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Development of a method to quantify total and free irinotecan and 7-ethyl-10-hydroxycamptothecin(SN-38) for pharmacokinetic and bio-distribution studies after administration of irinotecan liposomal formulation

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Asian Journal of Pharmaceutical Sciences 2019年第6期14卷 687-697页

作者： Wenqian yang Zimeng Yang Jieru Liu Dan Liu Yongjun Wang Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Structure-Based Drugs Design&Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China

In 2015,liposomal formulation of irinotecan(ONIVYDE)has been approved by FDA and widely applied in the treatment of pancreatic cancer.ONIVYDE is a novel liposome formulation,entrapping CPT-11 in the aqueous core of vesicles using a modified gradient loading method.Due to toxicity concerns,it is essential to explore a rapid and reliable method to effectively isolate and quantify the non-liposomal,namely,free CPT-11and total CPT-11 in plasma.This study focuses on separation of non-liposomal CPT-11,evaluation of the pharmacokinetics of free CPT-11 and total CPT-11 and bio-distribution after intravenous administration of CPT-11 liposome.Free CPT-11 in plasma was separated by solid-phase extraction(SPE).The amount of total CPT-11 and main metabolite 7-ethyl-10-hydroxycamptothecin(SN-38)in plasma was quantified by ultra-performance liquid chromatography–MS/MS.The calibration curves fitted well and lower limit of quantitation for SN-38,free CPT-11,total CPT-11 and CPT-11 in tissue and were 5 ng/ml,10 ng/ml,4.44 ng/ml and 25 ng/ml respectively.The recoveries,precision and accuracy of the method appear satisfactory.Using this method,the pharmacokinetics and bio-distribution of CPT-11 liposome formulation after an intravenous dose of 2.5 mg/kg were then investigated.

关键词： Irinotecan Liposome UPLC-MS-MS SPE Pharmacokinetics Bio-distribution

Self-adaptive non-covalent albumin-binding near-infrared probe conjugates enabling precise sentinel lymph node metastasis illumination and primary tumor imaging

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Nano Research 2023年第2期16卷 3010-3020页

作者： Qiu Wang Qikun Jiang Dan Li Chang Li Yao Feng Zimeng Yang Zhonggui He Cong Luo Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Kangya of Ningxia Pharmaceutical Co. LtdYinchuan 750000China

Tumor sentinel lymph node(SLN)metastasis plays a vital role in tumor staging and therapeutic decision-making process.However,precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imaging resolution and poor photostability of fluorescent probes.Herein,we report three novel IR820-fatty acid(FA)conjugates(IR-OA,IR-LA,and IR-PA)for precise lymphatic metastasis illumination and primary tumor diagnosis.The IR-FA conjugates are able to non-covalently bound to albumin in vivo,and the fluorescence quantum yield is significantly enhanced after incubation with bovine serum albumin(BSA)in vitro.Moreover,the BSA-IR-FA conjugates display large Stokes shift(>120 nm),dramatically improving in vivo imaging resolution.Among them,IR-PA demonstrates distinct advantage over IR-OA,IR-LA,and IR-maleimide(MAL)(fluorescent probe previously reported by our group)in terms of fluorescence quantum yield,photostability,and imaging resolution.As a result,IR-PA exhibits satisfactory imaging results with high fluorescence intensity and imaging resolution in sentinel lymph node metastasis illumination and primary tumor location.Our findings provide a self-adaptive albumin-binding near-infrared probe conjugate for accurate diagnosis of primary tumors and lymphatic metastases.

关键词： near-infrared probe conjugates non-covalent albumin-binding fluorescence imaging sentinel lymph node metastasis illumination primary tumor diagnosis

Emerging MoS_(2)Wafer-Scale Technique for Integrated Circuits

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Nano-Micro Letters 2023年第3期15卷 129-170页

作者： zimeng Ye Chao Tan Xiaolei Huang Yi Ouyang Lei yang Zegao Wang Mingdong Dong College of Materials Science and Engineering Sichuan UniversityChengdu 610065People’s Republic of China State Key Laboratory of Solidification Processing Center of Advanced Lubrication and Seal MaterialsNorthwestern Polytechnical UniversityXi’an 710072People’s Republic of China Interdisciplinary Nanoscience Center Aarhus University8000 Aarhus CDenmark

As an outstanding representative of layered materials,molybdenum disulfide(MoS_(2))has excellent physical properties,such as high carrier mobility,stability,and abundance on earth.Moreover,its reasonable band gap and microelectronic compatible fabrication characteristics makes it the most promising candidate in future advanced integrated circuits such as logical electronics,flexible electronics,and focal-plane photodetector.However,to realize the all-aspects application of MoS_(2),the research on obtaining high-quality and large-area films need to be continuously explored to promote its industrialization.Although the MoS_(2)grain size has already improved from several micrometers to sub-millimeters,the high-quality growth of wafer-scale MoS_(2)is still of great challenge.Herein,this review mainly focuses on the evolution of MoS_(2)by including chemical vapor deposition,metal–organic chemical vapor deposition,physical vapor deposition,and thermal conversion technology methods.The state-of-the-art research on the growth and optimization mechanism,including nucleation,orientation,grain,and defect engineering,is systematically summarized.Then,this review summarizes the wafer-scale application of MoS_(2)in a transistor,inverter,electronics,and photodetectors.Finally,the current challenges and future perspectives are outlined for the wafer-scale growth and application of MoS_(2).

关键词： Wafer-scale growth Molybdenum disulfide Gas deposition Integrated circuits

Elaborately engineering of lipid nanoparticle for targeting delivery of siRNA and suppressing acute liver injury

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Chinese Chemical Letters 2024年第2期35卷 323-328页

作者： Qiu Wang Qikun Jiang Dan Li Zimeng Yang Lin Gao Fan Liu Chang Li Yao Feng Zhonggui He Cong Luo Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Kangya of Ningxia Pharmaceutical Co.Ltd. Yinchuan 750000China

Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative charge.Currently,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of siRNA.Herein,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver injury.The M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin vitro.Additionally,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of mannose.As expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury model.Such a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.

关键词： Lipid nanoparticle Targeting siRNA delivery Acute liver injury Gene silencing Tumor necrosis factorα

A computer-aided chem-photodynamic drugs self-delivery system for synergistically enhanced cancer therapy

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Asian Journal of Pharmaceutical Sciences 2021年第2期16卷 203-212页

作者： Qiu Wang Mengchi Sun Chang Li Dan Li Zimeng Yang Qikun Jiang Zhonggui He Huaiwei Ding Jin Sun Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Structure-Based Drug Design and Discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China

The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer medicine.Nevertheless,co-delivery of photosensitizers(PSs)and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility.Herein,we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a(PPa,a common PS)and podophyllotoxin(PPT,a classical chemotherapeutic drug)for synergistic cancer therapy.First,the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules.Based on the molecular docking,the intermolecular interactions were found to includeπ-πstackings,hydrophobic interactions and hydrogen bonds.Next,both drugs could co-assemble into nanoparticles(NPs)via one-step nanoprecipitation method.The various spectral experiments(UV,IR and FL)were conducted to evaluate the formation mechanism of spherical NPs.Moreover,in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency,stronger cytotoxicity and higher accumulation in tumor sites,but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice.Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.

关键词： Photodynamic therapy Chemotherapy Self-delivery Computer-aided Synergistic cancer therapy

Exploring Splicing Variants and Novel Genes in Sacred Lotus Based on RNA-seq Data

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Phyton-International Journal of Experimental Botany 2023年第6期92卷 1665-1679页

作者： Xinyi Zhang zimeng Yu Pingfang yang State Key Laboratory of Biocatalysis and Enzyme Engineering School of Life SciencesHubei UniversityWuhan430026China

Sacred lotus(Nelumbo nucifera)is a typical aquatic plant,belonging to basal eudicot plant,which is ideal for genome and genetic evolutionary study.Understanding lotus gene diversity is important for the study of molecular genetics and breeding.In this research,public RNA-seq data and the annotated reference genome were used to identify the genes in lotus.A total of 26,819 consensus and 1,081 novel genes were identified.Meanwhile,a comprehensive analysis of gene alternative splicing events was conducted,and a total of 19,983“internal”alternative splicing(AS)events and 14,070“complete”AS events were detected in 5,878 and 5,881 multi-exon expression genes,respectively.Observations made from the AS events show the predominance of intron retention(IR)subtype of AS events representing 33%.IR is followed by alternative acceptor(AltA),alternative donor(AltD)and exon skipping(ES),highlighting the universality of the intron definition model in plants.In addition,functional annotations of the gene with AS indicated its relationship to a number of biological processes such as cellular process and metabolic process,showing the key role for alternative splicing in influencing the growth and development of lotus.The results contribute to a better understanding of the current gene diversity in lotus,and provide an abundant resource for future functional genome analysis in lotus.

关键词： Novel genes alternative splicing intron retention ontology

Optimizing Spatial Relationships in GCN to Improve the Classification Accuracy of Remote Sensing Images

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Intelligent Automation & Soft Computing 2023年第7期37卷 491-506页

作者： Zimeng Yang Qiulan Wu Feng Zhang Xuefei Chen Weiqiang Wang XueShen Zhang School of Information Science&Engineering Shandong Agricultural UniversityTaian271018China

Semantic segmentation of remote sensing images is one of the core tasks of remote sensing image interpretation.With the continuous develop-ment of artificial intelligence technology,the use of deep learning methods for interpreting remote-sensing images has matured.Existing neural networks disregard the spatial relationship between two targets in remote sensing images.Semantic segmentation models that combine convolutional neural networks(CNNs)and graph convolutional neural networks(GCNs)cause a lack of feature boundaries,which leads to the unsatisfactory segmentation of various target feature boundaries.In this paper,we propose a new semantic segmentation model for remote sensing images(called DGCN hereinafter),which combines deep semantic segmentation networks(DSSN)and GCNs.In the GCN module,a loss function for boundary information is employed to optimize the learning of spatial relationship features between the target features and their relationships.A hierarchical fusion method is utilized for feature fusion and classification to optimize the spatial relationship informa-tion in the original feature information.Extensive experiments on ISPRS 2D and DeepGlobe semantic segmentation datasets show that compared with the existing semantic segmentation models of remote sensing images,the DGCN significantly optimizes the segmentation effect of feature boundaries,effectively reduces the noise in the segmentation results and improves the segmentation accuracy,which demonstrates the advancements of our model.

关键词： Remote sensing image semantic segmentation GCN spatial relationship feature fusion

Migration of ammonium nitrogen in ion-absorbed rare earth soils during and post in situ mining: a column study and numerical simulation analysis

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环境科学与工程前沿(英文) 2023年第8期17卷 137-151页

作者： Gaosheng Xi Xiaojiang Gao Ming Zhou Xiangmei Zhai Ming Chen Xingxiang Wang Xiaoying yang Zezhen Pan zimeng Wang Department of Environmental Science and Engineering Fudan UniversityShanghai 200438China School of Resource and Environmental Engineering Jiangxi University of Science and TechnologyGanzhou 341000China CAS Key Laboratory of Soil Environment and Pollution Remediation Institute of Soil ScienceChinese Academy of SciencesNanjing 210008China National Observations and Research Station for Wetland Ecosystems of the yangtze Estuary Shanghai 202151China Shanghai Institute of Pollution Control and Ecological Security Shanghai 200001China

Ion-absorbed rare earth mines,leached in situ,retain a large amount of ammonium nitrogen(NH4–N)that continuously releases into the surrounding environments.However,quantitative descriptions and predictions of the transport of NH4–N across mining area with hill slopes are not fully established.Here,laboratory column experiments were designed with an inclined slope(a sand box)to examine the spatial temporal transport of NH4–N in soils collected from the ionic rare earth elements(REE)mining area.An HYDRUS-2D model simulation of the experimental data over time showed that soils had a strong adsorption capacity toward NH4–N.Chemical non-equilibrium model(CNEM)could well simulate the transport of NH4–N through the soil-packed columns.The simulation of the transport-adsorption processes at three flow rates of leaching agents revealed that low flow rate enabled a longer residence time and an increased NH4-N adsorption,but reduced the extraction efficiency for REE.During the subsequent rainwater washing process,the presence of slope resulted in the leaching of NH4–N on the surface of the slope,while the leaching of NH4–N deep inside the column was inhibited.Furthermore,the high-intensity rainfall significantly increased the leaching,highlighting the importance of considering the impact of extreme weather conditions during the leaching process.Overall,our study advances the understanding of the transport of NH4–N in mining area with hills,the impact of flow rates of leaching agents and precipitation intensities,and presents as a feasible modeling method to evaluate the environmental risks of NH4–N pollution during and post REE in situ mining activities.

关键词： Ion-absorbed rare earth Ammonium nitrogen transport HYDRUS-2D Numerical simulation

Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients

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Virologica Sinica 2024年第2期39卷 319-330页

作者： Guixin Li Danli yang Xin Liu Ting Zhang Hui Liu Jun Zou zimeng Xu Xiangmei Chen Lizhong Dai Hongsong Chen Fengmin Lu Peking University People's Hospital Peking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijing International Cooperation Base for Science and Technology on NAFLD DiagnosisBeijing100044China Department of Microbiology and Infectious Disease Center School of Basic Medical SciencesPeking UniversityBeijing100191China Baruch S.Blumberg Institute DoylestownPA18901USA Shenzhen Sanyuansheng Biotechnology Co. LtdShenzhen518000China Precision Medicine Center of Zhengzhou University Academy of Medical SciencesZhengzhou UniversityZhengzhou450001China Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine Sansure Biotech Co.LtdChangsha410205China

Naturally occurred precore(PC,G1896A)and/or basal core promoter(BCP,A1762T/G1764A)mutations are prevalent in chronic HBV-infected patients,especially those under HBeAg-negative status.However,the replicative capacity of HBV with PC/BCP mutations remains ambiguous.Herein,meta-analysis showed that,only under HBeAg-negative status,the serum HBV DNA load in patients with PC mutation was 7.41-fold higher than those without the mutation.Both PC mutation alone and BCPþPC mutations promoted HBV replication in cell and hydrodynamic injection mouse models.In human hepatocyte chimeric mouse model,BCPþPC mutations led to elevated replicative capacity and intrahepatic core protein accumulation.Mechanistically,preC RNA harboring PC mutation could serve as mRNA to express core and P proteins,and such pgRNA-like function favored the maintenance of cccDNA pool under HBeAg-negative status.Additionally,BCPþPC mutations induced more extensive and severe human hepatocyte damage as well as activated endoplasmic reticulum stress and TNF signaling pathway in livers of chimeric mice.This study indicates that HBeAg-negative patients should be monitored on HBV mutations regularly and are expected to receive early antiviral treatment to prevent disease progression.

关键词： Hepatitis B virus Precore mutation Basal core promoter mutations Endoplasmic reticulum stress