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Nanomedicine integrating the lipidic derivative of 5-fluorouracil,miriplatin and PD-L1 si RNA for enhancing tumor therapy

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Chinese Chemical Letters 2024年第6期35卷 385-391页

作者： An Lu Yuhao Guo Yi Yan Lin Zhai Xiangyu Wang Weiran Cao Zijie Li Zhixia Zhao Yujie Shi Yuanjun Zhu Xiaoyan Liu Huining He Zhiyu Wang Jian-Cheng Wang Beijing key laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China tianjin key laboratory on technologies enabling development of clinical therapeutics and diagnostics School of PharmacyTianjin Medical UniversityTianjin 300070China Department of Immuno-oncology The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050011China Department of Pharmacy Clinical Trial Research CenterChina-Japan Friendship HospitalBeijing 100029China laboratory of innovative formulations and pharmaceutical excipients Ningbo Institute of Marine MedicinePeking UniversityNingbo 315832China

Immunosuppressive microenvironments present critical problems in clinical *** regulate the tumor immune microenvironment for enhancing antitumor effect,a combination of immune checkpoint inhibitors(ICIs)with chemotherapeutics has been applied *** this study,miriplatin(MiPt),the lipidic derivative of 5-fluorouracil(Fu-OA),as well as the programmed death ligand 1(PD-L1)target si RNA(siPD-L1)were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles(NPs)for *** vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by ***,in vivo results revealed that LipPt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of Mi Pt,5-fluorouracil,and Lip@siPD-L1 NPs(delivery of siPD-L1 by liposomes).The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of Mi Pt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells,which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint *** Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.

关键词： Chemo-immunotherapy Immune checkpoint inhibition Gene silencing Miriplatin Macrophage phagocytosis Nanotechnology

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A Network Pharmacology-Based Study on Antidepressant Effect of Salicornia europaea *** with Experimental Support in Chronic Unpredictable Mild Stress Model Mice

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Chinese Journal of Integrative Medicine 2022年第4期28卷 339-348页

作者： SUN Dan-chen WANG Ran-ran XU Hao ZHU Xue-hui SUN Yan QIAO Shi-qing QIAO Wei tianjin key laboratory on technologies enabling development of clinical therapeutics and diagnostics School of PharmacyTianjin Medical UniversityTianjin300070China

Objective:To investigate the pharmacodynamic material basis,mechanism of actions and targeted diseases of Salicornia europaea L.(SE)based on the network pharmacology method,and to verify the antidepressant-like effect of the SE extract by pharmacological ***:Retrieval tools including Chinese medicine(CM),PubMed,PharmMapper,MAS 3.0 and Cytoscape were used to search the components of SE,predict its targets and related therapeutic diseases,and construct the"Component-TargetPathway"network of SE for central nervous system(CNS)***,protein-protein interaction(PPI)network,Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)function annotation of depression-related targets were analyzed to predict the antidepressant mechanism of *** unpredictable mild stress(CUMS)model was used to construct a mouse model with depression-like *** the animals were randomly divided into 6 groups(n=10)including the normal group(nonstressed mice administered with distilled water),the CUMS group(CUMS mice administered with distilled water),the venlafaxine group(CUMS mice administered with venlafaxine 9.38 mg/kg),SE high-,medium-,and low-dose groups(CUMS mice administered with SE 1.8,1.35 and 0.9 g/kg,respectively).Then some relevant indicators were determined for experimental verification by the forced swim test(FST),the tail suspension test(TST)and open-field test(OFT).Dopamine(DA)concentration in hippocampus and cerebral cortex,IL-2 and corticosterone(CORT)levels in blood,and nuclear factor E2 related factor 2(Nrf2),kelch-like epichlorohydrin related protein 1(Keap1),NAD(P)H dehydrogenase[quinone]1(NQO1)and heme oxygenase-1(HO-1)levels in mice were measured by enzyme linked immunosorbent assay(ELISA)and Western blot respectively to explore the possible ***:The"target-disease"network diagram predicted by network pharmacology,showed that the potential target of SE involves a variety of CNS diseases,among which depression ac

关键词： Salicornia europaea L. network pharmacology tail suspension test forced swim test depression

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Cell Membrane-camouflaged Multi-functional Dendritic Large Pore Mesoporous Silica Nanoparticles for Combined Photothermal Therapy and Radiotherapy of Cancer

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Chemical Research in Chinese Universities 2022年第2期38卷 562-571页

作者： WU Liting XIN Yujia GUO Zhaoyang GAO Wei ZHU Yanpeng WANG Yinsong RAN Ruixue YANG Xiaoying tianjin key laboratory on technologies enabling development of clinical therapeutics and diagnostics(Theranostics) School of PharmacyTianjin Medical UniversityTianjin 300070P.R.China

Combining photothermal therapy and radiotherapy(PTT-RT) with reducing tumor hypoxia acts as an important antitumor modality. However, it is a great challenge to realize photothermal therapy, radiotherapy and exogenous oxygen supply in one nanosystem. To realize a combination of the three functions, we fabricated a red blood cell membrane(RBCm)-camouflaged, red blood cell content(RBCc) and the copper sulfide(CuS) co-loaded dendritic large pore mesoporous silica nanoparticle(DLMSN/CuS/RBCc/ RBCm). The cell membrane coating endowed the nanoparticles with good stability in the physiological environment, and CuS allowed the nanoparticle exhibiting good photothermal and radiosensitization properties. RBCc loaded nanoparticle DLMSN/CuS/RBCc enhanced superior anti-tumor effect than DLMSN/CuS during combined PTT-RT therapy because the introduction of RBCc increased the exogenous oxygen supply. The in vitro study further demonstrated that the combination of photothermal therapy and radiotherapy induced superior antitumor efficacy than single therapy. Our work thus presents a unique multifunctional nanoscale platform favorable for combined PTT and RT.

关键词： Dendritic large pore mesoporous silica nanoparticle Photothermal therapy Radiosensitization Red blood cell membrane Oxygen carrying

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Bacterial therapy:a promising strategy for cancer immunotherapy

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Cancer Biology & Medicine 2023年第11期20卷 795-798页

作者： Yinsong Wang The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics(Theranostics)School of PharmacyTianjin Medical UniversityTianjin 300070China

Cancer immunotherapy is capable of stimulating the body's immune system to selectively attack cancer cells and has the advantages of high efficacy and low toxicity over traditional *** immunotherapies have been approved for clinical applications or clinical trials,including immune checkpoint blockade,adoptive cell therapy,recombinant cytokines,bispecific T-cell engagers,and cancer vaccines.

关键词： immunotherapy clinical cancer

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Long acting carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor resection

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Frontiers of Chemical Science and Engineering 2022年第4期16卷 536-545页

作者： Sunhui Chen Qiujun Qiu Dongdong Wang Dejun She Bo Yin Meihong Chai Huining He Dong Nyoung Heo Jianxin Wang Department of Pharmaceutics School of PharmacyFudan University&Key Laboratory of Smart Drug DeliveryMinistry of EducationShanghai 201203China Department of Radiology Huashan HospitalFudan UniversityShanghai 200040China tianjin key laboratory on technologies enabling development of clinical therapeutics and diagnostics School of PharmacyTianjin Medical UniversityTianjin 300070China Department of Dental Materials School of DentistryKyung Hee UniversitySeoul 02447Republic of Korea

Many scientific efforts have been made to penetrate the blood-brain barrier and target glioblastoma cells,but the outcomes have been *** attention should be given to local inhibition of recurrence after glioblastoma resection to meet real medical needs.A biodegradable wafer containing the chemotherapeutics carmustine(1,3-bis(2-chloroethyl)-1-nitrosourea,BCNU)was the only local drug delivery system approved for clinical glioblastoma treatment,but with a prolonged survival time of only two months and frequent side *** this study,to improve the sustained release and prolonged therapeutic effect of drugs for inhibiting tumor recurrence after tumor resection,both free BCNU and BCNU-poly(lactic-co-glycolic acid)(the ratio of lactic acid groups to glycolic acid groups is 75/25)nanoparticles were simultaneously loaded into natural extracellular matrix hydrogel from pigskin to prepare BCNU *** hydrogel was injected into the resection cavity of a glioblastoma tumor immediately after tumor removal in a fully characterized resection rat *** drugs were released instantly to kill the residual tumor cells,while drugs in nanoparticles were continuously released to achieve a continuous and effective inhibition of the residual tumor cells for 30 *** combined actions effectively restricted tumor growth in ***,this strategy of local drug implantation and delivery may provide a reliable method to inhibit the recurrence of glioblastoma after tumor resection in vivo.

关键词： BCNU glioblastoma recurrence tumor resection nanoparticles hydrogel

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Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy

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Acta Pharmaceutica Sinica B 2017年第1期7卷 27-37页

作者： Wennan Zhao Yuling Qiu Dexin Kong tianjin key laboratory on technologies enabling development of clinical therapeutics and diagnostics School of Pharmaceutical Sciences and Research Center of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China

The phosphatidylinositol 3-kinase(PI3K) pathway is frequently activated in human *** I PI3 Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate(PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate(PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin(m TOR) to play key roles in carcinogenesis. Therefore, PI3 K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3 K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3 K inhibitor for cancer therapy. Dozens of other PI3 K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3 K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers,etc. This review provides an introduction to PI3 K and summarizes key advances in the development of PI3 K inhibitors.

关键词： Phosphatidylinositol 3-kinase PI3K inhibitor Drug candidate Cancer therapy PI3K/m TOR selectivity Anticancer

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Synthesis, Crystal Structure, Magnetic Property and DFT Study of a Novel 2D Polymer [Cu(pdc)(bpy)]·H_2O

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Chinese Journal of Structural Chemistry 2014年第2期33卷 270-276页

作者：郭瑞齐西伟谢承志钟炳文刘宣文张跃宏苏娜 Hebei Provincial laboratory of Dielectric and Electrolyte Materials Northeastern University at Qinhuangdao BRANCH tianjin key laboratory on technologies enabling development of clinical therapeutics and diagnostics (Theranostics) School of Pharmacy Tianjin Medical University

A new copper complex [Cu（pdc）（bpy）]·H2 O（1, H2 pdc = 3,5-pyridinedicarboxylic acid, bpy = 2,2-bipyridine） has been solvothermally synthesized and characterized by single-crystal X-ray diffraction, elemental analysis, IR spectroscopy, UV-vis spectroscopy and magnetic measure- ments. Complex 1 crystallizes in monoclinic system, space group P21 /c, a = 10.893（2）, b = 7.3641（15）, c = 1.9921（4）, β = 92.16（3）, V = 1596.9（6）3, Dc = 1.676 g/cm3, Mr = 402.84, Z = 4, F（000） = 820, μ = 1.404 mm-1, the final R = 0.0237 and wR = 0.0693. The Cu（II） ion is five-coordinated by two O atoms from two pdc ligands, one N atom from another pdc ligand and two N atoms from the bpy ligand. The pdc anion, which acts as a tridentate ligand, links three Cu ions, forming（3,3）-connected two-dimensional（2D） sheets. We also studied the electronic structure and orbital energies of complex 1 by DFT methods, and the results are consistent with UV-vis spectrum.

关键词： pyridinedicarboxylic acid solvothermal synthesis,2D structure UV-vis magnetic properties

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development of an LC–MS/MS method for the quantitation of deoxyglycychloxazol in rat plasma and its application in pharmacokinetic study

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Journal of Pharmaceutical Analysis 2016年第3期6卷 184-189页

作者： Rongshan Li Ruixue Ran Quansheng Li Yurong Huang Yuan Gu Duanyun Si tianjin key laboratory on technologies enabling development of clinical therapeutics and diagnostics (Theranostics) School of Pharmacy Tianjin Medical University State key laboratory of Drug Delivery Technology and Pharmacokinetics Tianjin Institute of Pharmaceutical Research

Deoxyglycychloxazol （TY501） is a glycyrrhetinic acid derivative which exhibits high anti-inflammatory activity and reduced pseudoaldosteronism compared to glycyrrhetinic acid. In this study, a sensitive and rapid liquid chromatography-tandem mass spectrometry （LC-MS/MS） method was established for the quantitation of TY501 in rat plasma. Plasma samples were treated by precipitating protein with methanol and supernatants were separated by a Symmetry C8 column with the mobile phase consisting of methanol and 10 mM ammonium formate （containing 0.1% of formic acid）（90：10, v/v）. The selected reaction monitoring （SRM） transitions were performed at m/z 647.4→191.2 for TY501 and m/z 473.3→143.3 for astragaloside aglycone （IS） in the positive ion mode with atmospheric pressure chemical ionization （APCI） source. Calibration curve was linear over the concentration range of 5-5000 ng/mL. The lower limit of quantification was 5 ng/mL. The mean recovery was over 88%. The intra- and inter-day precisions were lower than 6.0% and 12.8%, respectively, and the accuracy was within ± 1.3%. TY501 was stable under usual storage conditions and handling procedure. The validated method has been successfully applied to a pharmacokinetic study after oral administration of TY501 to rats at a dosage of 10 mg/kg.

关键词： Deoxyglycychloxazol (TY501) LC-MS/MS APCI Pharmacokinetics Rat plasma

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A multifunctional nanoparticle system combines sonodynamic therapy and chemotherapy to treat hepatocellular carcinoma

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Nano Research 2017年第3期10卷 834-855页

作者： Yang Liu Guoyun Wan Hua Guo Yuanyuan Liu Ping Zhou Hemei wang Dan Wang Sipei Zhang Yinsong Wang Ning Zhang Cancer Institute and Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Medical University Tianjin 300060 China Research Center of Basic Medical Science & School of Pharmacy Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics) Tianjin Medical University Tianjin 300070 China

Hepatocellular carcinoma （HCC） is one of the most common and deadly malignancies worldwide. To date, the survival of patients with HCC has not improved because of the insensitivity of HCC to conventional treatments. Sonodynamic therapy （SDT） is a promising new approach that shows remarkable potential in the treatment of HCC. Here, we designed a simple, biocompatible, and multifunctional nanosystem that combines SDT and chemotherapy to treat HCC. This nanosystem, called HPDF nanoparticles, had a core-shell structure in which hematoporphyrin （HP） was complexed with doxorubicin （DOX） to form the hydrophobic core and the surface was coated with Pluronic F68 to form the hydrophilic shell. In HCC cells, HPDF nanoparticles in combination with ultrasonic irradiation （1.0 MHz, 1.5 W/cm2, 30 s） exhibited potent cytotoxicity, resulting from the synergistic effects of a large amount of reactive oxygen species generated from HP and DOX-induced DNA damage. Notabl~ HPDF nanoparticles in combination with ultrasonic irradiation significantly reversed drug resistance in Nanog-positive cancer stem cells （CSCs） in HCC. In nude mice bearing HCC tumors, HPDF nanoparticles efficiently accumulated in the tumors and reached the maximum levels within 6-8 h, post intravenous injection. HPDF nanoparticles, in combination with ultrasonic irradiation （1.0 MHz, 3 W/cm2, 5 min）, suppressed tumor growth, angiogenesis, and collagen deposition, considerably. In summary, our results show that HPDF nanoparticles can effectively combine SDT and chemotherapy to inhibit HCC growth and progression through multiple mechanisms in both cellular and animal models.

关键词： nanoparticle sonodynamic therapy chemotherapy combination treatment hepatocellular carcinoma

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Synthesis and anti-tumor activity evaluation of novel podophyllotoxin derivatives

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Chinese Chemical Letters 2013年第1期24卷 37-40页

作者： Ting Ai Shao-Yu Shi Li-Ting Chen Ling Li Bo Cao Ying Gao Hong Chen Jing Zhou tianjin key laboratory on technologies enabling development of clinical therapeutics and diagnostics School of PharmacyTianjin Medical University tianjin key laboratory for Biomarkers of Occupational and Environmental Hazard Department of PharmacognosyLogistics University of Chinese People's Armed Police Forces

In order to investigate the effects on the cytotoxicity of indole-3-oxalylamino podophyllotoxin analogs, seven novel podophyllotoxin derivatives were synthesized. The compounds were tested against Hela, K562 or K562/A02 cancer cells in vitro, four of which showed significant cytotoxicity. Among them 9a, 9b and 9c were superior to the positive control VP-16.

关键词： Podophyllotoxin C4-N-substitution Indole Cytotoxicity

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