.

Magnetic self-assembled zeolite clusters for sensitive detection and rapid removal of mercury(II).

We reported here the fabrication of a hierarchical mesoporous zeolite nanocomposite using 20 nm crystalline domins of zeolite L as building "bricks" by a simple and general one-step synthetic approach. By taking advantages of the large pore volumes, superparamagnetic iron oxide nanocrystals could be encapsulated into the nanocomposite conveniently for further facilitate separation and detection. In addition, by covalent coupling of fluorescent receptor (rhodamine-hydrazine), the combination of well-defined inorganic nanomaterials and organic receptors could be applied to selective detection of Hg(2+). Importantly, the unique adsorption capacity enabled by the hierarchical mesoporous zeolite and the efficient removal ability form complex multiphase systems by the magnetic characteristic made this multifunctional nanomaterial an excellent probe for detection, adsorption, and removal of Hg(2+) from waste aqueous solution.

Mutifuntional GdPO4:Eu3+ hollow spheres: synthesis and magnetic and luminescent properties.

Mondispersed submicrometer GdPO(4):Eu(3+) hollow spheres were synthesized via an effective one-pot hydrothermal process. These hollow spheres have the average diameter of 200 nm, and the shell thickness is about 20 nm. The surface of the spheres consists of a number of nanorods with diameters of about 10 nm and lengths of about 50-80 nm. Both magnetic and luminescent properties of the obtained Eu(3+)-doped GdPO(4) hollow spheres were investigated. The hysteresis plot (M-H) analysis result indicates their paramagnetic property. The fluorescence spectra demonstrate that they emit orange-red color light originated from the (5)D(0) → (7)F(J) transitions of the Eu(3+) ions. Therefore, the obtained GdPO(4) hollow spheres hold promise for encapsulate drugs with controlled release. Moreover, the GdPO(4):Eu(3+) hollow spheres are attributes for bimodal magnetic resonance imaging (MRI)/optical bioimaging labeling.

The use of multifunctional magnetic mesoporous core/shell heteronanostructures in a biomolecule separation system.

A multifunctional magnetic mesoporous core/shell heteronanostructure (designated as Fe(3)O(4)@NiSiO(3)) has been designed and constructed that combined the capacity of effective protein purification from protein mixture and selective low molecule weight (MW) biomolecule enrichment. The nanoparticle is composed by magnetite nanoparticle with immobilized metal ion surface and solid porous shell which presents a number of important features, such as controllable shell thickness, uniform pore size and excellent magnetism. By taking advantages of the high affinity of Ni(2+) on the shell surface toward His-tagged proteins and the fast response toward an assistant magnet, the heteronanoparticles can be applied to selectively bind to and magnetically separate of His-tagged proteins from a cell lysate of E. coli. Additionally, owing to the homogeneous 3D mesopores on the nickel silicate shell, the heteronanoparticles can selectively capture low MW biomolecules from complex mixture. Significantly, it is expected that this approach can be extended to other biomolecule separation and enrichment systems by changing the immobilized surface and the pore size.