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Bioactive Materials 2024年第3期33卷 377-395页

作者： Chaojie Zhu Qing Wu Tao Sheng Jiaqi Shi Xinyuan Shen Jicheng Yu Yang Du Jie Sun Tingxizi Liang Kaixin He Yuan Ding Hongjun Li Zhen Gu Weilin Wang Key laboratory of Advanced Drug Delivery systems of Zhejiang Province College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China Department of Hepatobiliary and Pancreatic Surgery The Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310009China Liangzhu laboratory Zhejiang University Medical CenterHangzhou311121China Department of Cell Biology School of MedicineZhejiang UniversityHangzhouZhejiang310058China Key laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic tumor of Zhejiang Province HangzhouZhejiang310009China ZJU-Pujian Research&Development Center of Medical Artificial Intelligence for Hepatobiliary and Pancreatic Disease HangzhouZhejiang310058China Jinhua Institute of Zhejiang University Jinhu1321299China Department of General Surgery Sir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China

Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy ***,its therapeutic validity has yet to be successfully achieved in solid *** from hematological cancers,solid tumors are characterized by dysregulated blood vessels,dense extracellular matrix,and filled with immunosuppressive signals,which together result in CAR-T cells’insufficient infiltration and rapid *** insufficient recognition of tumor cells and tumor heterogeneity eventually causes cancer *** addition,CAR-T therapy also raises safety concerns,including potential cytokine release storm,on-target/off-tumor toxicities,and neuro-system side *** we comprehensively review various targeting aspects,including CAR-T cell design,tumor modulation,and delivery *** believe it is essential to rationally design a combinatory CAR-T therapy via constructing optimized CAR-T cells,directly manipulating tumor tissue microenvironments,and selecting the most suitable delivery strategy to achieve the optimal outcome in both safety and efficacy.

关键词： CAR-T therapy Cancer immunotherapy Drug delivery CAR construct design tumor modulation Delivery strategy

Application of proteomic approaches to assess the effect of anti-epileptic drug on seizure foci

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Journal of Chinese Pharmaceutical Sciences 2020年第1期29卷 13-28页

作者： Yujing Song Xuyang Zhao Qian Chen Yan Song Wanyu Lei Yuxin Yin Weining Ma Zhuo Huang State Key laboratory of Natural and Biomimetic Drugs Department of Molecular and Cellular PharmacologySchool of Pharmaceutical SciencesInstitute of Systems BiomedicineDepartment of PathologySchool of Basic Medical SciencesBeijing Key Laboratory of Tumor Systems BiologyPeking-Tsinghua Center for Life SciencesPeking University Health Science CenterBeijing 100191China Department of Neurology Shengjing Hospital affiliated to China Medical UniversityShenyang 110000China

Epilepsy is one of the most common neurological disorders characterized by epileptic *** anti-epileptic drugs(AEDs)are the main form of treatment for people with ***,people thought that AEDs modify the activities of ion channels to suppress epileptic ***,accumulating evidence suggests that targeting at ion channels cannot completely account for the numerous effects of the AEDs on its broad clinical activity in epileptic *** our study,proteomic methods were used to quantify the proteome of hippocampal tissues from patients who were treated or not treated by AEDs(Carbamazepine).Further bioinformatics methods,including Gene Ontology(GO)annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,were utilized to analyze the differences between two patient *** found that more than 400 proteins,including metabolism and immune related proteins,had a higher expression level in the carbamazepine-treated group compared with the *** altered proteins were considered to be involved in many different biological *** these pathways,immune-system related pathway modulated by complement C3 and microglia was highly remarkable,which regulated the synapses elimination in physiological *** epilepsy,the carbamazepine induced up-regulation of complement C3 might decrease the abnormal synaptic connections between neurons and thus contribute to the therapeutic role of *** results of our study suggested that apart from ion channels,carbamazepine exerted numerous effects on human epileptic foci,which might be the fundamental mechanisms of AEDs for treatment,adverse-effects and pharmacoresistance of epilepsy.

关键词： Carbamazepine Proteomics Complement-related synaptic modification Glutathione S-transferase enzyme

tumor type classification and candidate cancer-specific biomarkers discovery via semi-supervised learning

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Biophysics Reports 2023年第2期9卷 57-66页

作者： Peng Chen Zhenlei Li Zhaolin Hong Haoran Zheng Rong Zeng School of Computer Science and Technology University of Science and Technology of China Anhui Key laboratory of Software Engineering in Computing and Communication University of Science and Technology of China 3. Department of Systems Biology University of Science and Technology of China 4. CAS Key Laboratory of Systems Biology Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell Science Chinese Academy of Sciences School of Life Science and Technology ShanghaiTech University

Identifying cancer-related differentially expressed genes provides significant information for diagnosing tumors, predicting prognoses, and effective treatments. Recently, deep learning methods have been used to perform gene differential expression analysis using microarray-based high-throughput gene profiling and have achieved good results. In this study, we proposed a new robust multiple-datasetsbased semi-supervised learning model, MSSL, to perform tumor type classification and candidate cancer-specific biomarkers discovery across multiple tumor types and multiple datasets, which addressed the following long-lasting obstacles:(1) the data volume of the existing single dataset is not enough to fully exert the advantages of deep learning;(2) a large number of datasets from different research institutions cannot be effectively used due to inconsistent internal variances and low quality;(3) relatively uncommon cancers have limited effects on deep learning methods. In our article, we applied MSSL to The Cancer Genome Atlas(TCGA) and the Gene Expression Comprehensive Database(GEO) pan-cancer normalized-level3 RNA-seq data and got 97.6% final classification accuracy, which had a significant performance leap compared with previous approaches. Finally, we got the ranking of the importance of the corresponding genes for each cancer type based on classification results and validated that the top genes selected in this way were biologically meaningful for corresponding tumors and some of them had been used as biomarkers, which showed the efficacy of our method.

关键词： tumor type classification Cancer-specific biomarkers MSSL Deep learning

Gene engineered exosome reverses T cell exhaustion in cancer immunotherapy

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Bioactive Materials 2024年第4期34卷 466-481页

作者： Peishan Li Ying Xie Jinling Wang Chunjie Bao Jialun Duan Yixuan Liu Qian Luo Jiarui Xu Yuxin Ren Min Jiang Jianwei Li Haitao Guo Huihui Zhao Guiling Wang Yanqin Liang Wanliang Lu State Key laboratory of Natural and Biomimetic Drugs Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery SystemsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China Modern Research Center for Traditional Chinese Medicine Beijing Research Institute of Chinese MedicineBeijing University of Chinese MedicineBeijing100029China Beijing Institute of Collaborative Innovation Beijing100044China

Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many ***,more than half of cancer patients are not responsive to this therapy due to immune ***,we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod(PD1-Imi Exo)for boosting response of cancer immune checkpoint blockage *** results showed that PD1-Imi Exo had a vesicular round shape(approximately 139 nm),revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell,and demonstrated a remarkable therapeutic efficacy in the melanoma-bearing mice and in the breast cancer-bearing *** mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8^(+)T cell with cancer cell,displaying a PD1/PDL1 immune checkpoint blockage effect,and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell,exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8^(+)T *** conclusion,the gene engineered exosome could be used for reversing T cell exhaustion in cancer *** study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy,preventing tumor recurrence or metastasis after surgery by rebuilding the patients’immunity,thus consolidating the overall prognosis.

关键词： Gene engineered exosomes T cell exhaustion PD1/PDL1 Imiquimod Cancer immunotherapy

cBAF and MYC:decision makers for T cell memory differentiation

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Signal Transduction and Targeted Therapy 2023年第1期8卷 1-2页

作者： Kaili Ma Hongcheng Cheng Lianjun Zhang CAMS Key laboratory of Synthetic Biology Regulatory Element Institute of Systems MedicineChinese Academy of Medical Sciences and Peking Union Medical College100005BeijingChina Suzhou Institute of systems Medicine Suzhou215123JiangsuChina Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy Cancer InstituteXuzhou Medical UniversityXuzhouChina

In a recent paper published in Nature,Guo et al.1 demonstrated that asymmetrically segregated MYC and canonical BRG1/BRM-associated factor(cBAF)at first division of activated CD8^(+)T cells cooperate to dictate T cell fate by remodeling of epigenetics and chromatin *** pharmacological or genetic inhibition of cBAF in chimeric antigen receptor T(CAR-T)cells considerably promotes their anti-tumor capacity in vivo,presumably by biased memory differentiation post transfer(Fig.1).

关键词： remodeling considerably

Combination losartan with hyaluronic acid modified diethyldithiocarbamate loaded hollow copper sulfide nanoparticles for the treatment of breast cancer and metastasis

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Chinese Chemical Letters 2024年第3期35卷 406-414页

作者： Haili Hu Weiwei Zhang Lei Lei Fan Tong Huilin Zhang Yiwei Zhang Wenqin Yang Yilu Tang Ruyi Lin Xue Xia Jiamei Li Shiyong Song Huile Gao Key laboratory of Drug Targeting and Drug Delivery systems West China School of PharmacySichuan UniversityChengdu 610041China School of Pharmacy Henan UniversityKaifeng 475004China Department of Public Health Chengdu Medical CollegeChengdu 610500China

The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer *** still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune *** solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor *** irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ***,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic *** vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.

关键词： Targeted drug delivery system Hollow copper sulfide nanoparticles Photothermal therapy Hyaluronic acid Breast cancer Anti-metastasis

Immunological effects of nano-enabled hyperthermia for solid tumors: opportunity and challenge

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Frontiers of Chemical Science and Engineering 2022年第3期16卷 333-344页

作者： Xiangsheng Liu Hui Sun Xueqing Wang Huan Meng CAS Key laboratory for Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology(NCNST)Beijing100190China The Cancer Hospital of the University of Chinese Academy of Sciences(Zhejiang Cancer Hospital) Institute of Basic Medicine and Cancer(IBMC)Chinese Academy of SciencesHangzhou310022China Beijing Key laboratory of Molecular Pharmaceutics and New Drug Delivery systems School of Pharmaceutical SciencesPeking UniversityBeijing100191China

Compared to conventional hyperthermia that is limited by low selectivity and severe side effects,nano-enabled hyperthermia yields great potentials to tackle these limitations for cancer *** major advance is the observation of immunological responses associated with nano-enabled hyperthermia,which introduces a new avenue,allowing a potential paradigm shift from the acutely effective and cytotoxicity-centric response to the next-phase discovery,i.e.,long-lasting and/or systemic anti-tumor *** perspective first discusses the temperature-gradient and the spatially-structured immunological landscape in solid tumors receiving nano-enabled *** includes the discussion about underlying mechanism such as immunogenic cell death,which initiates a profound immunological chain *** order to propagate the immune activation as a viable therapeutic principle,we further discussed the tumor type-specific complexity in the immunological tumor microenvironment,including the creative design of nano-enabled combination therapy to synergize with nano-enabled hyperthermia.

关键词： nano-enabled hyperthermia immunogenic cell death heterogeneous immunological landscape tumor microenvironment

Recent progress onmicrofluidic devices with incorporated 1D nanostructures for enhanced extracellular vesicle(EV)separation

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Bio-Design and Manufacturing 2022年第3期5卷 607-616页

作者： Yuting Xiong Hanyue Kang Hongzhao Zhou Liang Ma Xiaobin Xu Key laboratory of Advanced Civil Engineering Materials of Ministry of Education Shanghai Key Lab of D&A for Metal-Functional MaterialsSchool of Materials Science and EngineeringTongji UniversityShanghai 201804China Institute for Advanced Study Tongji UniversityShanghai 201804China State Key laboratory of Fluid Power and Mechatronic systems Zhejiang UniversityHangzhou 310058China School of Mechanical Engineering Zhejiang UniversityHangzhou 310058China

Extracellular vesicles(EVs)are lipid-bound vesicles secreted by cells into the extracellular *** are three types of EVs,including exosomes(30–150 nm)[1],microvesicles(100–1000 nm),and apoptotic bodies(50–4000 nm).EVs are also important intercellular communication carriers in many physiological and pathological processes such as immune response,tumor invasion,and metastasis[2,3].EVs circulate in various body fluids(e.g.,peripheral blood and urine),while carrying genetic information(e.g.,proteins and nucleic acids)from the parent cells[2,4,5].Thus,their source can be identified through gene analysis[6–10].

关键词： invasion urine metastasis

Palladium nanoplates scotch breast cancer lung metastasis by constraining epithelial-mesenchymal transition

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National Science Review 2021年第7期8卷 124-136页

作者： Shunhao Wang Jingchao Li Mei Chen Liting Ren Wenya Feng Lining Xu Xiaolan Chen Tian Xia Nanfeng Zheng Sijin Liu State Key laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental Sciences Chinese Academy of Sciences University of Chinese Academy of Sciences State Key laboratory for Physical Chemistry of Solid Surfaces Collaborative Innovation Center of Chemistry for Energy Materials Department of Chemistry Xiamen University College of Materials Science and Engineering Hunan University Division of Nanomedicine Department of Medicine California Nano Systems Institute University of CaliforniaLos Angeles

Metastasis accounts for the majority of cancer deaths in many tumor types including breast ***-mesenchymal transition(EMT) is the driving force for the occurrence and progression of metastasis, however, no targeted strategies to block the EMT program are currently available to combat metastasis. Diverse engineered nanomaterials(ENMs) have been reported to exert promising anti-cancer effects, however, no ENMs have been designed to target EMT. Palladium(Pd) nanomaterials, a type of ENM, have received substantial attention in nanomedicine due to their favorable photothermal performance for cancer therapeutics. Herein, Pd nanoplates(Pd PL) were found to be preferentially biodistributed to both primary tumors and metastatic tumors. Importantly, Pd PL showed a significant inhibition of lung metastasis with and without near-infrared(NIR) irradiation. Mechanistic investigations revealed that EMT was significantly compromised in breast cancer cells upon the Pd PL treatment, which was partially due to the inhibition of the transforming growth factor-beta(TGF-β) signaling. Strikingly, the Pd PL was found to directly interact with TGF-β proteins to diminish TGF-β functions in activating its downstream signaling, as evidenced by the reduced phosphorylation of Smad2. Notably,TGF-β-independent pathways were also involved in undermining EMT and other important biological processes that are necessary for metastasis. Additionally, NIR irradiation elicited synergistic effects on PdPL-induced inhibition of primary tumors and metastasis. In summary, these results revealed that the Pd PL remarkably curbed metastasis by inhibiting EMT signaling, thereby indicating the promising potential of Pd PL as a therapeutic agent for treating breast cancer metastasis.

关键词： palladium nanoplates tumor targeting lung metastasis epithelial-mesenchymal transition TGF-β