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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 limited.More 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 effects.In 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 gels.The hydrogel was injected into the resection cavity of a glioblastoma tumor immediately after tumor removal in a fully characterized resection rat model.Free 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 days.These combined actions effectively restricted tumor growth in rats.Thus,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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An injectable signal-amplifying device elicits a specific immune response against malignant glioblastoma

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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 challenge.Poor immunogenicity and deficient immune infiltrates are two major limitations to an effective cancer-specific immune response.Herein,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 GBM.We demonstrated the feasibility of this strategy in two scenarios of GBM.In 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 relapse.Encouraged 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 options.In 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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Selective ischemic-hemisphere targeting Ginkgolide B liposomes with improved solubility and therapeutic efficacy for cerebral ischemia-reperfusion injury

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Asian Journal of Pharmaceutical Sciences 2023年第2期18卷 76-93页

作者： Yang Li Miaomiao Zhang Shiyi Li Longlong Zhang Jisu Kim qiujun qiu Weigen Lu Jianxin Wang Department of Pharmaceutics School of PharmacyFudan University&Key Laboratory of Smart Drug DeliveryMinistry of EducationShanghai201203China National Pharmaceutical Engineering and Research Center China State Institute of Pharmaceutical IndustryShanghai 201203China

Cerebral ischemia-reperfusion injury(CI/RI)remains the main cause of disability and death in stroke patients due to lack of effective therapeutic strategies.One of the main issues related to CI/RI treatment is the presence of the blood-brain barrier(BBB),which affects the intracerebral delivery of drugs.Ginkgolide B(GB),a major bioactive component in commercially available products of Ginkgo biloba,has been shown significance in CI/RI treatment by regulating inflammatory pathways,oxidative damage,and metabolic disturbance,and seems to be a candidate for stroke recovery.However,limited by its poor hydrophilicity and lipophilicity,the development of GB preparations with good solubility,stability,and the ability to cross the BBB remains a challenge.Herein,we propose a combinatorial strategy by conjugating GB with highly lipophilic docosahexaenoic acid(DHA)to obtain a covalent complex GB-DHA,which can not only enhance the pharmacological effect of GB,but can also be encapsulated in liposomes stably.The amount of finally constructed Lipo@GB-DHA targeting to ischemic hemisphere was validated 2.2 times that of free solution in middle cerebral artery occlusion(MCAO)rats.Compared to the marketed ginkgolide injection,Lipo@GB-DHA significantly reduced infarct volume with better neurobehavioral recovery in MCAO rats after being intravenously administered both at 2 h and 6 h post-reperfusion.Low levels of reactive oxygen species(ROS)and high neuron survival in vitro was maintained via Lipo@GB-DHA treatment,while microglia in the ischemic brain were polarized from the pro-inflammatory M1 phenotype to the tissue-repairing M2 phenotype,which modulate neuroinflammatory and angiogenesis.In addition,Lipo@GB-DHA inhibited neuronal apoptosis via regulating the apoptotic pathway and maintained homeostasis by activating the autophagy pathway.Thus,transforming GB into a lipophilic complex and loading it into liposomes provides a promising nanomedicine strategy with excellent CI/RI therapeutic efficacy and industrialization prospects.

关键词： Ginkgolide B Cerebral ischemia reperfusion injury(CI/RI) Docosahexaenoic acid Liposomes Brain targeting Microglia

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Phyto-phospholipid complexes(phytosomes): A novel strategy to improve the bioavailability of active constituents

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Asian Journal of Pharmaceutical Sciences 2019年第3期14卷 265-274页

作者： Mei Lu qiujun qiu Xiang Luo Xinrong Liu Jing Sun Cunyang Wang Xiangyun Lin Yihui Deng Yanzhi Song College of Pharmacy Shenyang Pharmaceutical UniversityShenyang110016China College of Pharmaceutical Engineering Shenyang Pharmaceutical UniversityShenyang110016China

Although active constituents extracted from plants show robust in vitro pharmacological effects, low in vivo absorption greatly limits the widespread application of these compounds. A strategy of using phyto-phospholipid complexes represents a promising approach to increase the oral bioavailability of active constituents, which is consist of ‘‘label-friendly'phospholipids and active constituents. Hydrogen bond interactions between active constituents and phospholipids enable phospholipid complexes as an integral part. This review provides an update on four important issues related to phyto-phospholipid complexes: active constituents, phospholipids, solvents, and stoichiometric ratios. We also discuss recent progress in research on the preparation, characterization, structural verification, and increased bioavailability of phyto-phospholipid complexes.

关键词： Phyto-phospholipid complexes Active constituents Hydrogen bonds Bioavailability

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Effect of Kupffer cells depletion on ABC phenomenon induced by Kupffer cells-targeted liposomes

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Asian Journal of Pharmaceutical Sciences 2019年第4期14卷 455-464页

作者： Chaoyang Lai Cong Li Mengyang Liu qiujun qiu Xiang Luo Xinrong Liu Ling Hu Yihui Deng Yanzhi Song Shenyang Pharmaceutical University

Accelerated blood clearance(ABC) phenomenon is common in many PEGylated nanocarriers, whose mechanism has not been completely elucidated yet. In this study, the correlation between Kupffer cells(KCs) and ABC phenomenon has been studied by KCs-targeted liposomes inducing ABC phenomenon and KCs depletion. In other words, the 4-aminophenyl-α-D-mannopyranoside(APM) lipid derivative DSPE-PEG 2000-APM(DPM), and 4-aminophenyl-β-L-fucopyranoside(APF) lipid derivative DSPE-PEG 2000-APF(DPF) were conjugated and modified on alendronate sodium(AD) liposomes to specifically target and deplete KCs. The dualligand modified PEGylated liposomes(MFPL) showed stronger ability to damage KCs in vitro and in vivo, which also could indirectly illustrate that dual-ligand modification could better target KCs. Besides, the hepatic biodistribution and pharmacokinetics could directly prove that MFPL had a stronger targeting ability to KCs. In addition, in depletion rats, plasma concentration and splenic biodistribution of MFPL and PEGylated liposomes(PL) were significantly elevated and hepatic biodistribution was significantly reduced, which demonstrated that KCs played an important role on elimination of nanoparticles. What’s more, ABC phenomenon of the secondary injection of PL was stronger in KCs depletion rats than that in normal rats, which indicated that depletion of KCs prolonged the circulation of PL in the first injection repeatedly stimulating B-cells in the marginal region of the spleen and causing it to secrete more IgM antibodies. This could also illustrate that anti-PEG IgM takes up a major station compared with KCs. Most important of all, KCs-targeted liposomes could induce a stronger ABC phenomenon than PL in normal rats, which declared that based on the same IgM concentration, the more the KCs were stimulated, the stronger ABC phenomenon was induced. However, in depletion rats, this difference of ABC phenomenon between PL and MFPL could no more exist, further demonstrating that KCs could participate and play a certain role

关键词： Accelerated blood clearance (ABC) phenomenon Kupffer cells Depletion Liposomes Bio-distribution

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肠造口周围潮湿相关性皮肤损伤风险预测模型的构建及应用

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中华护理杂志 2021年第11期56卷 1612-1617页

作者：刘莺歌吴燕曹秋君邱群吕桂芬徐洪莲高键复旦大学附属中山医院护理部上海市200032 复旦大学附属中山医院营养科上海市200032 海军军医大学第一附属医院肛肠外科

目的构建肠造口周围潮湿相关性皮肤损伤(peristomal moisture-associated skin damage,PMASD)风险预测模型并应用于临床,验证该模型的预测效果。方法采用前瞻性研究设计,便利选取2019年11月—2020年9月在上海市4所三级甲等医院接受肠造... 详细信息

目的构建肠造口周围潮湿相关性皮肤损伤(peristomal moisture-associated skin damage,PMASD)风险预测模型并应用于临床,验证该模型的预测效果。方法采用前瞻性研究设计,便利选取2019年11月—2020年9月在上海市4所三级甲等医院接受肠造口术的329例患者作为建模组,根据患者术后3个月内是否发生PMASD分为并发症组(141例)和非并发症组(188例),基于单因素分析、Lasso变量筛选结果构建Logistic回归预测模型。采用Hosmer-Lemeshow检验判断模型的拟合度,受试者操作特征曲线下面积检验模型的区分度,Bootstrap重抽样法进行内部验证。于2020年10月—11月选取109例患者作为验证组对模型进行外部验证。结果建模组术后3个月内PMASD发生率为42.9%(141/329),验证组为37.6%(41/109)。最终纳入模型的预测变量为性别(OR=0.497)、造口部位(OR=4.338)、造口开口高度(OR=0.304)、底盘区域手术切口(OR=3.479)、底盘贴合情况(OR=2.399)、软食(OR=3.155)、半流质饮食(OR=3.325)。Hosmer-Lemeshow检验P=0.274,受试者操作特征曲线下面积为0.812,约登指数为0.500,灵敏度为0.688,特异度为0.798。外部验证Hosmer-Lemeshow检验P=0.515,受试者操作特征曲线下面积为0.860,灵敏度为0.610,特异度为0.882。结论该研究构建的预测模型预测效能良好,可为临床护理人员筛选PMASD高风险患者提供参考。

关键词：肠造口术造口周围潮湿相关性皮肤损伤皮肤保护模型统计学护理

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超高效液相色谱-串联质谱法同时测定环境水样中的15种抗生素

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环境化学 2020年第4期39卷 1065-1074页

作者：崔敬鑫石秋俊王国民唐柏彬邱德生魏世强张进忠西南大学资源环境学院重庆市农业资源与环境重点实验室重庆400715 重庆海关技术中心重庆400020 营山县环境监测站南充637700

采用固相萃取/超高效液相色谱-串联质谱法,建立了水样中磺胺类、四环素类、氟喹诺酮类、大环内酯类和氯霉素类15种抗生素的同时测定方法.水样经HLB固相萃取柱富集,ACQUITY UPLC BEH C18色谱柱分离,以乙腈和5 mmol·L-1乙酸铵溶液(含0.1... 详细信息

采用固相萃取/超高效液相色谱-串联质谱法,建立了水样中磺胺类、四环素类、氟喹诺酮类、大环内酯类和氯霉素类15种抗生素的同时测定方法.水样经HLB固相萃取柱富集,ACQUITY UPLC BEH C18色谱柱分离,以乙腈和5 mmol·L-1乙酸铵溶液(含0.1%甲酸)为流动相梯度洗脱,电喷雾离子源-串联质谱多反应监测模式检测.结果表明,同时测定15种抗生素的线性范围为5—100μg·L-1(相关系数均大于0.997),检出限为2.1—22.0 ng·L-1,定量限为6.9—71.8 ng·L-1;空白水样在加标水平为5、10、20μg·L-1时,抗生素的回收率为50.1%—109.0%,相对标准偏差为0.4%—8.5%(n=7).用本文建立的方法检测某农业小流域环境水样,发现5类抗生素可被不同程度检出,浓度范围为0.1—106.2 ng·L-1.

关键词：抗生素同时测定固相萃取超高效液相色谱-串联质谱环境水样

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口腔黏膜给药系统研究进展

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药学进展 2018年第12期42卷 905-912页

作者：凌榕镔陈秋君邱恒涛肖裕华叶英力品药业(厦门)有限公司福建厦门361027

口腔黏膜给药使药物通过颈内静脉直接进入全身循环,避免胃肠道中的酸水解及肝脏首过效应,具有生物利用度高、患者依从性良好的优点。口腔黏膜给药的主要特点是利用生物粘附现象,即生物膜表面与天然或合成聚合物之间的界面分子粘合力现象... 详细信息

口腔黏膜给药使药物通过颈内静脉直接进入全身循环,避免胃肠道中的酸水解及肝脏首过效应,具有生物利用度高、患者依从性良好的优点。口腔黏膜给药的主要特点是利用生物粘附现象,即生物膜表面与天然或合成聚合物之间的界面分子粘合力现象,延长制剂在生物黏膜表面上的停留时间,以获得更高、更稳定的药物吸收。对口腔黏膜的结构特征、黏膜生物粘附机制、影响黏膜粘附的因素、口腔黏膜剂型设计以及口腔黏膜给药系统的研究进展进行了介绍。

关键词：口腔黏膜生物粘附机制口腔黏膜给药系统

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不同化肥减施技术对设施辣椒产量及养分吸收利用的影响

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中国农学通报 2020年第17期36卷 99-107页

作者：王秋君郭德杰马艳梁永红仇美华江苏省农业科学院农业资源与环境研究所南京210014 江苏省耕地质量与农业环境保护站南京210036

针对苏北地区设施辣椒生产中化肥施用过量的问题,在淮安市设施辣椒主产区通过连续2季的田间小区试验研究了2种化肥减施技术对辣椒产量及养分吸收利用的影响。化肥减施技术包括:以商品有机肥替代基肥化肥(OF)、追肥中施用滴灌专用水溶肥... 详细信息

针对苏北地区设施辣椒生产中化肥施用过量的问题,在淮安市设施辣椒主产区通过连续2季的田间小区试验研究了2种化肥减施技术对辣椒产量及养分吸收利用的影响。化肥减施技术包括:以商品有机肥替代基肥化肥(OF)、追肥中施用滴灌专用水溶肥以减施化肥(RD)。研究结果表明,连续2季应用化肥减施技术后,OF和RD处理的产量较常规施肥处理分别增加了12.6%和30.2%。在第一季辣椒种植中,不同处理对辣椒植株各器官中氮、磷、钾养分含量未有显著影响;在第二季OF和RD处理均显著增加了辣椒果实中氮、磷、钾含量;且OF处理茎和叶中的氮、磷、钾含量都高于其他两个处理。在两季辣椒栽培中,两种化肥减施处理的化肥总养分偏生产力都显著高于常规施肥,其中OF处理的最高。以上结果说明,在本试验条件下,通过以商品有机肥替代基肥中部分化肥或者在追肥中以滴灌方式施用专用水溶肥均可在减施化肥条件下增产。

关键词：设施辣椒化肥减施商品有机肥替代滴灌专用水溶肥养分吸收利用

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