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Fine-tuning the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies via branched aliphatic functionalization

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Nano Research 2024年第4期17卷 2908-2918页

作者： Guanting Li Fengli Xia Hongying Xiao Shunzhe Zheng Shuwen Fu Han Qiao Qianhui Jin Xuanbo Zhang Dun Zhou Chutong Tian Jin Sun Zhonggui He Bingjun Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmaceutics College of PharmacyShenyang Pharmaceutical UniversityShenyang 110016China Emergency Department The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001China

Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery ***,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous *** rational design of camptothecins-based prodrug nanoassemblies remains a ***,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug ***,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical *** length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and ***,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and *** findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.

关键词： prodrug nanoassembly self-assembly antitumor efficacy tolerance 7-ethyl-10-hydroxycamptothecin(SN_(3)8)

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Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

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Acta Pharmaceutica Sinica B 2024年第1期14卷 1-19页

作者： Weile Ye Jiaojiao Wang Peter JLittle Jiami Zou Zhihua Zheng Jing Lu Yanjun Yin Hao Liu Dongmei Zhang Peiqing Liu Suowen Xu Wencai Ye Zhiping Liu International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of China Jinan UniversityGuangzhou 510632China Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research College of PharmacyJinan UniversityGuangzhou 510632China State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan UniversityGuangzhou 510632China pharmacy Australia Centre of Excellence School of PharmacyUniversity of QueenslandWoolloongabba QLD 4102Australia Sunshine Coast Health Institute and School of Health and Behavioural Sciences University of the Sunshine CoastBirtinya QLD 4575Australia National-Local Joint Engineering Lab of Druggability and New Drugs Evaluation Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat-sen UniversityGuangzhou 510006China School of pharmacy Bengbu Medical CollegeBengbu 233030China Institute of Endocrine and Metabolic Diseases the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230026China

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of *** biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for *** studies have shown that ginkgolide B,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease *** clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia ***,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide B in atherosclerosis prevention and *** highlight new molecular targets of ginkgolide B,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and ***,we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

关键词： Cardiovascular disease Atherosclerosis Ginkgo biloba Ginkgolide B Endothelial dysfunction LOX-1 PCSK9 PAF-R antagonist

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Investigating the Mechanism of Qu Du Qiang Fei 1 Hao Fang Formula against Coronavirus Disease 2019 Based on Network Pharmacology Method

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World Journal of Traditional Chinese Medicine 2024年第1期10卷 93-103页

作者： Yuan-Hua Wang He-Yang Zhou Jin-Yun Ma Gui-Qing Ding Hua Yu Yong-Sheng Jin Xiao-Dong Cheng Institute of Clinical Immunology Yue-Yang Hospital of Integrative MedicineShanghai University of Traditional Chinese MedicineShanghaiChina School of pharmacy Naval Medical UniversityShanghaiChina

Objective:Qu Du Qiang Fei 1 Hao Fang(QDQF1)is a novel Chinese herbal medicine formula used to treat coronavirus disease 2019(COVID-19).However,the pharmacological mechanisms of action of QDQF1 remain *** objective of this study was to identify the effective ingredients and biological targets of QDQF1 for COVID-19 *** and Methods:The effective ingredients and mechanisms of action of QDQF1 were analyzed by using network pharmacology methods,which included an analysis of the effective ingredients and corresponding targets,COVID-19-related target acquisition,compound-target network analyses,protein-protein interaction network analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)enrichment analyses,and molecular docking ***:In total,288 effective QDQF1 ingredients were *** identified 51 core targets from the 148 targets through an overlap between putative QDQF1 targets and COVID-19-related *** key components,including formononetin,kaempferol,luteolin,naringenin,quercetin,and wogonin were identified through component-target network *** functional enrichment analysis of the core targets revealed 1296 items,while KEGG pathway enrichment analysis identified 148 signaling *** central targets(CCL2,CXCL8,IL1B,IL6,MAPK1,MAPK3,MAPK8,STAT3,and TNF)related to the COVID-19 pathway were identified in the KEGG pathway enrichment ***,molecular docking analysis suggested that the docking scores of the six key components to the nine central targets were better than those to ***:QDQF1 may regulate multiple immune-and inflammation-related targets to inhibit the progression of severe acute respiratory syndrome coronavirus 2,and thus,may be suitable for the treatment of COVID-19.

关键词： Coronavirus disease 2019 molecular docking molecular mechanism network pharmacology Qu Du Qiang Fei 1 Hao Fang formula

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Atroposelective Synthesis of 2-Arylindoles via Chiral Phosphoric Acid-Catalyzed Direct Amination of Indoles

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Chinese Journal of Chemistry 2024年第7期42卷 731-735页

作者： Wen Bao Ye-Hui Chen Yu-Wei Liu Shao-Hua Xiang Bin Tan School of pharmacy&StateKey Laboratory of Applied Organic Chemistry Lanzhou UniversityLanzhouGansu 730000China Shenzhen Grubbs Institute Department of ChemistrySouthern University of Science and TechnologyShenzhenGuangdong 518055China

Indole-based atropisomers are a very important class of axially chiral ***,the atroposelective synthesis of axially chiral 2-arylindole remains largely *** this study,we report the successful synthesis of atropisomeric 2-arylindoles using direct amination of indoles with p-quinonediimines in the presence of chiral phosphoric acid as a *** acts as an aminating reagent through formal polarity inversion of *** malonate group on the 2-aryl of 2-indoles was found to be essen-tial for high enantioselectivity of the *** could be due to the additional interaction between the ester group and the cata-lyst,as well as the intramolecular hydrogen *** findings provide a new strategy for the asymmetric construction of 2-arylindole atropisomers.

关键词： Chiral phosphoric acid Quinonediimines Direct amination Nucleophilic addition Asymmetric catalysis Enantioselectivity Axially chiral 2-arylindole Atroposelective synthesis

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A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1457-1466页

作者： Yaqin Wei Xiangqing Xu Qiang Guo Song Zhao Yinli Qiu Dongli Wang Wenwen Yu Yani Liu KeWei Wang School of pharmacy Xuzhou Medical UniversityXuzhou 221004China Institute of Pharmaceutical Research Jiangsu Nhwa Pharmaceutical Co.Ltd.&Jiangsu Key Laboratory of Central Nervous System Drug Research and DevelopmentXuzhou 221116China Department of Pharmacology School of PharmacyQingdao University Medical CollegeQingdao 266073China Institute of Innovative Drug Qingdao UniversityQingdao 266021China Center for Brain Science and Brain-Inspired Intelligence Guangdong-Hong Kong-Macao Greater Bay AreaGuangzhou 510515China

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving *** this study,we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01(a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative)that exhibits both anti-depression effects and improvements in cognition.D01 inhibits serotonin transporters(K_(i)=30.1±6.9 nmol/L)and M channels(IC_(50)=10.1±2.4μmol/L).D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on *** administrations of D01(20 and 40 mg/kg)can significantly shorten the immobility time in a mouse model of chronic restraint stress(CRS)-induced depression-like ***,D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice,but not ***,D01 reverses the long-term potentiation(LTP)inhibition induced by *** together,our findings demonstrate that D01,a dual-target serotonin reuptake and M channel inhibitor,is highly effective in the treatment-resistant depression and cognitive deficits,thus holding potential for development as therapy of depression with cognitive deficits.

关键词： SERT 5-HT Kv7/KCNQ/M current D01 Depression Cognition

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Advanced oxidation via the synergy of C-defective/C-O band modified ultrathin porous g-C3N4 and PMS for efficient photothermal degradation of bisphenol pollutants and lignin derivatives

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Green Energy & Environment 2024年第7期9卷 1159-1170页

作者： Liquan Jing Meng Xie Yuanguo Xu Chun Tong Xia Du Heng Zhao Na Zhong Huaming Li Jinguang Hu School of Chemistry and Chemical Engineering Jiangsu University Department of Chemical and Petroleum Engineering University of Calgary School of pharmacy Jiangsu University School of Material Science & Chemical Engineering Harbin University of Science and Technology Institute for Energy Research Jiangsu University

This work uses thermal polymerization of urea nitrate, oxyacetic acid and urea as the raw material to prepare ultra-thin porous carbon nitride with carbon defects and C-O band（OA-UN-CN）. Density functional theory（DFT） calculations showed OA-UN-CN had narrower band gap,faster electron transport and a new internal construction electric field. Additionally, the prepared OA-UN-CN significantly enhanced photocatalytic activation of peroxymonosulfate（PMS） due to enhanced light absorption performance and faster electron overflow. As the result, the OA-UN-CN/PMS could entirely degrade bisphenol A（BPA） within 30 min, where the photodegradation rate was 81.8 and 7.9 times higher than that of g-C3N4and OA-UN-CN, respectively. Beyond, the OA-UN-CN/PMS could likewise degrade other bisphenol pollutants and sodium lignosulfonate efficiently. We suggested possible photocatalytic degradation pathways accordingly and explored the toxicity of its degradation products. This work provides a new idea on the development of advanced photocatalytic oxidation processes for the treatment of bisphenol pollutants and lignin derivatives, via a metal-free photothermal-catalyst.

关键词： Photothermal-catalytic G-C 3 N 4 Peroxymonosulfate Bisphenol Sodium lignosulfonate

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Rh(Ⅱ)catalyzed efficient sigmatropic rearrangement reaction of pyridotriazoles and sulfides

Green Synthesis and Catalysis

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Green Synthesis and Catalysis 2024年第2期5卷 77-79页

作者： Yuting Chen Guanghui Lv Zhiyang Li Meiling Ye Tianle Huang Li Hai Yong Wu Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu610041China Department of pharmacy Taihe HospitalHubei University of MedicineShiyan442000China

The[2,3]-and[1,2]-sigmatropic rearrangement reactions between pyridotriazoles and sulfides catalyzed by rhodium(II)were *** utilization of pyridotriazoles as the carbene precursors in this kind of reaction efficiently... 详细信息

关键词： Pyridotriazole Sulfide -Sigmatropic rearrangement -Sigmatropic rearrangement Rhodium catalysis

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Bi_(2)WO_(6)/AgInS_(2)S-scheme heterojunction:Efficient photodegradation of organic pollutant and toxicity evaluation

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Journal of Materials Science & Technology 2024年第3期170卷 200-211页

作者： Yanyan Zhao Xu Fan Hongxing Zheng Enzhou Liu Jun Fan Xuejun Wang College of Biology pharmacy and Food Engineering Shangluo UniversityShangluo 726000China QinLing-Bashan Mountains Bioresources Comprehensive Development C.I.C. Shaanxi University of TechnologyHanzhong 723001China School of Chemical Engineering Northwest UniversityXi’an 710069China

Constructing of heterojunction was identified as a feasible way to improve photocatalytic activity of *** this work,a n-p type Bi_(2)WO_(6)/AgInS_(2)S-scheme heterojunction was successfully prepared for organic pollutants *** Bi_(2)WO_(6)/AgInS_(2)S-scheme heterojunction exhibited much higher pho-tocatalytic activity towards Rhodamine B(92.24%,expose to visible light for 60 min),norfloxacin(81.73%,expose to visible light for 90 min)and levofloxacin(87.46%,expose to visible light for 90 min)than pure Bi_(2)WO_(6)and pure AgInS_(2).Toxicity analysis indicated the low environmental toxicity of Rhodamine B degradation intermediates for Rye seeds and Sudangrass seeds germination and *** study displayed that AgInS_(2)and Bi_(2)WO_(6)work as the primary photocatalyst to form·O_(2)−and ·OH,*** improved photocatalytic activity of the Bi_(2)WO_(6)/AgInS_(2)S-scheme heterojunction was due to the im-proved light response range and intensified carrier separation ***,a S-scheme charge transfer mechanism including multiple charge transfer channels was *** work could provide an effective strategy for organic pollutants degradation in wastewater.

关键词： Photocatalysis S-scheme heterojunction AgInS_(2) Bi_(2)WO_(6) Toxicity experiments

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Anti-osteosarcoma trimodal synergistic therapy using NiFe-LDH and MXene nanocomposite for enhanced biocompatibility and efficacy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1329-1344页

作者： Yani Xu Lan Yang Min Li Haozhou Shu Na Jia Yunzhen Gao Rongying Shi Xiaojia Yang Zhirong Zhang Ling Zhang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry West China School of PharmacySichuan UniversityChengdu 610041China Med-X Center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Osteosarcoma is usually resistant to immunotherapy and,thus primarily relies on surgical resection and high-dosage ***,less invasive or toxic therapies such as photothermal therapy(PTT)and chemodynamic therapy(CDT)generally failed to show satisfactory *** multimodal therapies with proper safety profiles may provide better solutions for ***,a simple nanocomposite that synergistically combines CDT,PTT,and chemotherapy for osteosarcoma treatment was *** this composite,small 2D Ni Fe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil(5-FU)with high loading *** nanospheres were then adsorbed onto larger 2D Ti3C2MXene monolayers and finally shielded by bovine serum albumin(BSA)to form 5-FU@Ni Fe-LDH/Ti3C2/BSA nanoplatforms(5NiTiB).Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy,Ni Fe-LDH driven chemodynamic effects,and MXene-based photothermal killing collectively exhibited a synergistic“all-in-one”anti-tumor effect.5NiTiB improved tumor suppression rate from<5%by 5-FU alone to~80.1%.This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose,thereby minimizing side ***,the composite is simple to produce,enabling the fine-tuning of dosages to suit different ***,the platform is versatile and efficient,with potential for further development.

关键词： Osteosarcoma NiFe-LDH MXene Chemodynamic therapy Photothermal therapy Chemotherapy 5-Fluorouracil Nanocomposite

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Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 854-868页

作者： Yunzhu Lin Xiang Wang Shi He Zhongxin Duan Yunchu Zhang Xiaodong Sun Yuzhu Hu Yuanyuan Zhang Zhiyong Qian Xiang Gao Zhirong Zhang Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of EducationWest China School of PharmacySichuan UniversityChengdu 610041China Department of pharmacy Evidence-based Pharmacy CenterWest China Second University HospitalKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenSichuan UniversityChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Radiation Oncology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(i PDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of p IL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation,macrophage polarization and DC maturation. The F-DPC/p IL-12/i PDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/p IL-12/i PDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

关键词： IL-12encodinggene Checkpointblocker Nanoparticles Targeted delivery Tumormicroenvironment Immune escape Ovarian cancer Immunotherapy

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