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Hypoxia response element-directed expression of bFGF in dental pulp stem cells improve the hypoxic environment by targeting pericytes in SCI rats

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Bioactive Materials 2021年第8期6卷 2452-2466页

作者： Sipin Zhu Yibo Ying Yan He Xingxing Zhong Jiahui Ye Zhiyang Huang Min Chen Qiuji Wu Yifan Zhang Ziyue Xiang Yurong Tu Weiyang Ying Jian Xiao Xiaokun Li Qingsong Ye Zhouguang Wang Department of Orthopaedics The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China Molecular Pharmacology research center School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiangChina Department of Pain Medicine The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhou325000ZhejiangChina School and Hospital of Stomatology Wenzhou Medical UniversityWenzhou325035China Laboratory of Regenerative Medicine Tianyou HospitalWuhan University of Science and TechnologyWuhan430064China The Department of Cardiology The First Affiliated HospitalSchool of MedicineZhejiang UniversityChina Massachusetts General Hospital Harvard UniversityBoston02114USA research Units of Clinical Translation of Cell Growth Factors and Diseases research Chinese Academy of Medical ScienceChina center of Regenerative Medicine Renmin Hospital of Wuhan UniversityWuhan630060China

Cell-based transplantation strategies possess great potential for spinal cord injury(SCI)*** fibroblast growth factor(bFGF)has been reported to have multiple neuro-promoting effects on developing and adult nervous system of mammals and considered a promising therapy for nerve injury following *** dental pulp stem cells(DPSCs)are abundant stem cells with low immune rejection,which can be considered for cell replacement *** purpose of this study was to investigate the roles of DPSCs which express bFGF under the regulation of five hypoxia-responsive elements(5HRE)using an adeno-associated virus(AAV-5HRE-bFGF-DPSCs)in SCI repairing *** this study,DPSCs were revealed to differentiate into CD13^(+)pericytes and up-regulate N-cadherin expression to promote the re-attachment of CD13^(+)pericytes to vascular endothelial *** re-attachment of CD13^(+)pericytes to vascular endothelial cells subsequently increased the flow rate of blood in microvessels via the contraction of *** a result,increased numbers of red blood cells carried more oxygen to the damaged area and the local hypoxia microenvironment in SCI was ***,this study represents a step forward towards the potential use of AAV-5HRE-bFGF-DPSCs in SCI treatment in clinic.

关键词： Spinal cord injury Adeno-associated virus Basic fibroblast growth factor Dental pulp stem cell vascular regulation Hypoxic microenvironment

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Biomarkers of aging

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Science China(Life Sciences) 2023年第5期66卷 893-1066页

作者： Aging Biomarker Consortium Hainan Bao Jiani Cao Mengting Chen Min Chen Wei Chen Xiao Chen Yanhao Chen Yu Chen Yutian Chen Zhiyang Chen Jagadish K Chhetri Yingjie Ding Junlin Feng Jun Guo Mengmeng Guo Chuting He Yujuan Jia Haiping Jiang Ying Jing Dingfeng Li Jiaming Li Jingyi Li Qinhao Liang Rui Liang Feng Liu Xiaoqian Liu Zuojun Liu Oscar Junhong Luo Jianwei Lv Jingyi Ma Kehang Mao Jiawei Nie Xinhua Qiao Xinpei Sun Xiaoqiang Tang Jianfang Wang Qiaoran Wang Siyuan Wang Xuan Wang Yaning Wang Yuhan Wang Rimo Wu Kai Xia Fu-Hui Xiao Lingyan Xu Yingying Xu Haoteng Yan Liang Yang Ruici Yang Yuanxin Yang Yilin Ying Le Zhang Weiwei Zhang Wenwan Zhang Xing Zhang Zhuo Zhang Min Zhou Rui Zhou Qingchen Zhu Zhengmao Zhu Feng Cao Zhongwei Cao Piu Chan Chang Chen Guobing Chen Hou-Zao Chen Jun Chen Weimin Ci Bi-Sen Ding Qiurong Ding Feng Gao Jing-Dong JHan Kai Huang Zhenyu Ju Qing-Peng Kong Ji Li Jian Li Xin Li Baohua Liu Feng Liu Lin Liu Qiang Liu Qiang Liu Xingguo Liu Yong Liu Xianghang Luo Shuai Ma Xinran Ma Zhiyong Mao Jing Nie Yaojin Peng Jing Qu Jie Ren Ruibao Ren Moshi Song Zhou Songyang Yi Eve Sun Yu Sun Mei Tian Shusen Wang Si Wang Xia Wang Xiaoning Wang Yan-Jiang Wang Yunfang Wang Catherine CL Wong Andy Peng Xiang Yichuan Xiao Zhengwei Xie Daichao Xu Jing Ye Rui Yue Cuntai Zhang Hongbo Zhang Liang Zhang Weiqi Zhang Yong Zhang Yun-Wu Zhang Zhuohua Zhang Tongbiao Zhao Yuzheng Zhao Dahai Zhu Weiguo Zou Gang Pei Guang-Hui Liu Aging Biomarker Consortium(ABC) Beijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Department of Dermatology Xiangya HospitalCentral South UniversityChangsha 410008China Hunan Key Laboratory of Aging Biology Xiangya HospitalCentral South UniversityChangsha 410008China National Clinical research center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410008China Clinic center of Human Gene research Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Hubei Clinical research center of Metabolic and Cardiovascular Disease Huazhong University of Science and TechnologyWuhan 430022China Hubei Key Laboratory of Metabolic Abnormalities and vascular Aging Huazhong University of Science and TechnologyWuhan 430022China Stem Cell Translational research center Tongji HospitalTongji University School of MedicineShanghai 200065China Department of Nuclear Medicine Daping HospitalThird Military Medical UniversityChongqing 400042China CAS Key Laboratory of Nutrition Metabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China Shanghai Key Laboratory of Maternal Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China The Department of Endovascular Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Ageing and Regenerative MedicineJ

Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological *** a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly *** immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this ***,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory *** fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.

关键词： aging senescence biomarker clock

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Activation of SUR2B/Kir6.1-type K ATP channels protects glomerular endothelial,mesangial and tubular epithelial cells against oleic acid renal damage

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中国应用生理学杂志 2012年第6期28卷 572-576页

作者： Ying ZHAO Hai WANG Cardiovascular Drug research center Institute of Health and Environmental Medicine Academy of Military Medical Sciences Beijing 100850 Thadweik Academy of Medicine Beijing 100039 China

Cumulative evidence suggests that renal vascular endothelial injury play an important role in initiating and extending tubular epithelial injury and contribute to the development of ischemic acute renal *** previous studies have demonstrated that iptakalim's endothelium protection is related to activation of SUR2B/Kir6.1 subtype of ATP sensitive potassium channel(K ATP) in the *** has been reported that SUR2B/Kir6.1 channels are widely distributed in the tubular epithelium,glomerular mesangium,and the endothelium and the smooth muscle of blood ***,we hypothesized that activating renal K ATP channels with iptakalim might have directly neroprotective *** this study,glomerular endothelial,mesangial and tubular epithelial cells which are the main cell types to form nephron were exposed to oleic acid(OA) at various concentrations for 24 h.0.25 μl/ml OA could cause cellular damage of glomerular endothelium and mesangium,while 1.25μl/ml OA could lead to the injury of three types of renal *** was observed that pretreatment with iptakalim at concentrations of 0.1,1,10 or 100 μmol/L prevented cellular damage of glomerular endothelium and tubular epithelium,whereas iptakalim from 1 to 100 μmol/L prevented the injury of mesangial *** data showed iptakalim significantly increased survived cell rates in a concentration-dependent manner,significantly antagonized by glibenclamide,a K ATP *** played a protective role in the main cell types of kidney,which was consistent with natakalim,a highly selective SUR2B/Kir6.1 channel *** exerted protective effects through activating SUR2B/Kir6.1 channels,suggesting a new strategy for renal injury by its endothelial and renal cell protection.

关键词： ATP敏感性钾通道肾小球系膜细胞肾小管上皮细胞血管内皮细胞保护作用肾功能损害激活油酸

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Corrigendum:Edible seaweed-derived constituents:an undisclosed source of neuroprotective compounds

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Neural Regeneration research 2021年第12期16卷 2564-2568页

作者： Melissa Schepers Nikita Martens Assia Tiane Kenneth Vanbrabant Hong-Bing Liu Dieter Lütjohann Monique Mulder Tim Vanmierlo Department of neuroimmunology Biomedical Research InstituteHasselt UniversityEuropean Graduate School of Neuroscience(EURON)HasseltBelgium Department of Psychiatry&neuropsychology Division of Translational NeuroscienceSchool for Mental Health and NeuroscienceMaastricht UniversityEuropean Graduate School of Neuroscience(EURON)MaastrichtThe Netherlands Department of Internal Medicine Laboratory of Vascular MedicineErasmus MC University Medical CenterRotterdamthe Netherlands Institue for Clinical Chemistry and Clinical Pharmacology BonnGermany Key Laboratory of Marine Drugs Ministry of EducationSchool of Medicine and PharmacyOcean University of ChinaQingdaoShandong ProvinceChina

Edible marine algae,or seaweeds,are a rich source of several bioactive compounds including phytosterols,carotenoids,and *** the last decades,seaweedderived constituents turned out to not only reside in the systemic circulation,but are able to cross the blood-brain barrier to exert neuro-active functions both in homeostatic and pathological ***,seaweed-derived constituents have gained increasing interest for their neuro-immunomodulatory and neuroprotective properties,rendering them interesting candidates for the management of several neurodegenerative *** particular seaweed-derived phytosterols gained interest for the treatment of neurodegenerative disorders as they potentiate neuroplasticity,enhance phagocytic clearance of neurotoxic peptides and have anti-inflammatory ***,the antiinflammatory and anti-oxidative properties of other constituents including carotenoids,phenols and polysaccharides have recently gained more *** this review,we provide an overview of a selection of the described neuro-active properties of seaweed-derived constituents with a focus on phytosterols.

关键词： algae carotenoids neuro-active phenols phytosterols polysaccharides seaweed

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Application of multimodal image fusion technology in brain tumor surgical procedure

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Translational neuroscience and Clinics 2016年第4期2卷 215-226页

作者： Jiefei Li Yuqi Zhang Le He Huancong Zuo Department of neurosurgery Medical Center Tsinghua UniversityYuquan Hospital center for Biomedical Imaging research Tsinghua University

Objective: To construct brain tumors and their surrounding anatomical structures through the method of registration, fusion and, three-dimensional(3D) reconstruction based on multimodal image data and to provide the visual information of tumor, skull,brain, and vessels for preoperative evaluation, surgical planning, and function ***: The image data of computed tomography(CT) and magnetic resonance imaging(MRI) were collected from fifteen patients with confirmed brain *** reconstructed brain tumors and their surrounding anatomical structures using neuro Tech software. Results: The whole 3D structures including tumor, brain surface, skull, and vessels were successfully reconstructed based on the CT and MRI images. Reconstruction image clearly shows the tumor size, location, shape, and the anatomical relationship of tumor and surrounding structures. We can hide any reconstructed images such as skull,brain tissue, blood vessles, or tumors. We also can adjust the color of reconstructed images and rotate images to observe the structures from any direction. Reconstruction of brain and skull can be semi transparent to display the deep structure; reconstruction of the structures can be axial, coronal, and sagittal cutting to show relationship among tumor and surrounding structures. The reconstructed 3D structures clearly depicted the tumor features, such as size, location, and shape, and provided visual information of the spatial relationship among its surrounding structures. Conclusions: The method of registration, fusion, and 3D reconstruction based on multimodal images to provide the visual information is feasible and practical. The reconstructed 3D structures are useful for preoperative assessment, incision design,the choice of surgical approach, tumor resection, and functional protection.

关键词： neurosurgical procedures imaging three-dimensional multimodal imaging magnetic resonance imaging

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Effects of Kaixin Jieyu Decoction (开心解郁汤) on Behavior and Glial Fibrillary Acidic Protein Expression in Cerebral Hippocampus of A Rat vascular Depression Model

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Chinese Journal of Integrative Medicine 2015年第3期21卷 223-228页

作者：张先慧黄世敬王彦云张颖潘菊华郑军李多娇雷小明 Traditional Chinese Medicine research and Development center Guang'anmen HospitalChina Academy of Chinese Medical Sciences

Objective：To explore the effects and anti-depression mechanisms of Kaixin Jieyu Decoction（开心解郁汤,KJD）.Methods：The rat vascular depression（VD） model was established by ligation of bilateral common carotid arteries（LBCCA） combined with chronic unpredictable mild stress（CUMS）.Forty Wistar rats were randomly divided into sham,VD model,VD ＋ high-dose KJD[15.4 g/（kg·d） of crude drug],VD ＋ medium-dose KJD[7.7 g/（kg·d） of crude drug],and VD ＋ fluoxetine[2.4 mg/（kg·d）]groups（r〉=8 in each group）,and the treatments lasted for 21 *** of behavior and hippocampus pathology were *** level of glial fibrillary acidic protein（GFAP）protein and mRNA in hippocampus was detected respectively by immunohistochemistry and real-time polymerase chain ***：Compared with the sham group,rats in model group showed a variety of behavioral obstacles,including a significant reduction in sucrose consumption percentage,horizontal and vertical activity scores in open-field tests（P〈0.05 or P〈0.01）,pathological damage like neuronal degeneration,necrosis,and a significant decrease of GFAP protein and mRNA in hippocampus（P〈0.01）;compared with the model group,rats in the high-dose KJD group,medium-dose KJD group and fluoxetine group obtained notable higher behavioral scores,and pathological injury lessened in hippocampus with a increased expression of GFAP protein and mRNA（P〈0.05 or P〈0.01）;compared with the medium-dose KJD group and fluoxetine group,GFAP mRNA in highdose KJD group expressed higer（P〈0.05）.Conclusion：LBCCA combined with CUMS may cause depression-like behavioral changes resulting in the VD model of rats whose depression state can be ameliorated by KJD,and the mechanism of cerebral protection is related possibly with promoting expression of GFAP in hippocampus.

关键词： vascular depression Kaixin Jieyu Decoction behavior glial fibrillary acidic protein Chinese meicine

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Hyperthermia differentially affects specific human stem cells and their differentiated derivatives

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Protein & Cell 2022年第8期13卷 615-622页

作者： Si Wang Fang Cheng Qianzhao Ji Moshi Song Zeming Wu Yiyuan Zhang Zhejun Ji Huyi Feng Juan Carlos Izpisua Belmonte Qi Zhou Jing Qu Wei Li Guang-Hui Liu Weiqi Zhang Advanced Innovation center for Human Brain protection National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical University 100053 Beijing China Aging Translational Medicine center International Center for Aging and Cancer Xuanwu Hospital Capital Medical University 100053 Beijing China Chongqing Renji Hospital University of Chinese Academy of Sciences 400062 Chongqing China National Laboratory of Biomacromolecules CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences 100101 Beijing China University of Chinese Academy of Sciences 100049 Beijing China State Key Laboratory of Membrane Biology Institute of Zoology Chinese Academy of Sciences 100101 Beijing China Institute for Stem Cell and Regeneration Chinese Academy of Sciences 100101 Beijing China Beijing Institute for Stem Cell and Regenerative Medicine 100101 Beijing China State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences 100101 Beijing China Gene Expression Laboratory Salk Institute for Biological Studies La Jolla CA USA CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of Genomics Chinese Academy of Sciences 100101 Beijing China China National center for Bioinformation 100101 Beijing China

Dear Editor,The human body operates optimally at a core temperature of 37 degrees *** at this temperature is essential for cellular and physiological functions(Cheshire,2016).However,infectious diseases,inflammation,injury,neoplasia,and elevated climate temperature can cause a regulated rise in body core temperature,i.e.,fever(Pasi-khova et al,2017).Indeed,an acute or chronic increase in temperature leads to detrimental effects on vasculature by altering a number of indices of vascular structure and function(DuBose et al.,1998).

关键词： elevated inflammation acute

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The neuro-glial coagulonome: the thrombin receptor and coagulation pathways as major players in neurological diseases

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Neural Regeneration research 2019年第12期14卷 2043-2053页

作者： Shany G.Gofrit Efrat Shavit-Stein Department of neurology and Joseph Sagol neuroscience center Sheba Medical Center Tel Hashomer Sackler Faculty of Medicine Tel Aviv University

The neuro-glial interface extends far beyond mechanical support alone and includes interactions through coagulation cascade proteins. Here, we systematically review the evidence indicating that synaptic and node of Ranvier glia cell components modulate synaptic transmission and axonal conduction by a coagulation cascade protein system, leading us to propose the concept of the neuro-glial coagulonome. In the peripheral nervous system, the main thrombin receptor protease activated receptor 1 (PAR1) is located on the Schwann microvilli at the node of Ranvier and at the neuromuscular junction. PAR1 activation effects can be both neuroprotective or harmful, depending on thrombin activity levels. Low physiological levels of thrombin induce neuroprotective effects in the Schwann cells which are mediated by the endothelial protein C receptor. High levels of thrombin induce conduction deficits, as found in experimental autoimmune neuritis, the animal model for Guillaine-Barre syndrome. In the central nervous system, PAR1 is located on the peri-synaptic astrocyte end-feet. Its activation by high thrombin levels is involved in the pathology of primary inflammatory brain diseases such as multiple sclerosis, as well as in other central nervous system insults, including trauma, neoplasms, epilepsy and vascular injury. Following activation of PAR1 by high thrombin levels the seizure threshold is lowered. On the other hand, PAR1 activation by lower levels of thrombin in the central nervous system protects against a future ischemic insult. This review presents the known structure and function of the neuro-glial coagulonome, focusing on coagulation, thrombin and PAR1 in a pathway which may be either physiological (neuroprotective) or detrimental in peripheral nervous system and central nervous system diseases. Understanding the neuro-glial coagulonome may open opportunities for novel pharmacological interventions in neurological diseases.

关键词： thrombin protease activated receptor 1 protease nexin 1 glia node of Ranvier synapse epilepsy glioblastoma Guillaine-Barre syndrome

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FTO stabilizes MIS12 and counteracts senescence

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Protein & Cell 2022年第12期13卷 954-960页

作者： Sheng Zhang Zeming Wu Yue Shi Si Wang Jie Ren Zihui Yu Daoyuan Huang Kaowen Yan Yifang He Xiaoqian Liu Qianzhao Ji Beibei Liu Zunpeng Liu Jing Qu Guang-Hui Liu Weimin Ci Xiaoqun Wang Weiqi Zhang State Key Laboratory of Brain and Cognitive Science CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of Brain-Intelligence Technology(Shanghai)Institute of BiophysicsChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China China National center for Bioinformation Beijing 100101China Advanced Innovation center for Human Brain protection and National Clinical Research Center for Geriatric DisordersXuanwu HospitalCapital Medical UniversityBeijing 100053China Aging Translational Medicine center International Center for Aging and CancerXuanwu HospitalCapital Medical UniversityBeijing 100053China Chongqing Renji Hospital University of Chinese Academy of SciencesChongqing 400062China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Institute for Brain Disorders Beijing 100069China

Dear Editor, N6-methyladenosine(m6A)is an abundant epitranscriptomic modification that regulates messenger RNA(mRNA)*** m6A modification regulates mRNA splicing,transport,stability,and translation through coordinated activities by methyltransferases(writers),binding proteins(readers),and demethylases(erasers)(Huang et al.,2020;Wu et al.,2020).Among m6A regulators,fat mass of obesity-associ-ated protein(FTO),is the first discovered eraser with RNA m6A demethylation activity(Jia et al.,2011).Since then,FTO has been reported to play m6A-dependent roles in a variety of physiological processes including adipogenesis,neuro-genesis and tumorigenesis(Fischer et al.,2009;Li et al.,2017;Huang et al.,2020).Consequently,FTO deficiency in mice leads to dramatic phenotypes,such as decreased fat mass and impaired brain development(Fischer et al.,2009;Li et al.,2017).Similarly,inhibition of FTO reduces tumori-genesis in multiple types of cancer models,while FTO is highly expressed in many cancers(Huang et al.,2020).

关键词： Fischer impaired

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Deep tumor-penetrating nano-delivery strategy to improve diagnosis and therapy in patient-derived xenograft(PDX)oral cancer model and patient tissue

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Nano research 2023年第2期16卷 2927-2937页

作者： Longmeng Li Aaron R.Lindstrom Andrew C.Birkeland Menghuan Tang Tzu-Yin Lin Yikai Zhou Bai Xiang Xiangdong Xue Yuanpei Li State Key Laboratory of Environment Health(Incubation) Key Laboratory of Environment and HealthMinistry of EducationKey Laboratory of Environment and Health(Wuhan)Ministry of Environmental ProtectionSchool of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Biochemistry and Molecular Medicine UC Davis Comprehensive Cancer CenterUniversity of California Davis2700 Stockton BlvdSacramentoCalifornia 95817USA Department of Otolaryngology-Head and Neck Surgery University of California Davis2521 Stockton BlvdSacramentoCalifornia 95817USA Division of Hematology and Oncology Department of Internal MedicineSchool of MedicineUniversity of California Davis2700 Stockton BlvdSacramentoCalifornia 95817USA Key Laboratory of Hebei Province for Innovative drug research and evaluation School of Pharmaceutical SciencesHebei Medical UniversityShijiazhuang 050017China School of Pharmacy Pharm-X CenterShanghai Jiao Tong UniversityShanghai 200240China

Nanoprodrugs that are directly assembled by prodrugs attract considerable attention with high anticancer ***,their stability and efficiency of tumor-targeted delivery remain a major challenge in practical biomedical ***,we report a new deep tumor-penetrating nano-delivery strategy to achieve enhanced anti-cancer performance by systematic optimization of a porphyrin-doxorubicin-based nanoprodrug using various PEGylations/crosslinks and co-administration of targeting peptide *** glycols(PEGs)with different molecular weights and grafts are employed to crosslink the nanoprodrug and optimize size,charge,tumor accumulation and penetration,and anti-cancer efficiency,*** tumor penetration was validated in syngeneic oral cancer mouse models,patient-derived xenograft(PDX)models,and oral cancer tissue from *** optimized nanoprodrug co-administrated with iRGD remarkably enhances the accumulation and penetration both in tumor vascular and PDX tumor *** is effective and safe to improve in vivo therapeutic efficacy via the passive tumor targeting dependent and independent *** tumor-penetrating nano-delivery strategy is promising to strengthen the nanoprodrugs in clinical implementation.

关键词： nanoprodrug tumor-penetrating tumor-targerting multilevel delivery optimization drug delivery

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