Radiation-Synthesized Metal-Organic Frameworks with Ligand-Induced Lewis Pairs for Selective CO2 Electroreduction.

The electrochemical activation of inert CO2 molecules through C─C coupling reactions under ambient conditions remains a significant challenge but holds great promise for sustainable development and the reduction of CO2 emission. Lewis pairs can capture and react with CO2, offering a novel strategy for the electrosynthesis of high-value-added C2 products. Herein, an electron-beam irradiation strategy is presented for rapidly synthesizing a metal-organic framework (MOF) with well-defined Lewis pairs (i.e., Cu- Npyridinic). The synthesized MOFs exhibit a total C2 product faradic efficiency of 70.0% at -0.88 V versus RHE. In situ attenuated total reflection Fourier transform infrared and Raman spectra reveal that the electron-deficient Lewis acidic Cu sites and electron-rich Lewis basic pyridinic N sites in the ligand facilitate the targeted chemisorption, activation, and conversion of CO2 molecules. DFT calculations further elucidate the electronic interactions of key intermediates in the CO2 reduction reaction. The work not only advances Lewis pair-site MOFs as a new platform for CO2 electrochemical conversion, but also provides pioneering insights into the underlying mechanisms of electron-beam irradiated synthesis of advanced nanomaterials.

"One suction and one extrusion" mode-based wash-free platform for determination of breast cancer cell-derived exosomes.

A simple and wash-free POCT platform based on microcapillary was developed, using breast cancer cell-derived exosomes as a model. This method adopted the "one suction and one extrusion" mode. The hybridized complex of epithelial cell adhesion molecule (EpCAM) aptamer and complementary DNA-horseradish peroxidase conjugate (CDNA-HRP) was pre-modified on the microcapillary's inner surface. "One suction" meant inhaling the sample into the functionalized microcapillary. The exosomes could specifically bind with the EpCAM aptamer on the microcapillary's inner wall, and then the CDNA-HRP complex was released. "One extrusion" referred to squeezing the shedding CDNA-HRP into the 3,3',5,5'-tetramethylbenzidine (TMB)/H2O2 solution, and then the enzyme-catalyzed reaction would occur to make the solution yellow using sulfuric acid as the terminator. Therefore, exosome detection could be realized. The limit of detection was 2.69 × 104 particles mL-1 and the signal value had excellent linearity in the concentration range from 2.75 × 104 to 2.75 × 108 particles⋅mL-1 exosomes. In addition, the wash-free POCT platform also displayed a favorable reproducibility (RSD = 2.9%) in exosome detection. This method could effectively differentiate breast cancer patients from healthy donors. This work provided an easy-to-operate method for detecting cancer-derived exosomes without complex cleaning steps, which is expected to be applied to breast cancer screening.

Moroidin, a Cyclopeptide from the Seeds of Celosia cristata That Induces Apoptosis in A549 Human Lung Cancer Cells.

Interference of microtubule dynamics with tubulin-targeted drugs is a validated approach for cancer chemotherapy. Moroidin (1) is an Urticaceae-type cyclopeptide having a potent inhibitory effect on purified tubulin polymerization. So far, moroidin has not been chemically synthesized, and its effect on cancer cells remains unknown. Herein, the cyclopeptide moroidin was isolated and identified from the seeds of Celosia cristata, and a revised assignment of its NMR data was presented. For the first time, moroidin (1) was demonstrated as having cytotoxic effects for several cancer cells, especially A549 lung cancer cells. The cellular evidence obtained showed that moroidin disrupts microtubule polymerization and decreases ß-tubulin protein levels, but is not as potent as colchicine. Molecular docking indicated that 1 has a high binding potential to the vinca alkaloid site on tubulin. Moreover, moroidin arrested A549 cells in the G2/M phase and induced cell apoptosis. The intrinsic mitochondrial pathway and AKT were involved in the moroidin-induced cell apoptosis. In addition, moroidin (1) inhibited the migration and invasion of A549 cells at sublethal concentrations.

Senolytics Cocktail Dasatinib and Quercetin Alleviate Human Umbilical Vein Endothelial Cell Senescence via the TRAF6-MAPK-NF-κB Axis in a YTHDF2-Dependent Manner.

INTRODUCTION: Senescent cells play a key role in the initiation and development of various age-related diseases. Human umbilical vein endothelial cells (HUVECs) senescence is closely associated with age-related cardiovascular diseases. Accumulating evidence has demonstrated that senolytics, the combination of dasatinib and quercetin (D+Q), could selectively eliminate senescent cells. N6-methyladenosine (m6A), the most abundant internal transcript modification, greatly influences RNA metabolism and modulates gene expression. We aimed to investigate whether RNA m6A functions in lipopolysaccharide (LPS)-induced HUVECs senescence and D+Q suppress HUVECs senescence by regulating RNA m6A. METHODS: Senescence-associated ß-galactosidase activity, western blot, and real-time quantitative polymerase chain reaction were performed to demonstrate that D+Q suppress HUVECs senescence. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay and RIP-qPCR confirmed that RNA m6A plays a key role in the suppression of HUVECs senescence by D+Q. Chromatin immunoprecipitation and mRNA stability assay were carried out to prove that D+Q alleviate HUVECs senescence in a YTHDF2-dependent manner. RESULTS: Here, we demonstrate that D+Q alleviate LPS-induced senescence in HUVECs via inhibiting autocrine and paracrine of the senescence-associated secretory phenotype (SASP). We further confirm that D+Q alleviate HUVECs senescence via the TNF receptor-associated factor 6 (TRAF6)-MAPK pathway. Mechanically, this study validates that D+Q suppress SASP by upregulating m6A reader YTHDF2. Besides, YTHDF2 regulates the stability of MAP2K4 and MAP4K4 mRNAs. CONCLUSION: Collectively, we first identified that D+Q alleviate LPS-induced senescence in HUVECs via the TRAF6-MAPK-NF-κB axis in a YTHDF2-dependent manner, providing novel ideas for clinical treatment of age-related cardiovascular diseases.

Design, synthesis and evaluation of novel small molecules acting as Keap1-Nrf2 protein-protein interaction inhibitors.

Direct interference with Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 protein-protein interaction (PPI) has recently been introduced as an attractive approach to control life-threatening diseases like myocarditis. The present study aimed to investigate the potential application in myocarditis of a series of novel non-naphthalene derivatives as potential Keap1-Nrf2 PPI inhibitors. Our results indicated that the optimal compound K22 displayed the highest metabolic stability and showed notable Keap1-Nrf2 PPI inhibitory activities in vitro. K22 effectively triggered Nrf2 activation and increased the protein and mRNA expression of Nrf2-regulated genes in H9c2 cells. Moreover, pre-treatment with K22 was shown to mitigate LPS-induced damage to H9c2 cells, causing a marked decrease in the levels of inflammatory factors as well as reactive oxygen species (ROS). Furthermore, K22 was also shown to be non-mutagenic in the Ames test. Overall, our findings suggest that K22 may be a promising drug lead as a Keap1-Nrf2 PPI inhibitor for myocarditis treatment.

Enhancing ZnO nanowire gas sensors using Au/Fe2O3 hybrid nanoparticle decoration.

Heterojunctions are an important strategy for designing high performance electrical sensor materials and related devices. Herein, a new type of metal-semiconductor hybrid nanoparticle has been successfully used to remarkably sensitize the surface of ZnO nanowires for detecting NO2 with high responses over a broad temperature window ranging from room temperature to 600 °C. These hybrid nanoparticles are comprised of iron oxide nanowires with well dispersed single crystalline Au nanoparticles. The hybrid nanoparticle decorated ZnO nanowires have achieved a giant response, as high as 74 500 toward NO2 gas, about 42 times that of Au decorated ZnO nanowire sensors. This dramatic enhancement may be attributed to the efficient charge transfer across the Au-Fe2O3 Schottky and Fe2O3-ZnO semiconductor heterojunction interfaces. Due to the incorporation of thermally-stable Fe2O3 nanoparticles as the support of Au nanoparticles, the working temperature of nanowire sensors was successfully extended to higher temperatures, with an increase of 200 °C, from 400 °C to 600 °C. Such a combination of semiconductor heterojunction and semiconductor-metal Schottky contact presents a new strategy for designing high performance electrical sensors with high sensitivity, stability, selectivity, and wide operation temperature window, which are potentially suitable for advanced energy systems such as automotive engines and power plants.

Targeted delivery of intranasally administered nanoparticles-mediated neuroprotective peptide NR2B9c to brain and neuron for treatment of ischemic stroke.

The lack of effective therapies mandates the development of new treatment strategies for ischemic stroke. The NR2B9c peptide can prevent N-Methyl-D-aspartate receptor (NMDAR)-mediated neurotoxicity induced by ischemia without affecting essential NMDAR activity and brings hope for stroke therapy. However, it is very difficult for NR2B9c to cross by itself the blood-brain barrier (BBB) and the neuron membrane. To provide a suitable delivery for unleashing the therapeutic potential of NR2B9c, in consideration of a high affinity of wheat germ agglutinin (WGA) for WGA receptors abundantly present on olfactory epithelium and neuronal surface, we developed WGA-modified nanoparticles carrying NR2B9c (NR2B9c-WGA-NPs). Following intranasal administration, NR2B9c-WGA-NPs are able to bypass the BBB and effectively transport NR2B9c into the brain and neuron, and therefore can protect neurons against excitotoxicity, reduce ischemic brain injury in rats and ameliorate their neurological function deficits. The intranasal administration of NR2B9c-WGA-NPs may serve as a practical stroke therapy.

Network Pharmacology Followed by Experimental Validation to Explore the Mechanism of Stigmasterol in Sangbaipi Decoction Regulating PI3K/Akt Signaling to Alleviate Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Purpose: Sangbaipi decoction (SBPD), a traditional Chinese medicine (TCM) prescription, has been widely used to treat acute exacerbation of chronic obstructive pulmonary disease (AECOPD), while the underlying pharmacological mechanism remains unclear due to the complexity of composition. Methods: A TCM-active ingredient-drug target network of SBPD was constructed utilizing the TCM-Systems-Pharmacology database. AECOPD-relevant proteins were gathered from Gene Cards and the Online-Mendelian-Inheritance-in-Man database. Protein-protein interaction, GO and KEGG enrichment analyses of the targets from the intersection of SBPD and AECOPD targets were performed to identify the core signaling pathway, followed by molecular docking verification of its interaction with active ingredients. The network pharmacology results were checked using in-vivo experiments. To induce AECOPD, rats were exposure to combined tobacco smoke and lipopolysaccharide (LPS). Then rats underwent gavage with stigmasterol (SM) after successful modeling. The involvement of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling was investigated using its inhibitor, LY294002. Lung function and histopathology were examined. The levels of inflammatory cytokines in the lung and serum were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot and/or Enzyme-linked immunosorbent assay (ELISA). Results: SM was recognized as an active ingredient of SBPD and stably bound to Akt1. SM improved lung function and histological abnormalities, concomitant with suppressed PI3K/Akt signaling, downregulated lung and serum Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) levels and serum transforming growth factor-ß (TGF-ß) levels and upregulated lung and serum Interleukin 10 (IL-10) levels in AECOPD rats. In AECOPD rats, LY294002 restored lung function, and it also improved lung histological abnormalities and inflammation, which was found to be potentiated by SM. Conclusion: SM targets PI3K/Akt signaling to reduce lung injury and inflammation in AECOPD rats.

Amine-Functionalized Metal-Free Nanocarbon to Boost Selective CO2 Electroreduction to CO in a Flow Cell.

Highly efficient electrochemical CO2-to-CO conversion is a promising approach for achieving carbon neutrality. While nonmetallic carbon electrocatalysts have shown potential for CO2-to-CO utilization in H-type cells, achieving efficient conversion in flow cells at an industrial scale remains challenging. In this study, we present a cost-effective synthesis strategy for preparing ultrathin 2D carbon nanosheet catalysts through simple amine functionalization. The optimized catalyst, NCNs-2.5, demonstrates exceptional CO selectivity with a maximum Faradaic efficiency of 98% and achieves a high current density of 55 mA cm-2 in a flow cell. Furthermore, the catalyst exhibits excellent long-term stability, operating continuously for 50 h while maintaining a CO selectivity above 90%. The superior catalytic activity of NCNs-2.5 is attributed to the presence of amine-N active sites within the carbon lattice structure. This work establishes a foundation for the rational design of cost-effective nonmetallic carbon catalysts as sustainable alternatives to metals in energy conversion systems.

Phloretin targets SIRT1 to alleviate oxidative stress, apoptosis, and inflammation in deep venous thrombosis.

Deep vein thrombosis (DVT) is a type of venous thromboembolism posing a serious threat to health on a global scale. Phloretin is a potential natural product that has a variety of pharmacological activities. Besides, some Chinese medicines reported that deacetylase sirtuin (SIRT)1 treats DVT by anti-inflammatory and anti-platelet production. However, the specific binding targets and binding modes have not been elaborated. The present study was to investigate whether phloretin attenuates DVT in model rats and oxidized low­density lipoprotein (ox­LDL) induced human umbilical vein endothelial cells (HUVECs), and to explore its potential target. The results revealed that the treatment of phloretin, especially pretreatment of it elevated tissue plasminogen activator (t-PA), superoxide dismutase (SOD), prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), and cell apoptosis proteins whereas it suppressed plasminogen activator inhibitor (PAI), malondialdehyde (MDA), reactive oxygen species (ROS), fibrinogen (FIB) in DVT rats and cells. Concurrently, phloretin inhibited collagen type I alpha 1 (COL1A1), transforming growth factor-ß1 (TGF-ß1), and inflammatory factors while it enhanced nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase 1 (HO-1). In addition, 20 µM phloretin exerted powerful effective protection in HUVECs with DVT model. Later, the surface plasmon resonance (SPR) confirmed that phloretin has a high affinity with SIRT1. Furthermore, siRNA-SIRT1 transfection abolished the protective effect of phloretin against ox­LDL­induced DVT in HUVECs, indicating that phloretin targets SIRT1 to alleviate oxidative stress, cell apoptosis, and inflammation in DVT rats and HUVECs. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00207-y.

Machine learning-guided realization of full-color high-quantum-yield carbon quantum dots.

Carbon quantum dots (CQDs) have versatile applications in luminescence, whereas identifying optimal synthesis conditions has been challenging due to numerous synthesis parameters and multiple desired outcomes, creating an enormous search space. In this study, we present a novel multi-objective optimization strategy utilizing a machine learning (ML) algorithm to intelligently guide the hydrothermal synthesis of CQDs. Our closed-loop approach learns from limited and sparse data, greatly reducing the research cycle and surpassing traditional trial-and-error methods. Moreover, it also reveals the intricate links between synthesis parameters and target properties and unifies the objective function to optimize multiple desired properties like full-color photoluminescence (PL) wavelength and high PL quantum yields (PLQY). With only 63 experiments, we achieve the synthesis of full-color fluorescent CQDs with high PLQY exceeding 60% across all colors. Our study represents a significant advancement in ML-guided CQDs synthesis, setting the stage for developing new materials with multiple desired properties.

Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

Impact of Pharmacist-Led PDCA Cycle in Reducing Prescription Abandonment: An Action Research from China.

Purpose: Taking medicine as prescribed in time plays an important role in the treatment of diseases. However, some prescriptions have not picked up in time for various reasons. To analyze the influencing factors in patients with prescription abandonment and the role of pharmacists in Plan-Do--Check-Act (PDCA) cycle, we conducted a study in our hospital of Hangzhou, China. Methods: Based on the prescription abandonment from October 1, 2021 to March 31 2022, we collected and analyzed the possible causes. According to the PDCA management method, we conducted improvement measures and supervised the implementation of measures from April 1, 2022 to September 30, 2022. The number, the proportion and the amount of prescription abandonment before and after establishment of the PDCA cycle were analyzed. Results: Three measures were proposed and applied to improve the prescription abandonment:(I) Enhancing the education and training to the staff. (II) Improving the medical environment for patients, especially the environment for taking medicine. (III) Updating the computer information software. After the implementation of PDCA, the number of prescription abandonment decreased from 2030 to 775, there was significant reduction in the proportion of prescription abandonment (4.75‰ vs 1.77‰, P<0.05), and the amount of prescription abandonment decreased from $36,161.11 to $17,041.59. The target compliance rate was 108.36%. Conclusion: The implementation of pharmacist-led PDCA can effectively reduce the number, the proportion and the amount of prescription abandonment, Moreover, Pharmacists play an important role in improving the management quality of outpatient pharmacy, and PDCA is a feasible and effective management tool for reducing prescription abandonment.

Investigation on protein dimerization and evaluation of medicine effects by single molecule force spectroscopy.

Monitoring the dimerization state of the mesenchymal-epithelial transition factor (Met) was essential for in-depth understanding of the tumor signal transduction network. At present, the dimerization activation pathway of Met protein was mainly studied at the macro level, while the research at the single molecule level was far from comprehensive. Herein, the dimerization activation of Met protein's extracellular domain induced by ligand hepatocyte growth factor (HGF) was dynamically studied by single-molecule force spectroscopy. Met protein was immobilized on a biomimetic lipid membrane for ensuring its physiological environment, and then the Met dimers were recognized by bivalent probe which was formed by two Met-binding aptamers. Then the dimeric state of Met protein could be distinguished from monomeric state of Met protein through some parameters, (such as unimodal ratio, bimodal ratio and separation work). The unimodal indicates the occurrence of single molecule binding event, and the bimodal represents the occurrence of double binding event (also represents the presence of Met dimer). Before HGF treatment, most of the Met protein on the lipid membrane was still in the form of monomer, so the unimodal ratio in the force curve was larger (78.8 ± 5.2%), and the bimodal ratio was smaller (17.0 ± 4.1%). After HGF treatment, the unimodal ratio decreased to 54.0 ± 7.4%, and the bimodal ratio increased to 43.2 ± 7.3%. It was due to the formation of dimers after the binding of Met protein on the fluidity lipid membrane with HGF. In addition, the average separation work increased to about 2 times after HGF treatment. Given that studies of Met protein dimerization inhibitors have contributed to the development of more potent and safe inhibitors to significantly inhibit tumor metastasis, the effects of different medicines (including anticoagulant medicines, different antibiotics and anti-cancer medicines) on the dimerization activation of Met protein were then explored by the platform described above. The results showed that anticoagulant medicines heparin and its analogs can significantly inhibit HGF-mediated Met protein activation, while different antibiotics and anticancer medicines had no significant effect on the dimerization of Met protein. This work provided a platform for studying protein dimerization as well as for screening Met protein dimerization inhibitors at the single-molecule level.

One-step multiplex analysis of breast cancer exosomes using an electrochemical strategy assisted by gold nanoparticles.

Exosomes, as a non-invasive biomarker, perform an important role in breast cancer screening and prognosis monitoring. However, establishing a simple, sensitive, and reliable exosome analysis technique remains challenging. Herein, a one-step multiplex analysis electrochemical aptasensor based on a multi-probe recognition strategy was constructed to analyze breast cancer exosomes. HER2-positive breast cancer cell (SK-BR-3) exosomes were selected as the model targets and three aptamers including CD63, HER2 and EpCAM aptamers were used as the capture units. Methylene blue (MB) functionalized HER2 aptamer and ferrocene (Fc) functionalized EpCAM aptamer, which were modified on gold nanoparticles (Au NPs), i.e. MB-HER2-Au NPs and Fc-EpCAM-Au NPs, were used as signal units. When the mixture of target exosomes, MB-HER2-Au NPs and Fc-EpCAM-Au NPs were added on the CD63 aptamer modified gold electrode, two Au NPs modified by MB and Fc could be specifically captured on the electrode by the recognition of three aptamers with target exosomes. Then one-step multiplex analysis of exosomes was achieved by detecting two independent electrochemical signals. This strategy can not only distinguish breast cancer exosomes from other exosomes (including normal exosomes and other tumor exosomes) but also HER2-positive breast cancer exosomes and HER2-negative breast cancer exosomes. Besides, it had high sensitivity and can detect SK-BR-3 exosomes with a concentration as low as 3.4 × 103 particles mL-1. Crucially, this method can be applicable to the examination of exosomes in complicated samples, which is anticipated to afford assistance for the screening and prognosis of breast cancer.

An Injectable Hydrogel for Treatment of Chronic Neuropathic Pain.

Current treatments for chronic neuropathic pain often fall short. A small-molecular compound ZL006 can suppress N-Methyl-d-aspartate receptor (NMDAR)-mediated neuropathic pain behaviors without blocking essential NMDAR function and brings new hope for neuropathic pain therapy. The persistent nature of neuropathic pain mandates the long-term treatment. However, similar to existing analgesics, ZL006 has only a short duration of action. To unleash the therapeutic potential of ZL006, the stability of ZL006 in aqueous solutions is investigated, and a ZL006-incorporated P407-based thermoresponsive injectable hydrogel is developed. The computational analysis is performed to help achieve the desired ZL006-loaded hydrogel system and elucidate the gelation mechanism. The hydrogel matrix can be loaded with ZL006 in an aqueous phase at room temperature without costly specialized equipment and no organic solvent, where the sol is formed and injectable. On subcutaneous administration and subsequent rapid warming to physiological temperature, the sol is converted to a gel. The thermoresponsive hydrogel at body temperature enables the extended release of encapsulated ZL006, and therefore a single subcutaneous injection of ZL006-hydrogel produces a prolonged and stable analgesic action in mice with spinal nerve ligation. The study provides a practical chronic neuropathic pain therapy and a new perspective on future applications of ZL006.

High-resolution mass spectrometry-based approach for the identification and profiling of the metabolites of taletrectinib formed in liver microsomes.

Taletrectinib is a potent, orally active, and selective ROS1/NTRK kinase inhibitor. The aim of this study was to study the metabolism of taletrectinib in rat, dog, and human liver microsomes. The biotransformation of taletrectinib was carried out using rat, dog, and human liver microsomes supplemented with nicotinamide adenine dinucleotide phosphate tetrasodium salt (NADPH) and uridine diphosphate glucuronic acid (UDPGA). The microsomal incubations were conducted at 37°C for 60 min. The formed metabolites were identified by ultrahigh performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-HRMS) using electrospray ionization in the positive ion mode. They were identified by accurate masses and MS/MS spectra and based on their fragmentation pathways. With UHPLC-HRMS, a total of 10 metabolites including one glucuronide conjugate (M7) were structurally identified. M9 and M10 were unambiguously identified as taletrectinib alcohol and taletrectinib ketone, respectively, using reference standards. The phase I metabolic pathways of taletrectinib involved N-dealkylation, O-dealkylation, oxidative deamination, and oxygenation; the phase II metabolic pathways referred to glucuronidation. The current study investigated the in vitro metabolic fate of taletrectinib in animals and human species, which would bring us considerable benefits for the subsequent studies focusing on the pharmacological effect and toxicity of this drug.

H7K(R2)2-modified pH-sensitive self-assembled nanoparticles delivering small interfering RNA targeting hepatoma-derived growth factor for malignant glioma treatment.

The lack of effective glioma therapeutics mandates the development of novel treatment strategies. Hepatoma-derived growth factor (HDGF) has been considered as a potential glioma therapeutic target, and its expression level in gliomas is positively related to the malignant grade. Although there are no effective and specific inhibitors against this target, small interfering RNA targeting HDGF (siHDGF)-mediated RNA interference (RNAi) can inhibit the target protein function by knockdown of HDGF expression. However, the application of siHDGF in glioma research and therapy is hampered by the challenge to safe and effective in vivo systemic delivery of siHDGF to gliomas. To address this question, we develop the peptide H7K(R2)2-modified pH-sensitive self-assembled hybrid nanoparticles encapsulating siHDGF (H7K(R2)2-PSNPs (siHDGF)). The acidic glioma microenvironment is beneficial to the membrane penetration of H7K(R2)2-PSNPs and the encapsulated siHDGF. Following systemic administration, H7K(R2)2-PSNPs (siHDGF) can effectively deliver siHDGF into the brain and malignant glioma cells, and therefore can significantly downregulate HDGF expression, inhibit malignant phenotypes of glioma cells, result in reduced tumor volumes and prolonged survival times in nude mice bearing U251 human glioblastoma. Thus, systemic administration of H7K(R2)2-PSNPs (siHDGF) offers an effective way for the targeted delivery of siHDGF and may serve as a practical malignant glioma therapy.

Preparation, optimization, and characterization of chitosan-coated solid lipid nanoparticles for ocular drug delivery.

The present study aimed to develop and optimize chitosan coated solid lipid nanoparticles (chitosan-SLNs) encapsulated with methazolamide. Chitosan-SLNs were successfully prepared by a modified oil-in-water emulsification-solvent evaporation method with glyceryl monostearate as the solid lipid and phospholipid as the surfactant. Systematic screening of formulation factors was carried out. The optimized formula for preparation was screened by orthogonal design as well as Box-Behnken design with entrapment efficiency, particle size and zeta potential as the indexes. The entrapment efficiency of the optimized formulation (methazolamide-chitosan-SLNs) prepared was (58.5±4.5)%, particle size (247.7±17.3) nm and zeta potential (33.5±3.9) mV. Transmission electron microscopy showed homogeneous spherical particles in the nanometer range. A prolonged methazolamide in vitro release profile was obtained in the optimized chitosan-SLNs suspension compared with methazolamide solution. No ocular damages were observed in the susceptibility test on albino rabbits. The results suggest that the combination of orthogonal design and Box-Behnken design is efficient and reliable in the optimization of nanocarriers, and chitosan-SLNs is a potential carrier for ophthalmic administration.

Enhanced Antiglioma Efficacy of Ultrahigh Loading Capacity Paclitaxel Prodrug Conjugate Self-Assembled Targeted Nanoparticles.

Glioblastoma multiforme (GBM) presents one of the most lethal brain tumor with a dismal prognosis. And nanodrug delivery system (nano-DDS) have raised a lot of concern, while the conventional nanoformulations addressed many limitations, especially the low drug loading capacity and poor stability in vivo. Herein, we proposed PTX prodrug (PTX-SS-C18) conjugate self-assembled nanoparticles (PSNPs) functionalized with Pep-1, glioma homing peptide, to overcome the blood brain tumor barrier (BBTB) via interleukin 13 receptor α2 (IL-13Rα2)-mediated endocytosis for targeting GMB. This nanocarrier was with ultrahigh drug loading capacity (56.03%) and redox-sensitivity to the up-expression of glutathione in glioma tumors. And compared with PEG-PSNPs, Pep-PSNPs could significantly enhance cellular uptake in U87MG cells via IL-13Rα2-mediated endocytosis. Enhanced cytotoxicity of Pep-PSNPs against U87MG cells and BCEC cells pretreated with glutathione monoester (GSH-OEt) confirmed that this nanosystem was sensitive to reduction environment, and there was significant difference between targeting and nontargeting groups in MTT assay. Real-time fluorescence image of intracranialU87MG glioma-bearing mice revealed that Pep-PSNPs could more efficiently accumulate at tumor site and improve the penetration. Furthermore, the ex vivo fluorescence imaging and corresponding semiquantitative results displayed that the glioma fluorescence intensity of Pep-PSNPs group was 1.74-fold higher than that of nontargeting group. Pep-PSNPs exhibited remarkable antiglioblastoma efficacy with an extended median survival time. In conclusion, Pep-PSNPs had a promising perspective as a targeting drug delivery system of PTX for glioma treatment.