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An injectable signal-amplifying device elicits a specific immune response against malignant glioblastoma

Acta Pharmaceutica Sinica B 2023年第12期13卷 5091-5106页

作者： Qiujun Qiu Sunhui Chen Huining He Jixiang Chen Xinyi Ding Dongdong Wang Jiangang Yang Pengcheng Guo Yang Li Jisu Kim Jianyong Sheng Chao Gao Bo Yin Shihao Zheng Jianxin Wang Department of Pharmaceutics School of PharmacyFudan University&Key Laboratory of Smart Drug DeliveryMinistry of EducationShanghai 201203China Department of Pharmacy Fujian Provincial Hospital&Provincial Clinical Medical College of Fujian Medical UniversityFuzhou 350001China Institute of Materia Medica Academy of Chinese and Western Integrative MedicineFudan UniversityShanghai 201203China Tianjin Key Laboratory on Technologies Enabling development of Clinical Therapeutics and Diagnostics School of PharmacyTianjin Medical UniversityTianjin 300070China Department of Radiology Huashan HospitalFudan UniversityShanghai 200040China Institute of Tropical medicine Guangzhou University of Chinese MedicineGuangzhou 510006China Department of Neurosurgery Fujian Provincial Hospital&Provincial Clinical Medical College of Fujian Medical UniversityFuzhou 350001China

Despite exciting achievements with some malignancies,immunotherapy for hypoimmunogenic cancers,especially glioblastoma(GBM),remains a formidable clinical *** immunogenicity and deficient immune infiltrates are two major limitations to an effective cancer-specific immune ***,we propose that an injectable signal-amplifying nanocomposite/hydrogel system consisting of granulocyte-macrophage colony-stimulating factor and imiquimod-loaded antigen-capturing nanoparticles can simultaneously amplify the chemotactic signal of antigen-presenting cells and the"danger"signal of *** demonstrated the feasibility of this strategy in two scenarios of *** the first scenario,we showed that this simultaneous amplification system,in conjunction with local chemotherapy,enhanced both the immunogenicity and immune infiltrates in a recurrent GBM model;thus,ultimately making a cold GBM hot and suppressing postoperative *** by excellent efficacy,we further exploited this signal-amplifying system to improve the efficiency of vaccine lysate in the treatment of refractory multiple GBM,a disease with limited clinical treatment *** general,this biomaterial-based immune signal amplification system represents a unique approach to restore GBM-specific immunity and may provide a beneficial preliminary treatment for other clinically refractorymalignancies.

关键词： Immunotherapy Glioblastoma Antigen-capturing nanoparticles Recombinant chemokines Immune signal-amplifying

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Effect of the structure of ginsenosides on the in vivo fate of their liposomes

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Asian Journal of Pharmaceutical Sciences 2022年第2期17卷 219-229页

作者： Chen Chen Jiaxuan Xia Hongwei Ren Anni Wang Ying Zhu Ru Zhang Zicheng Gan Jianxin Wang Department of Pharmaceutics School of PharmacyFudan University&Key Laboratory of Smart Drug DeliveryMinistry of EducationShanghai 201203China Institute of Tropical medicine Guangzhou University of Chinese MedicineGuangzhou 510006China Institute of Integrated Chinese and Western medicine Fudan UniversityShanghai 200040China

To utilize themultiple functions and give full play of ginsenosides,a variety of ginsenosides with different structures were prepared into liposomes and evaluated for their effect on the stability,pharmacokinetics and tumor targeting capability of *** results showed that the position and number of glycosyl groups of ginsenosides have significant effect on the in vitro and in vivo properties of their *** pharmacokinetics of ginsenosides liposomes indicated that the C-3 sugar group of ginsenosides is beneficial to their liposomes for longer circulation in *** C-3 and C-6 glycosyls can enhance the uptake of their liposomes by 4T1 cells,and the glycosyls at C-3 position can enhance the tumor active targeting ability significantly,based on the specific binding capacity to Glut 1 expressed on the surface of 4T1 *** to the results in the study,ginsenoside Rg3 and ginsenoside Rh2 are potential for exploiting novel liposomes because of their cholesterol substitution,long blood circulation and tumor targeting *** results provide a theoretical basis for further development of ginsenoside based liposome delivery systems.

关键词： Ginsenosides Liposomes Structure activity relationship Rg3 liposomes Long circulation Tumor targeting Glut 1

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Mature dendritic cell-derived dendrosomes swallow oxaliplatin-loaded nanoparticles to boost immunogenic chemotherapy and tumor antigen-specific immunotherapy

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Bioactive Materials 2022年第9期7卷 15-28页

作者： Xing Chen Xiang Ling Jiaxuan Xia Ying Zhu Longlong Zhang Yuwei He Anni Wang Guolong Gu Bo Yin Jianxin Wang Department of Pharmaceutics School of PharmacyFudan UniversityKey Laboratory of Smart Drug DeliveryMinistry of EducationShanghai201203China Department of Pharmaceutics School of PharmacyChina Pharmaceutical UniversityState Key Laboratory of Natural MedicinesNanjing210009China Department of Radiology Huashan HospitalFudan UniversityShanghai200040China Institutes of integrative medicine of Fudan University Shanghai200040China

The cytomembrane-derived delivery platform represents a promising biomimetic strategy in *** achieve durable and reliable tumor inhibition,mature dendrosomes(mDs),which were isolated from bone marrow-derived dendritic cells undergoing CT26 tumor antigen(TA)stimulation,were fused with redox-responsive nanoparticles(NPs)that were composed of poly(disulfide ester amide)polymers with an intensified disulfide density and hydrophobic oxaliplatin(OXA)prodrugs with the ability to potentiate *** vitro and in vivo results revealed that NP/mDs could induce tumor cell death through mitochondrial pathway and thus created immunogenic microenvironments,but also elicited immunocyte differentiation by TA cross-dressing and infiltration by direct *** further neutralizing immune-regulatory interaction,the administration of PD-L1 antibody(αPD-L1)greatly improved antitumor efficiency of NP/***,the effectors of host immune systems effectively inhibited the growth and metastasis of distal tumors,likely because the autologous TA evoked by OXA and allogeneic TA delivered by mDs acted as additional stimuli to reinforce the immune response of tumor-specific T cells and immunosurveillance toward *** results demonstrated that NP/mDs could simultaneously realize immunogenic chemotherapeutics and specific TA *** combination withαPD-L1,the antitumor effect was further ***,NP/mDs provide a promising strategy for the comprehensive treatment of malignancy.

关键词： Dendritic cell Dendrosome Antigen delivery Immunotherapy Chemotherapy

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The mutational pattern of homologous recombination(HR)-associated genes and its relevance to the immunotherapeutic response in gastric cancer

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Cancer Biology & medicine 2020年第4期17卷 1002-1013页

作者： Yue Fan Haifeng Ying Xueying Wu Huan Chen Ying Hu Henghui Zhang Lijia Wu Ying Yang Beibei Mao Lan Zheng Department of integrated Traditional Chinese medicine and Western medicine Zhongshan HospitalFudan UniversityShanghai 200032China Department of Traditional Chinese medicine Ruijin HospitalShanghai Jiaotong UniversityShanghai 200025China Genecast Precision medicine Technology Institute Beijing 100191China Center of integrative medicine Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China

Objective:Currently,there is an urgent need to identify immunotherapeutic biomarkers to increase the benefit of immune checkpoint inhibitors(ICIs)for patients with gastric cancer(GC).Homologous recombination deficiency(HRD)can modify the tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic *** aimed to analyze the mutational pattern of HR-associated genes in Chinese patients with GC and its relevance to the tumor immune profile and clinical immunotherapeutic ***:A panel of 543 cancer-associated genes was used to analyze genomic profiles in a cohort comprising 484 Chinese patients with *** between HR gene mutations and tumor immunity or clinical outcomes were identified via bioinformatic analysis using 2 GC genomic datasets(TCGA and MSK-IMPACT).Results:Fifty-one of the 484(10.54%)patients carried at least one somatic mutation in an HR gene;ATM(16/484,3.31%)was among the most frequently mutated HR genes in the Chinese *** in HR genes were associated with elevated tumor mutational burden,enhanced immune activity,and microsatellite instability *** the MSK-IMPACT cohort comprising 49 patients with stomach adenocarcinoma or gastroesophageal junction adenocarcinoma treated with ICIs,patients with HR-mut GC(n=12)had significantly better overall survival than those with HR-wt GC(n=37)(log-rank test,P<0.05).Conclusions:Our data suggest that detection of somatic mutations in HR genes might aid in identifying patients who might benefit from immune checkpoint blockade therapy.

关键词： Gastric cancer homologous recombination deficiency immunotherapy biomarker

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A novel tumor-targeting treatment strategy uses energy restriction via co-delivery of albendazole and nanosilver

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Nano Research 2018年第9期11卷 4507-4523页

作者： Jianming Liang Ruixiang Li Yuwei He Chengli Ling Qi Wang Yongzhuo Huang Jing Qin Weigen Lu Jianxin Wang Department of Pharmaceutics School of Pharmacy Fudan University & Key Laboratory of Smart Drug Delivery Ministry of Education Shanghai 201203 China Institute of Clinical Pharmacology Guangzhou University of Traditional Chinese Medicine Guangzhou 510006 China shanghai Institute of Materia Medica Chinese Academy of Sciences 501 Haike Rd. Shanghai201203 China shanghailnstitute of Pharmaceuticallndustry China State Institute of Pharmaceutical Industry 285 Gebaini Rd. Shanghai201203 China School of Pharmacy Chengdu University of Traditional Chinese Medicine No 1166 Liu TaiAvenue Wenjiang District Chengdu 610072 China

Although nanotechnology has been rapidly developed and applied in tumor targeting, the outcome of chemotherapy remains greatly restricted by the toxicity of cytotoxic drugs in normal tissues and cells. Therefore, the development of alternative delivery systems, with few side effects in normal cells, has attracted increasing attention. Energy restriction is a novel and promising approach to cancer treatment, which can restrict tumor growth via inhibition of cellular energy metabolism. In this study, a novel tumor targeting system, based on folate-conjugated bovine serum albumin （BSA）, was developed to co-deliver albendazole and nanosilver simultaneously, to restrain the energy metabolism of tumor cells. This nanosystem showed stronger anti-tumor efficacy than those using nanoparticles without folic acid modification, nanosilver, or albendazole, both in vitro and in vivo. This nanosystem depleted cellular ATP via direct inhibition of glycolytic enzymes and mitochondrial damage, resulting in inhibition of proliferation, cell-cycle arrest, and apoptosis of tumor cells. The enhanced anti-tumor activity contributed to the tumor-targeting ability of this system, resulting in specific energy inhibition in tumor cells. Toxicity evaluation was performed to confirm the safety of this system. This nanosystem provides an efficient and safe strate~ for tumor therapy.

关键词： albendazole nano silver co-delivery tumor targeting energy metabolism

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Inhibition of post-trabeculectomy fibrosis via topically instilled antisense oligonucleotide complexes co-loaded with fluorouracil

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Acta Pharmaceutica Sinica B 2020年第9期10卷 1754-1768页

作者： Kuan Jiang Junyi Chen Lingyu Tai Chang Liu Xishan Chen Gang Wei Weiyue Lu Weisan Pan Key Laboratory of Smart Drug Delivery Ministry of EducationDepartment of PharmaceuticsSchool of PharmacyFudan UniversityShanghai 201203China Department of Ophthalmology Eye&ENT HospitalFudan UniversityShanghai 200031China School of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China The Institutes of integrative medicine of Fudan University Shanghai 200040China shanghai Engineering Research Center of Immunotherapeutics Shanghai 201203China

Trabeculectomy is the mainstay of surgical glaucoma treatment,while the success rate was unsatistying due to postoperative scarring of the filtering *** countermeasures for scar prevention are intraoperative intervention or repeated subconjunctival ***,we designed a codelivery system capable of transporting fluorouracil and anti-TGF-β2 oligonucleotide to synergistically inhibit fibroblast proliferation via topical *** co-delivery system was built based on a cationic dendrimer core(PAMAM),which encapsulated fluorouracil within hydrophobic cavity and condensed oligonucleotide with surface amino groups,and was further modified with hyaluronic acid and cell-penetrating peptide *** co-delivery system was self-assembled into nanoscale complexes with increased cellular uptake and enabled efficient inhibition on proliferation of fibroblast *** vivo studies on rabbit trabeculectomy models further confirmed the anti-fibrosis efficiency of the complexes,which prolonged survival time of filtering blebs and maintained their height and extent during wound healing process,exhibiting an equivalent effect on scar prevention compared to intraoperative infiltration with *** observation by immunohistochemistry staining and quantitative analysis by Western blotting both suggested that TGF-β2 expression was inhibited by the co-delivery *** study provided a potential approach promising to guarantee success rate of trabeculectomy and prolong survival time of filtering blebs.

关键词： Trabeculectomy Fibrosis prevention Gene delivery Penetratin Fluorouracil

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One Stone Four Birds:A Novel Liposomal Delivery System Multi-functionalized with Ginsenoside Rh2 for Tumor Targeting Therapy

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Nano-Micro Letters 2020年第10期12卷 69-86页

作者： Chao Hong Jianming Liang Jiaxuan Xia Ying Zhu Yizhen Guo Anni Wang Chunyi Lu Hongwei Ren Chen Chen Shiyi Li Dan Wang Huaxing Zhan Jianxin Wang Department of Pharmaceutics School of PharmacyFudan University&Key Laboratory of Smart Drug DeliveryMinistry of EducationShanghai 201203People’s Republic of China Institute of Tropical medicine Guangzhou University of Chinese MedicineGuangzhou 510006People’s Republic of China Institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhou 510006People’s Republic of China School of Pharmacy Shanghai Jiao Tong UniversityShanghai 200240People’s Republic of China shanghai Ginposome Pharmatech Co. LtdShanghai 201600People’s Republic of China Institute of Integrated Chinese and Western medicine Fudan UniversityShanghai 200040People’s Republic of China

Liposomes hold great potential in anti-cancer drug delivery and the targeting treatment of ***,the clinical therapeutic efficacy of liposomes is still limited by the complexity of tumor microenvironment(TME)and the insufficient accumulation in tumor ***,the application of cholesterol and polyethylene glycol(PEG),which are usually used to prolong the blood circulation and stabilize the structure of liposomes respectively,has been questioned due to various ***,we developed a ginsenoside Rh2-based multifunctional liposome system(Rh2-lipo)to effectively address these challenges once for *** with the conventional’wooden’liposomes,Rh2-lipo is a much more brilliant carrier with multiple *** Rh2-lipo,both cholesterol and PEG were substituted by Rh2,which works as membrane stabilizer,long-circulating stealther,active targeting ligand,and chemotherapy adjuvant at the same ***,Rh2 could keep the stability of liposomes and avoid the shortcomings caused by ***,Rh2-lipo showed a specifically prolonged circulation behavior in the ***,the accumulation of the liposomes in the tumor was significantly enhanced by the interaction of glucose transporter of tumor cells with ***,Rh2-lipo could remodel the structure and reverse the immunosuppressive environment in *** tested in a 4T1 breast carcinoma xenograft model,the paclitaxel-loaded Rh2-lipo realized high efficient tumor growth ***,Rh2-lipo not only innovatively challenges the position of cholesterol as a liposome component,but also provides another innovative potential system with multiple functions for anti-cancer drug delivery.

关键词： Ginsenoside Rh2 Liposomes Cholesterol Multifunction Tumor targeting

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In vivo and in situ real-time fluorescence imaging of peripheral nerves in the NIR-II window

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Nano Research 2019年第12期12卷 3059-3068页

作者： Zhujun Feng Yimeng Yang Jian Zhang Kan Wang Yunxia Li Heng Xu Zhen Wang Ewelina Biskup Shixian Dong Xing Yang Yuefeng Hao Jun Chen Yan Wo Department of Anatomy and Physiology School of MedicineShanghai Jiao Tong UniversityShanghai 200025China Sports medicine Institute ofFudan University Department of Orthopedic Sports MedicineHuashan HospitalFudan UniversityShanghaiChina Department of Instrument Science and Engineering School of Electronic Information and Electrical EngineeringShanghai Jiao long UniversityShanghai Engineering Research Center for Intelligent diagnosis and treatment instrumentKey Laboratory of Thin Film and Microfabrication(Ministry of Education)Shanghai 200240China Department of Plastic Surgery Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Department cf physical education Fudan UniversityShanghai 200040China Department of Internal medicine University Hospital of BaselPetersgraben 44051 BaselSwitzerland Department of orthopedics Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou 215500China

The peripheral nervous system(PNS)is essential for performing and maintaining various motor and sensory *** can lead to a series of peripheral neurological conditions,such as paraesthesia,pain,or spasms,which are debilitating and lowering the quality of *** guidelines for diagnosis rely predominantly on clinical symptoms resulting from PNS dysfunction,which occur already at an *** are currently no effective methods that visually reflect the extent of peripheral *** our study,we present a novel in vivoand in situ real-time imaging of peripheral nerves based on the second near-infrared window(NIR-II)fluoresce *** NIR-II system,lead sulfidequa ntum dots(PbS Qds)with NIR-II fluoresce nee specifically bound to motor neuro rvspecific protein agrin,acting as image con *** micemodel,peripheral nerves were visible as soon as after 2 h post *** provide evidenee for the efficacy of this approach,which allows todirectly dem on strate peripheral nerves,their structure,and pote ntial damagesites and ***,our products were of goodbiocompatibility,while the n eural fluoresce nee signal was solid,bright and stable for 4 h in ***,overall,our results suggest that NIR-II isan effective new method for direct imaging of peripheral nerves in vivo,opening new horizons on early,improved and more precise,targeteddiag no sis.A resulti ng more rapid installatio n of perso nalized therapy facilitates a better prognosis of clinical peripheral neuropathy.

关键词： peripheral nerve the second near-infrared window(NIR-II) fluorescent imaging Agrin@PbS Qds biocompatibility

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Involvement of NF-κB and the CX3CR1 Signaling Network in Mechanical Allodynia Induced by Tetanic Sciatic Stimulation

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Neuroscience Bulletin 2018年第1期34卷 64-73页

作者： Zhe-Chen Wang Li-Hong Li Chao Bian Liu Yang Ning Lv Yu-Qiu Zhang Institutes of Brain Science State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Science Fudan University Department of Anesthesiology Fudan University Shanghai Cancer Center Department of Oncology Shanghai Medical College Fudan University

Tetanic stimulation of the sciatic nerve （TSS） triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1- CX3CR1 signaling is an important pathway in neuronal- microglial activation. Nuclear factor nB （NF-KB） is a key signal transduction molecule that regulates neuroinflamma- tion and neuropathic pain. Here, we set out to determine whether and how NF-~B and CX3CR1 are involved in the mechanism underlying the pathological changes induced by TSS. After unilateral TSS, significant bilateral mechanical allodynia was induced, as assessed by the von Frey test. The expression of phosphorylated NF-nB （pNF-nB） and CX3CR1 was significantly up-regulated in the bilateral dorsal horn. Immunofluorescence staining demonstrated that pNF-κB and NeuN co-existed, implying that the NF-κB pathway is predominantly activated in neurons following TSS. Administration of either the NF-κB inhibitor ammo- nium pyrrolidine dithiocarbamate or a CX3CR1-neutralizing antibody blocked the development and maintenance of neuropathic pain. In addition, blockade of NF-κB down- regulated the expression of CX3CL1-CX3CR1 signaling,and conversely the CX3CRl-neutralizing antibody also down-regulated pNF-rd3. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR 1-neutralizing antibodies in treating pathological pain.

关键词： CX3CR1 Mechanical allodynia NF-κB Tetanic sciatic stimulation Microglia Spinal dorsal horn

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Opposite Sex Contact and Isolation: A Novel Depression/Anxiety Model

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Neuroscience Bulletin 2016年第1期32卷 92-98页

作者： Liu Yang Li-Jun Shi Bei Tang Qiu-Qin Han Jin Yu Gen-Cheng Wu Yu-Qiu Zhang Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Institute of Neurobiology Institutes of Brain Science and State Key Laboratory of Medical NeurobiologyCollaborative Innovation Center for Brain Science Liver Cancer Institute Zhongshan Hospital Shanghai Medical College Fudan University Department of integrative medicine and Neurobiology Shanghai Medical College Fudan University

To mimic human mood disorders, traditional chronic stresses and social defeat stress have been developed and widely applied. However, these active stresses do not mimic the emotional flaws induced by stresses, and their input levels vary greatly. Also, emotional stresses resulting from social unobtainability remain largely elusive due to the lack of useful animal models. In this study, we developed a mouse model named ‘‘opposite sex contact and isolation’’(OSCI) and found that OSCI induced significant social avoidance, anhedonia, and anxiety. These behavioral defects developed differently after 7 days of OSCI. The social avoidance behavior was self-curable while anxiety gradually worsened but was alleviated by re-pairing with the same female partner. Corresponding to the behavior changes, the plasma corticosterone and phosphorylated c AMP response element binding protein levels were decreased in the nucleus accumbens of the mice that experienced isolation. Together,this study has developed a novel strategy for depression/anxiety modeling and shows that OSCI may be a useful tool for studying the lovelorn/lovesick type of depression.

关键词： Social isolation Depression Anxiety Opposite sex contact Social stress Lovelorn

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