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Inhalable metal–organic framework-mediated cuproptosis combined with PD-L1 checkpoint blockade for lung metastasis synergistic immunotherapy

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2281-2297页

作者： Chongzheng Yan Ying Liu Guozhi Zhao Huatian Yang Huaiyou Lv Genju Li Yuhan Li Yaqing Fu Fengqin Sun Yafei Feng Yizhe Li Zhongxi Zhao Department of Pharmaceutics Key Laboratory of Chemical Biology of Ministry of EducationSchool of Pharmaceutical SciencesCheelloo College of MedicineShandong UniversityJinan 250012China key University laboratory of Pharmaceutics&drug Delivery Systems of Shandong Province School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cuproptosis shows enormous application prospects in lung metastasis ***,the glycolysis,Cu^(+)efflux mechanisms,and insufficient lung drug accumulation severely restrict cuproptosis ***,an inhalable poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)(OPDEA)-coated copper-based metal–organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA(siPDK)is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy,namely *** inhalation,OMP shows highly efficient lung accumulation and long-term retention,ascribing to the OPDEA-mediated pulmonary mucosa *** tumor cells,OMP is degraded to release Cu2+under acidic condition,which will be reduced to toxic Cu^(+)to induce cuproptosis under glutathione(GSH)***,siPDK released from OMP inhibits intracellular glycolysis and adenosine-5ʹ-triphosphate(ATP)production,then blocking the Cu^(+)efflux protein ATP7B,thereby rendering tumor cells more sensitive to OMP-mediated ***,OMP-mediated cuproptosis triggers immunogenic cell death(ICD)to promote dendritic cells(DCs)maturation and CD8^(+)T cells ***,OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1(PD-L1)expression and induces soluble PD-L1 secretion,and thus synergizes with anti-PD-L1 antibodies(aPD-L1)to reprogram immunosuppressive tumor microenvironment,finally yielding improved immunotherapy ***,OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.

关键词： Cuproptosis Immunogenic cell death PD-L1 checkpoint blockade Copper-based metal-organic framework Immunotherapy Tumor microenvironment Transmucosal deliveryLung metastasis

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Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： Ge Song Minghui Li Shumin Fan Mengmeng Qin Bin Shao Wenbing Dai Hua Zhang Xueqing Wang Bing He Qiang Zhang Beijing key laboratory of Molecular Pharmaceutics and New drug Delivery Systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State key laboratory of Natural and Biomimetic drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted *** is critical to inspire new potential to remodel the value of this classical therapeutic ***,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic *** in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle *** synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic *** from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with ***,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology

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Cardioprotective Potential of Cymbopogon citratus Essential Oil against Isoproterenol-induced Cardiomyocyte Hypertrophy:Possible Involvement of NLRP3 Inflammasome and Oxidative Phosphorylation Complex Subunits

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Current Medical Science 2024年第2期44卷 450-461页

作者： Xiao-yun DING Hao ZHANG Yu-mei QIU Meng-die XIE Hu WANG Zheng-yu XIONG Ting-ting LI Chun-ni HE Wei DONG Xi-lan TANG School of Pharmacy Jiangxi Science&Technology Normal UniversityNanchang 330013China key laboratory of Modern Preparation of Chinese Medicine Ministry of EducationJiangxi University of Chinese MedicineNanchang 330004China Jiangxi Provincial key laboratory of drug Design and Evaluation Nanchang 330013China

Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive *** this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte ***:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass *** were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 *** hypertrophy-related indicators and NLRP3 inflammasome expression were ***,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying ***:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene ***,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated *** further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col ***:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.

关键词： Cymbopogon citratus essential oil cardiac hypertrophy NLRP3 inflammasome oxidative phosphorylation complex subunits

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Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 188-203页

作者： Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin Zhong Zhonggui He Chutong Tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China key laboratory of Advanced drug Delivery Systems of Zhejiang Province Hangzhou 310058China Joint International Research laboratory of Intelligent drug Delivery Systems Ministry of EducationShenyang 110016China Liaoning Provincial Institute of drug Inspection and Testing Shenyang 110036China

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关键词： Steric disulfide bond Triglyceride-like pr odrugs Cabazitaxel Lymphatic transport Oral chemotherapy

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Visualization of nasal powder distribution using biomimetic human nasal cavity model

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Acta Pharmaceutica Sinica B 2024年第1期14卷 392-404页

作者： Jiawen Su Yan Liu Hongyu Sun Abid Naeem Huipeng Xu Yue Qu Caifen Wang Zeru Li Jianhua Lu Lulu Wang Xiaofeng Wang Jie Wu Lixin Sun Jiwen Zhang Zhigang Wang Rui Yang Li Wu key laboratory of Modern Preparation of TCM Ministry of EducationJiangxi University of Chinese MedicineNanchang 330004China key laboratory of Molecular Pharmacology and drug Evaluation School of PharmacyMinistry of EducationYantai UniversityYantai 264005China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201210China Nantong Haimen People’s Hospital Nantong 226199China Yangtze Delta drug Advanced Research Institute Nantong 226126China Shenyang Pharmaceutical University Shenyang 110016China National Institutes for Food and drug Control Beijing 100000China Nanjing University of Chinese Medicine Nanjing 210023China

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal ***,no reliable method is currently available to assess its impact on delivery *** this study,a biomimetic nasal model based on three-dimensional(3D)reconstruction and three-dimensional printing(3DP)technology was developed for visualizing the deposition of drug powders in the nasal *** results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and *** nasal cavity model was modified with dimethicone and validated to be suitable for the deposition *** experimental device produced the most satisfactory results with five spray ***,particle sizes and spray angles were found to significantly affect the experimental device’s performance and alter drug distribution,***,mometasone furoate(MF)nasal spray(NS)distribution patterns were investigated in a goat nasal cavity model and three male goat noses,confirming the in vitro and in vivo *** conclusion,the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

关键词： Nasal drug deposition Nasal drug distribution Nasal drug delivery Biomimetic nasal model Nasal powder Three-dimensional reconstruction Three-dimensional printing Nasal drug distribution

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When mRNA meets gene editing

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Nano Research 2024年第8期17卷 7337-7356页

作者： Weijie Li Chen Wang Yuan Lu key laboratory of Industrial Biocatalysis Ministry of EducationDepartment of Chemical EngineeringTsinghua UniversityBeijing 100084China Department of Chemical Engineering Tsinghua UniversityBeijing 100084China

The critical challenge of gene therapy lies in delivering gene editing *** with DNA,while RNA is less stable and more accessible to degrade,it comes with the benefit of lower off-target effects since permanent insertion is not *** review focuses on mRNA-based delivery of gene editing agents,highlighting novel mRNA delivery *** provide context,a comparison is made between three main gene editing agents:programmable nucleases,base editors,and prime *** potential of Cas\pi and transposons is also discussed in this ***,a summary of four main barriers to mRNAbased in vivo delivery is ***,this review detailedly introduced different delivery systems,both viral(lentivirus)and non-viral vectors(genome editing via oviductal nucleic acids delivery,lipid nanoparticles,polymer-based nanoparticles,viruslike-particles,extracellular vesicles,and migrasome).Each delivery strategy is assessed by comparing its advantages and disadvantages to offer a comprehensive and objective overview of the delivery ***,we emphasized the vital role of the protein corona as a critical regulator for ***,we concluded the challenges of mRNA-based gene editing strategies(RNA stability,targeting,potential immunogenicity,cytotoxicity,heterogeneity,and rational design).The purpose of this review is to guide further research and provide a comprehensive analysis of mRNA-based in vivo delivery of gene editing agents in this promising field.

关键词： gene editing mRNA delivery viral vectors non-viral vectors CRISPR

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Ergothioneine and its congeners:anti-ageing mechanisms and pharmacophore

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Protein & Cell 2024年第3期15卷 191-206页

作者： Li Chen Liping Zhang Xujun Ye Zixin Deng Changming Zhao Department of Geriatrics Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430072China key laboratory of Combinatory Biosynthesis and drug Discovery School of Pharmaceutical SciencesMinistry of EducationWuhan UniversityWuhan 430072China tThese authors contributed equally.

Ergothioneine,Ovothiol,and Selenoneine are sulfur/selenium-containing histidine-derived natural products widely distributed across different *** exhibit significant antioxidant properties,making them as potential lead compounds for promoting *** evidence suggests that Ergothioneine is positively correlated with healthy ageing and *** mechanisms underlying Ergothioneine's regulation of the ageing process at cellular and molecular levels are beginning to be *** this review,we provide an in-depth and extensive coverage of the anti-ageing studies on Ergothioneine and discuss its possible intracellular targeting *** addition,we highlight the recent efforts in elucidating the biosynthetic details for Ergothioneine,Ovothiol,and Selenoneine,with a particular focus on the study of their pharmacophore-forming enzymology.

关键词： Ergothioneine antioxidant anti-ageing longevity biosynthesis enzymology

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Photocatalytic Site-Selective Cascade Radical Addition of Biaryl Ynones for the Construction of Spiro-and Fused Carbon Rings

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Chinese Journal of Chemistry 2024年第14期42卷 1599-1605页

作者： Kairui Liu Chunhang Zhao Liji Gu Xiang Li Jiali Yan Siqi Lao Weiwei Huan Yan Zhang key laboratory of the ministry of education for Advanced Catalysis Materials and Drug Discovery&Innovation CenterCollege of Chemistry and Materials ScienceZhejiang Normal UniversityJinhuaZhejiang321004 China Zhejiang Provincial key laboratory of Chemical Utilization of Forestry Biomass College of Chemistry and Materials EngineeringZhejiang A&F UniversityHangzhouZhejiang311300 China

Functionalized free radical addition/cyclization reactions represent an efficient way for introducing new functionality or coupling fragments to *** are good regional selectivity radical acceptors in organic synthesis,and many of bio-relevant cyclic compounds could be easily obtained by direct radical cyclization ***,we report a photocatalytic cascade radical addition of biaryl ynones,for the divergent synthesis of privileged carbon ***,further transformation of the multi-functional group product into a variety of other derivatives demonstrates the synthetic value of this developed method.

关键词： Ynones Photocatalysis Cascade cyclization Alkoxycarbonyl radical Dearomatization Biaryls Regioselectivity Radical reactions

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RNA interference in insects:the link between antiviral defense and pest control

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Insect Science 2024年第1期31卷 2-12页

作者： Jinzhi Niu Ruoyu Chen Jin-Jun Wang key laboratory of Entomology and Pest Control Engineering College of Plant ProtectionSouthwest UniversityChongqingChina key laboratory of Agricultural Biosafety and Green Production of Upper Yangtze River(ministry of education) Southwest UniversityChongqingChina

RNA interference(RNAi)is a form of gene silencing triggered by double-stranded RNA(dsRNA)that operates in all eukaryotic *** has been widely investigated in insects to determine the underlying molecular mechanism,to investigate its role in systemic antiviral defense,and to develop strategies for pest *** insect cells are infected by viruses,viral dsRNA signatures trigger a local RNAi response to block viral replication and generate virus-derived DNA that confers systemic ***-based insect pest control involves the application of exogenous dsRNA targeting genes essential for insect development or survival,but the efficacy of this approach has limited potency in many pests through a combination of rapid dsRNA degradation,inefficient dsRNA uptake/processing,and ineffective RNAi *** could be addressed by dsRNA screening and evaluation,focusing on dsRNA design and off-target management,as well as dsRNA production and *** review summarizes recent progress to determine the role of RNAi in antiviral defense and as a pest control strategy in insects,addressing gaps between our fundamental understanding of the RNAi mechanism and the exploitation of RNAi-based pest control strategies.

关键词： RNAi response systemic RNAi insecticidal dsRNA biological control off-targets

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Cationic Conjugated Oligomers for Efficient and Rapid Antibacterial Photodynamic Therapy via Both Type Ⅰ and Type Ⅱ Pathways

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Chinese Journal of Chemistry 2024年第1期42卷 61-66页

作者： Huan Wang Shuwen Guo Qiong Yuan Meiqi Li Yanli Tang Country key laboratory of Analytical Chemistry for Life Science of Shaanxi Province Key Laboratory of Applied Surface and Colloid ChemistryMinistry of EducationSchool of Chemistry and Chemical EngineeringShaanxi Normal UniversityXi'anShaanxi 710119China

Recently,photodynamic therapy(PDT)has attracted wide attention due to its less susceptibility to drug resistance,broad-spectrum biocidal activity and biosafety in normal ***,the traditional photosensitizers(Ps)face the disadvantage of poor therapeutic efficacy due to the requirement of an aerobic environment to generate ^(1)O_(2) through Type Ⅱ ***,we designed and synthesized a novel cationic conjugated oligomer oligo(phenylene vinylene)(OPV)and studied its antibacterial photodynamic activity against both Gram-negative Escherichia coli(***)and Gram-positive bacteria methicillin-resistant Staphylococcus aureus(MRSA).Importantly,the OpV can rapidly produce reactive oxygen species(ROs)through double pathways,Type Ⅰ and Ⅱ mechanism under white light irradiation,and efficiently kill *** and MRSA at a nanomolar *** dual type photosensitizing capability makes OPV promising for enhanced PDT to treat pathogens and tumors in complex environments.

关键词： Conjugated oligomers Antibacterial photodynamic therapy Oligo(phenylene vinylene) Reactive oxygen species Typelandll pathways

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