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Intracellular and extracellular enzymatic responsive micelle for intelligent therapy of cancer

Nano Research 2023年第2期16卷 2851-2858页

作者： Dong wan Qinan Zhu Jianxin Zhang Xi Chen Fangzhou Li Yi Liu Jie Pan School of Chemical Engineering and Technology Tiangong UniversityTianjin 300387China School of Chemistry Tiangong UniversityTianjin 300387China CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety CAS Center for Excellence in NanoscienceNational Center for Nanoscience and TechnologyBeijing 100190China

Recently,the incidence of cancer keeps increasing,seriously endangers human health,and has evolved into the main culprit of human death.Conventional chemotherapeutic drugs,such as paclitaxel and doxorubicin(DOX),have some disadvantages,including low therapeutic effect,poor water solubility,high toxic side effects,short blood circulation time in the body,and so on.To improve the anti-tumor effect of the drug in vivo and reduce its side effects on the body,researchers have designed and developed a variety of responsive nanocarriers.In this work,we synthesized D-α-tocopherol polyethylene glycol 3350 succinate(TPGS3350)-Gly-Pro-Leu-Gly-Val-Arg(GPLGVR)-DOX(TPD)prodrugs in response to extracellular enzymes of matrix metalloproteinase(MMP-9)in the tumor microenvironment and FA-Asp-Glu-Val-Asp(DEVD)-DOX(FPD)prodrugs responsive to intracellular enzymes of caspase-3.Then,intracellular and extracellular enzyme-responsive TPD&FPD micelles with DOX(TPD&FPD&D)were successfully prepared through dialysis method.The outer layer of TPGS3350 can prolong the blood circulation time of micelles in vivo,followed by accumulation of micelles at tumor tissue through enhanced permeability and retention(EPR)effect.The peptide of GPLGVR can be cleaved by MMP-9 enzymes to remove the outer layer of TPGS3350,exposing the targeting molecule of folate,and then the micelles are engulfed by tumor cells through folate receptor-mediated endocytosis.After entering the tumor cells,the free DOX loaded in the micelles is released,which induces tumor cell apoptosis to activate caspase-3 in the cells,cutting the peptide DEVD to accelerate the intracellular release of the DOX,which further enhances cytotoxicity to improve antitumor effect.

关键词： cancer micelle peptide enzyme-responsive folate

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Light-activated arginine-rich peptide-modified nanoparticles for deep-penetrating chemo-photo-immunotherapy of solid tumor

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Nano Research 2023年第7期16卷 9804-9814页

作者： Yonghua Gong Jinyang Zhang Yan Lu Dong wan Jie Pan Guilei Ma Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy The Tianjin Key Laboratory of BiomaterialsInstitute of Biomedical EngineeringPeking Union Medical College&Chinese Academy of Medical SciencesTianjin 300192China School of Environmental and Chemical Engineering Tiangong UniversityTianjin 300387China

Poor permeation of drugs and“immune-cold”tumor microenvironment in solid tumors are the two major challenges which lead to the inefficient therapeutic efficacy for cancer treatment.Here,light-activated penetrable nanoparticles(PEGVAL&DOX&ICG@RNPs)for co-delivery of the chemotherapeutic drug doxorubicin(DOX),the photosensitizer agent indocyanine green(ICG),and the angiotensin II receptor blockers valsartan(VAL)were developed to achieve deep drug penetration and synergistic photo-chemo-immunotherapy of solid tumor.Studies showed that under the first-wave of laser irradiation,the polyethylene glycol(PEG)hydrophilic layer as an“inert”surface could detach from the nanoparticles,release VAL and expose the arginine-rich peptide modified-cores that can facilitate deep drug penetration via a transcytosis pathway.When exposed to the second-wave of laser irradiation,the synergistic chemo-photo-immunotherapy can be achieved.As expected,in 4T1 tumorbearing mice,PEG-VAL&DOX&ICG@RNPs treatment could effectively inhibit the growth of tumors,down-regulateα-smooth muscle actin expression level of cancer-associated fibroblasts cells in tumors,induce dendritic cells(DCs)maturation,and promote intratumoral infiltration of cytotoxic T lymphocytes.Moreover,combination therapy by PEG-VAL&DOX&ICG@RNPs and anti-PD-1 monoclonal antibody can elicit memory T cell response for preventing tumor recurrence and metastasis in vivo.This work provides a promising delivery strategy to overcome the current limitations of nanomedicine for achieving more effective therapeutic index of“immune-cold”solid tumor treatment.

关键词： light-activated nanoparticles transcytosis deep penetration chemo-photo-immunotherapy solid tumor

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A micelle-based stage-by-stage impelled system for efficient doxorubicin delivery

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Bioactive Materials 2023年第7期25卷 783-795页

作者： Sunfan Li Fangzhou Li Dong wan Zuqin Chen Jie Pan Xing-Jie Liang School of Chemical Engineering and Technology Tiangong UniversityTianjin300387PR China CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety CAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology of ChinaNo.11First North RoadZhongguancunBeijing100190PR China University of Chinese Academy of Sciences Beijing100049PR China Medical School of Chinese PLA No.28 Fuxing RoadBeijing100853PR China Department of Radiology The First Medical CentreChinese PLA General HospitalBeijingPR China Department of Radiology Chinese PAP Guangxi Corps HospitalNanningGuangxiPR China

Chemotherapy remains the mainstay of cancer treatment,benefiting millions of patients each year,but the side effects of chemotherapy drugs severely limit their clinical use.Doxorubicin(DOX)can cause various side effects such as heart damage and treatment-related tumors.The effective use of active and passive targeting will improve the clinical application of DOX.Here,TPGS3350 and bioactive peptides were utilized to construct a micelle-based stage-by-stage impelled efficient system(missiles)for DOX delivery(DOX missiles).By taking advantage of the EPR effect,DOX missiles are efficiently enriched at the tumor site.After being cleaved by matrix metalloproteinase2(MMP2),the peptide(VRGD)targets tumor cells to facilitate uptake of the missiles by the tumor cells via receptor-mediated endocytosis.The intracellular activated caspase-3-catalyzed explosion of DOX missiles further enables efficient tumor killing.This study provides an efficient approach for DOX delivery and toxicity reduction.

关键词： Doxorubicin Delivery Peptide Missiles Chemotherapy

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Strengthened Initialization of Adaptive Cross-Generation Differential Evolution

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Computer Modeling in Engineering & Sciences 2022年第3期129卷 1495-1516页

作者： Wei wan Gaige wang Junyu dong Department of Computer Science of Technology Ocean University of ChinaQingdao266100China Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education Jilin UniversityChangchun130012China Guangxi Key Laboratory of Hybrid Computation and IC Design Analysis Guangxi University for NationalitiesNanning530006China

Adaptive Cross-Generation Differential Evolution(ACGDE)is a recently-introduced algorithm for solving multiobjective problems with remarkable performance compared to other evolutionary algorithms(EAs).However,its convergence and diversity are not satisfactory compared with the latest algorithms.In order to adapt to the current environment,ACGDE requires improvements in many aspects,such as its initialization and mutant operator.In this paper,an enhanced version is proposed,namely SIACGDE.It incorporates a strengthened initialization strategy and optimized parameters in contrast to its predecessor.These improvements make the direction of crossgeneration mutation more clearly and the ability of searching more efficiently.The experiments show that the new algorithm has better diversity and improves convergence to a certain extent.At the same time,SIACGDE outperforms other state-of-the-art algorithms on four metrics of 24 test problems.

关键词： Differential Evolution(DE) multi-objective optimization(MO) opposition-based learning parameter adaptation

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Intelligent self-assembly prodrug micelles loading doxorubicin in response to tumor microenvironment for targeted tumors therapy

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Chinese Journal of Chemical Engineering 2021年第11期34卷 219-227页

作者： Dong wan Sunfan Li Jianxin Zhang Guilei Ma Jie Pan School of Chemistry and Chemical Engineering Tiangong UniversityTianjin 300387China The Tianjin Key Laboratory of Biomaterials Institute of Biomedical EngineeringPeking Union Medical College&Chinese Academy of Medical SciencesTianjin 300192China

Compared with physical drug-loaded nanocarriers,polymeric prodrug micelles have many advantages such as high drug loading and enhanced stability in blood,so they have great potential in cancer therapy.However,these micelles have a big disadvantage,which cannot achieve long-term circulation in vivo and high absorption of tumor cells simultaneously,resulting in low administration efficiency and poor therapeutic effect on cancer.To solve problems of traditional polymeric prodrug micelles,novel polymeric micelles with tumor microenvironment response were designed in this work.The prodrug formed by covalently linking D-α-tocopherol polyethylene glycol succinate(TPGS_(3350)),peptide(Pep),and doxorubicin(DOX)(TPGS_(3350)-Pep-DOX)was self-assembled into micelles by encapsulating DOX physically.When the micelles entered the tumor tissue,the long-chain polyethylene glycol(PEG)was sensitively cut by the matrix metalloproteinase 2/9(MMP2/9)enzyme,exposing the targeting molecule folate,then it entered the cell through the endocytic pathway mediated by the folate receptor.The drug loading content,encapsulation efficiency,critical micelle concentration,and invitro release of the micelles invented in this study were measured to characterize their properties.The particle size and zeta potential of micelles were characterized by dynamic light scattering.Images were scanned by transmission electron microscopes.In vitro cytotoxicity,cellular uptake,and in vivo antitumor effect evaluation experiments were measured to show that smart micelles have made much progress in material chemistry and drug delivery,making it possible to apply a stimulus-response carrier drug delivery system in clinical application.

关键词： Micelles Drug delivery Tumor Enzyme Polymers Peptide

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New mechanism of FA in composted sludge inducing Cu fixation on Albite in open-pit mine soil

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Journal of Environmental Sciences 2022年第6期34卷 142-150页

作者： Jiapeng wan Yifan Zeng Mei wang Bin dong Zuxin Xu State Key Laboratory of Pollution Control and Resource Reuse College of Environmental Science and EngineeringTongji UniversityShanghai 200092China YANGTZE Eco-Environment Engineering Research Center China Three Gorges CorporationBeijing 100038China Shanghai Investigation Design&Research Institute Co.Ltd Shanghai 200335China

Fulvic acid(FA),typical organic matter derived from humification process in composted sludge,possesses the potential to remediate mine soils contaminated by heavy metals.To understand the cooper(Cu)immobilizing process in open-pit mine soil induced by FA,changes of Cu speciation in mixture of open-pit mine soil and composted sludge was tracked over 180 days.It was observed that the organic-bound and residual fraction of Cu increased dramatically with the corresponding decrease of Fe/Mn oxide-bound Cu in the first 60 days,then the organic-bound fraction decreased to about its initial proportion during 60-120 days,while residual fraction still increased,and the proportion of residual Cu accounted for over85%and became stable after 120 days.To reveal the mechanism of FA inducing Cu fixation on Albite which is the main phase of soil primary ore,two groups of Cu adsorption experiments with and without FA were designed.With the addition of FA,the adsorption capacity of Cu by Albite increased by 1.55 times and the content of residual Cu in Albite increased by7.7 times.It was found that the Cu absorbed in smaller Albite particle induced by FA formed a secondary mineral——Chrysocolla,causing increase of residual fraction of Cu.These results revealed the mechanism:FA was absorbed on the surface of Albite after complexing with Cu ions in the solution,and then it induced Cu into the interlayer and pore channels of Albite.The Cu in the Albite was immobilized by forming Chrysocolla finally.

关键词： Fulvic acid Composted sludge Heavy metal Open-pit mine Mineralization

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Thickness-Dependent Microstructure and its Effect on Anisotropic Mechanical Properties of Duplex Stainless Steel 2205 Multi-pass Welded Joints

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Acta Metallurgica Sinica(English Letters) 2023年第11期36卷 1883-1892页

作者： Zhilong dong Xue-Fang Xie Jingwen Li Yu wan State Key Laboratory of Heavy Oil Processing College of New EnergyChina University of Petroleum(East China)Qingdao266580China China National Offshore Oil Corporation Petrochemical Engineering Company Limited Jinan250000China

In this study,the thickness-dependent microstructural characteristics of duplex stainless steel 2205 multi-pass welded joints were first investigated by the combination of optical microscope and electron back-scattered diffraction observation.Subsequently,a series of tensile tests of miniature samples cut from different passes and directions were performed to analyze the thickness-dependent and anisotropic mechanical properties.The results demonstrate that the microstructure changed with the welded passes,i.e.,a large number of grain boundary austenite,Widmanstätten austenite and a small number of tiny intragranular austenite existed at the surface passes,while a mass of intragranular austenite were found at the middle passes.Meanwhile,the Kurdjumov–Sachs orientation relationship was widespread at the welded zone.In addition,the yield and tensile strengths of the middle passes were greater than that of the surface passes due to the grain-boundary strengthening by tiny intragranular austenite.Furthermore,due to the existence of Kurdjumov–Sachs orientation relationship,the longitudinal yield and tensile strength were greater than transverse values,particularly for the middle passes.

关键词： Duplex stainless steel Multi-pass welded joints Thickness-dependent microstructure Anisotropic mechanical properties

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Synthesis and Rheological Investigation of Model Symmetric 3-Arm Star Polyethylene

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Chinese Journal of Polymer Science 2014年第1期32卷 51-63页

作者： Feng Liu Dong wan 唐涛 State Key Laboratory of Polymer Physics and Chemistry Changchun Institute of Applied ChemistryChinese Academy of Sciences Graduate School of the Chinese Academy of Sciences

A variety of linear and 3-arm star polyethylene （PE） model polymers covering a wide range of molecular weight are synthesized by the living polymerization of butadiene and the subsequent hydrogenation. Several rheological parameters of these model linear and 3-arm star PE samples are analyzed for detecting the long chain branching （LCB） structure. It is found that the analyses based on zero shear viscosity, vGP plot and flow activation energy are very sensitive to the 3-arm star PEs. The information on the presence of LCB can be obtained with these methods even for low molecular weight samples, which can not be determined by GPC-MALLS. However the information about the LCB structure can not be obtained by the rheological methods alone.

关键词： Long chain branching Rheology Star polymers Polyethylene Thermorheology.

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Paternal Zn-deficiency abolishes metabolic effects in offspring induced by diet type

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Animal Nutrition 2022年第1期8卷 310-320页

作者： Guanya Li Zhenglin dong Shusheng Yue Dan wan Yulong Yin Key Laboratory of Agro-Ecological Processess in Subtropical Region Hunan Research Center of Livestock&Poultry SciencesSouth-Central Experimental Station of Animal Nutrition and Feed Science in Ministry of AgricultureInstitute of Subtropical AgricultureThe Chinese Academy of SciencesChangshaHunan 410125China Hunan International Joint Laboratory of Animal Intestinal Ecology and Health Laboratory of Animal Nutrition and Human HealthCollege of Life SciencesHunan Normal UniversityChangshaHunan410081China

Accumulating evidence implicates that offspring are susceptible to paternal alterations in numerous fetal disorders,such as growth and metabolic defects.However,less study has been conducted to define the relationship between paternal zinc deficiency(ZnD)and energy metabolism of offspring.In the present study,we used a paternal ZnD exposure(Zn at 0.3 mg/g)model to test energy metabolism of male and female offspring with the intervention of diet type(high-fat diet and low-fat diet).Our results demonstrated that paternal ZnD decreased body weight(BW)gain per week(P<0.01)and ME intake per week(P<0.05)at 11 weeks in male offspring with high-fat diet intervention but not in female offspring.Further,anabolism and catabolism of hepatic energy products also exhibited alterations.ZnD attenuated liver glucose but increased lipids content accompanied with elevated adiponectin and reduction in leptin level in serum,which exhibited lipid metabolic disturbance and smaller ratio of liver weight to BW in male but not female offspring.The qRT-PCR and liver energy metabolites analysis revealed that paternal ZnD mainly induced reduction in glucose tolerance and lowered glucose uptaking ability in male offspring and thereby alleviated glycolysis and the tricarboxylic acid cycle(TCA)cycle,which displayed a male gender-dependency.Therefore,we propose that paternal ZnD abolishes metabolic effects in male offspring induced by diet type intervention.Our findings reveal a novel link between paternal Zn-D and offspring energy metabolism.

关键词： Zinc-deficiency Paternal Energy metabolism Offspring

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Reveal Hydrogen Behavior at Grain Boundaries in Fe-22Mn-0.6C TWIP Steel via In Situ Micropillar Compression Test

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Acta Metallurgica Sinica(English Letters) 2023年第7期36卷 1095-1104页

作者： Xu Lu Dong wang Di wan Xiaofei Guo Roy Johnsen Department of Mechanical and Industrial Engineering Norwegian University of Science and Technology7491 TrondheimNorway School of Materials Science and Engineering Shanghai UniversityShanghai 200444China Steel Institute(IEHK) RWTH Aachen University52072 AachenGermany

In this study,the effect of hydrogen on dislocation and twinning behavior along various grain boundaries in a high-manganese twinning-induced plasticity steel was investigated using an in situ micropillar compression test.The compressive stress in both elastic and plastic regimes was increased with the presence of hydrogen.Further investigation by transmission electron backscatter diffraction and scanning transmission electron microscope demonstrated that hydrogen promoted both dislocation multiplication and twin formation,which resulted in higher stress concentration at twin-twin and twin-grain boundary intersections.

关键词： Hydrogen TWIP steel Micropillar compression Grain boundary t-EBSD

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