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Hyperthermia based individual in situ recombinant vaccine enhances lymph nodes drainage for de novo antitumor immunity

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3398-3409页

作者： Cuixia Zheng Xinxin Liu Yueyue Kong Lei Zhang qingling song Hongjuan Zhao Lu Han Jiannan Jiao Qianhua Feng Lei Wang Luoyang Central Hospital Affiliated to Zhengzhou University Luoyang 471009China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Key Laboratory of Advanced Drug Preparation Technologies Ministry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhou 450001China Department of Gynecology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000China Tumor Immunity and Biomaterials Advanced Medical Center Zhengzhou UniversityLuoyang 471009China

The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes(LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin(SV) adjuvant loaded Au nanocages(AuNCs)as cores(AuNCs/SV) and folic acid modified thermal-sensitive liposomes(FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy(PTT) induced the release of tumor-derived protein antigens(TDPAs) and the shedding of FATSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine(AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.

关键词： Au nanocages Simvastatin Photothermal therapy Tumor-derived protein antigens Recombinant vaccine Tumor targeting Lymph node drainage De novo antitumor immunity

Orchestrating antigen delivery and presentation efficiency in lymph node by nanoparticle shape for immune response

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Acta Pharmaceutica Sinica B 2023年第9期13卷 3892-3905页

作者： Hongjuan Zhao Yatong Li Beibei Zhao Cuixia Zheng Mengya Niu qingling song Xinxin Liu Qianhua Feng Zhenzhong Zhang Lei Wang School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Luoyang Central Hospital Affiliated to Zhengzhou University Luoyang 471009China Key Laboratory of Advanced Pharmaceutical Technology Ministry of Education of ChinaZhengzhou UniversityZhengzhou 450001China Biotherapy Center the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Tumor Immunity and Biomaterials Advanced Medical Center Zhengzhou UniversityLuoyang 471009China

Activating humoral and cellular immunity in lymph nodes(LNs)of nanoparticle-based vaccines is critical to controlling ***,how the physical properties of nanovaccine carriers orchestrate antigen capture,lymphatic delivery,antigen presentation and immune response in LNs is largely ***,we manufactured gold nanoparticles(AuNPs)with the same size but different shapes(cages,rods,and stars),and loaded tumor antigen as nanovaccines to explore their disparate characters on above four *** revealed that star-shaped AuNPs captured and retained more repetitive antigen *** lymphatic delivery,both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention.A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity,which is mediated by CD4^(+)T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic ***,cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8^(+)T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor *** results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs,and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.

关键词： Nanovaccines Nanoparticle shape Lymph node Antigen capture Lymphatic delivery Antigen presentation Humoral immunity Cellular immunity

Colon-specific controlled release of oral liposomes for enhanced chemo-immunotherapy against colorectal cancer

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Acta Pharmaceutica Sinica B 2024年第11期14卷 4977-4993页

作者： Mengya Niu Yihan Pei Tiantian Jin Junxiu Li Liming Bai Cuixia Zheng qingling song Hongjuan Zhao Yun Zhang Lei Wang School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment Zhengzhou 450001China Henan University Huaihe HospitalTranslational Medicine CenterKaifeng 475000China

A colon-specific drug delivery system has great potential for the oral administration of colorectal ***,the uncontrollable in vivo fate of liposomes makes their effectiveness for colonic location,and intratumoral accumulation remains ***,an oral colon-specific drug delivery system(CBS-CS@Lipo/Oxp/MTZ)was constructed by covalently conjugating Clostridium butyricum spores(CBS)with drugs loaded chitosan(CS)-coated liposomes,where the model chemotherapy drug oxaliplatin(Oxp)and anti-anaerobic bacteria agent metronidazole(MTZ)were *** oral administration,CBS germinated into Clostridium butyricum(CB)and colonized in the *** with colonic specificallyβ-glucosidase responsive degrading of CS,dual colon-specific release of liposomes was *** the accumulation of liposomes at the CRC site furtherly increased by ***,the released liposomes penetrated deep tumor tissue via the permeation enhancement effect of CS to kill localized intratumoral *** with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB,the intratumoral pathogenic bacteria were eliminated fundamentally,blocking their recruitment to immunosuppressive ***,synchronized with lipopolysaccharide(LPS)released from MTZ-induced dead Fusobacterium nucleatum and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells,they jointly enhanced tumor infiltration of CD8^(+)T cells and reactivated robust antitumor immunity.

关键词： Colorectal cancer Colon-specific delivery Oral liposomes Oxaliplatin Intratumoral bacteria Chemo-immunotherapy Clostridium butyricum spores Gut microbiota

A biomimetic spore nanoplatform for boosting chemodynamic therapy and bacteria-mediated antitumor immunity for synergistic cancer treatment

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Asian Journal of Pharmaceutical Sciences 2024年第3期19卷 102-114页

作者： Cuixia Zheng Lingling Sun Hongjuan Zhao Mengya Niu Dandan Zhang Xinxin Liu qingling song Weijie Zhong Baojin Wang Yun Zhang Lei Wang School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Huaihe Hospital of Henan University Translational medicine CenterKaifeng 475000China Pingyuan Lab Henan Normal UniversityXinxiang 453007China Gynecology the Third Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Weihai Municipal Hospital Cheeloo College of MedicineShandong UniversityWeihai 264200China

Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting ***,the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial ***,monotherapy is ineffective in completely eliminating complex cancer with multiple contributing *** this study,based on our discovery that spore shell(SS)of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity,we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy,chemodynamic therapy and antitumor immunity for synergistic cancer *** detail,SS is separated from probiotic spores and then attached to the surface of liposome(Lipo)that was loaded with hemoglobin(Hb),glucose oxidase(GOx)and JQ1to construct SS@Lipo/Hb/GOx/*** tumor tissue,highly toxic hydroxyl radicals(·OH)are generated via sequential catalytic reactions:GOx catalyzing glucose into H_(2)O_(2)and Fe^(2+)in Hb decomposing H_(2)O_(2)into·*** combination of·OH and SS adjuvant can improve tumor immunogenicity and activate immune ***,JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune *** this manner,SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and *** summarize,the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.

关键词： Biomimetic spore shell Bacteria-mediated antitumor therapy Chemodynamic therapy Immunotherapy Tumor microenvironment

酰胺质子转移加权成像联合动态对比增强MRI定量参数术前评估子宫内膜癌人表皮生长因子受体2基因表达的价值

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中华放射学杂志 2024年第6期58卷 620-626页

作者：马长军田士峰宋庆玲陈丽华王楠宋清伟刘爱连大连医科大学附属第一医院放射科大连116011

目的探讨酰胺质子转移加权(APTw)成像和动态对比增强(DCE)MRI的定量参数术前评估子宫内膜癌(EC)人表皮生长因子受体2(Her-2)基因表达的价值。方法该文为诊断性试验研究。回顾性收集2019年8月至2023年8月在大连医科大学附属第一医院经病... 详细信息

目的探讨酰胺质子转移加权(APTw)成像和动态对比增强(DCE)MRI的定量参数术前评估子宫内膜癌(EC)人表皮生长因子受体2(Her-2)基因表达的价值。方法该文为诊断性试验研究。回顾性收集2019年8月至2023年8月在大连医科大学附属第一医院经病理证实的68例EC患者,根据术后Her-2基因表达结果分为Her-2阳性组(33例)和Her-2阴性组(35例)。基于APTw和DCE-MRI序列,分别获得病变部位的APTw定量参数不对称性磁化转移率(MTR_(asym))和DCE-MRI定量参数容积转移常数(K^(trans))、血浆容积分数(Vp)、血管外细胞外空间容积分数(Ve)和速率常数(Kep)。2组间各定量参数比较采用独立样本t检验或Mann-Whitney U检验,通过logistic回归分析获得EC Her-2基因表达的独立预测因素,使用二元logistic回归分析基于2组间差异有统计学意义的参数构建诊断模型。采用受试者操作特征曲线评价预测EC Her-2基因表达的效能,采用DeLong检验比较曲线下面积(AUC)的差异。结果Her-2阳性组与Her-2阴性组EC患者间MTR_(asym)、K^(trans)和Ve差异有统计学意义(Z=2.55,P=0.011;t=-2.03,P=0.047;t=-2.13,P=0.037),Vp和Kep差异无统计学意义(Z=0.58,P=0.560;Z=0.19,P=0.849)。MTR_(asym)为EC Her-2基因表达的独立预测因子(OR=1.016,95%CI 1.003~1.030,P=0.014)。MTR_(asym)、K^(trans)、Ve及三者联合建立的诊断模型评估EC Her-2基因表达的AUC(95%CI)分别为0.680(0.551~0.808)、0.623(0.485~0.760)、0.656(0.523~0.789)、0.745(0.625~0.864)。诊断模型的AUC与MTR_(asym)、K^(trans)及Ve的AUC差异无统计学意义(Z=1.40、1.92、1.37,P=0.163、0.055、0.171)。结论APTw和DCE-MRI序列定量参数可从不同角度评估EC Her-2基因表达,MTR_(asym)是Her-2基因表达的独立预测因子。

关键词：子宫内膜肿瘤磁共振成像酰胺质子转移加权成像人表皮生长因子受体2

脑血管疾病诊断中血浆同型半胱氨酸水平测定的应用价值研究

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实用心脑肺血管病杂志 2020年第S02期28卷 73-75页

作者：宋清玲林洁临潼康复疗养中心检验病理科陕西省西安市710600

目的探究心脑血管疾病诊断中测定血浆同型半胱氨酸(Hcy)水平的临床价值。方法选择2017年6月—2019年6月临潼康复疗养中心100例心脑血管疾病患者,将其中50例冠心病患者作为试验组1,另50例脑梗死患者作为试验组2,同期选择50例健康体检志... 详细信息

目的探究心脑血管疾病诊断中测定血浆同型半胱氨酸(Hcy)水平的临床价值。方法选择2017年6月—2019年6月临潼康复疗养中心100例心脑血管疾病患者,将其中50例冠心病患者作为试验组1,另50例脑梗死患者作为试验组2,同期选择50例健康体检志愿者作为对照组,对试验组1与试验组2患者采取常规治疗,比较对照组、治疗前试验组与试验组Hcy水平以及治疗后试验组和试验组Hcy水平变化。结果治疗前,试验组1Hcy(28.43±4.80)μmol/L、试验组2(27.85±2.30)μmol/L与对照组(10.34±1.05)μmol/L比较,差异有统计学意义(t=26.0335,P0.05);治疗后,试验组1Hcy(12.52±1.73)μmol/L与治疗前(28.43±4.80)μmol/L及试验组2治疗后Hcy(12.40±1.65)μmol/L与治疗前(27.85±2.30)μmol/L比较,差异均有统计学意义(t=22.0493,P<0.05;t=38.5949,P<0.05)。结论Hcy水平测定用于心脑血管疾病诊断中可行性高,能反映患者病情及治疗好转状态,能为心脑血管疾病的诊治提供可靠参考,建议进一步推广。

关键词：心脑血管疾病诊断价值同型半胱氨酸临床检测

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D-半乳糖诱导的小鼠耳蜗带状突触损伤

中华耳科学杂志 2019年第2期17卷 154-158页

作者：杜政德宋青玲韩曙光柳柯龚树生首都医科大学附属北京友谊医院耳鼻咽喉科北京100050 中国航天科工集团731医院耳鼻咽喉科北京100074

目的研究D-半乳糖诱导的衰老小鼠耳蜗带状突触数量的变化。方法 1)D-半乳糖诱导的衰老小鼠模型的构建:24只5周龄雄性C57BL/6J小鼠适应性喂养1周后随机分为2组(每组12只):①对照组:小鼠颈背部皮下注射同体积的生理盐水,每日1次,连续6周;... 详细信息

目的研究D-半乳糖诱导的衰老小鼠耳蜗带状突触数量的变化。方法 1)D-半乳糖诱导的衰老小鼠模型的构建:24只5周龄雄性C57BL/6J小鼠适应性喂养1周后随机分为2组(每组12只):①对照组:小鼠颈背部皮下注射同体积的生理盐水,每日1次,连续6周;②D-半乳糖组:小鼠颈背部皮下注射1000mg/kg D-半乳糖,每日1次,连续6周;2)ABR检测听小鼠听功能;3)免疫组织化学染色检测小鼠耳蜗线粒体DNA氧化损伤产物8-羟基-2-脱氧鸟苷(8-hydroxy-2-deoxyguanosine, 8-OHdG)的表达;4)免疫组织化学染色检测小鼠耳蜗带状突触突触前标记物CtBP2的数量;5)Western blot检测小鼠耳蜗CtBP2蛋白的表达。结果 1)D-半乳糖诱导的衰老小鼠听功能表现为ABR I波幅值的降低,而无阈值的改变;2)8-OHdG在D-半乳糖诱导的衰老小鼠耳蜗表达明显增加;3)D-半乳糖耳蜗带状突触数量明显减少;4)CtBP2蛋白在D-半乳糖诱导的衰老小鼠耳蜗表达明显减少。结论耳蜗带状突触是D-半乳糖诱导的衰老小鼠耳蜗早期出现的病变部位,D-半乳糖诱导的衰老小鼠可作为研究老年性聋耳蜗带状突触损伤的动物模型。

关键词：老年性聋带状突触线粒体DNA氧化损伤 D-半乳糖

T2 mapping联合mDixon-Quant多参数成像定量评估子宫内膜癌微卫星不稳定状态的研究

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磁共振成像 2022年第8期13卷 48-54页

作者：马长军田士峰陈丽华宋庆玲宋清伟林良杰刘爱连大连医科大学附属第一医院放射科大连116011 大连市医学影像人工智能工程技术研究中心大连116011 飞利浦(中国)投资有限公司上海200040

目的探讨T2定量成像(T2 mapping)联合魔镜成像(mDixon-Quant)的多参数成像定量评估子宫内膜癌(endometrial cancer, EC)微卫星不稳定状态(microsatellite instability, MSI)中的应用价值。材料与方法回顾性分析大连医科大学附属第一医... 详细信息

目的探讨T2定量成像(T2 mapping)联合魔镜成像(mDixon-Quant)的多参数成像定量评估子宫内膜癌(endometrial cancer, EC)微卫星不稳定状态(microsatellite instability, MSI)中的应用价值。材料与方法回顾性分析大连医科大学附属第一医院2019年6月至2021年9月经病理证实的34例EC患者的影像资料。所有患者术前两周均行3.0 T MRI检查,扫描序列包括T1WI、T2WI、T2 mapping、mDixon-Quant等。由两位观察者采用独立盲法测量病灶T2 mapping序列的T2值及mDixon-Quant序列的脂肪分数(fat fraction, FF)值、R2^(*)值、T2^(*)值。采用组内相关系数(intra-class correlation coefficient, ICC)评估两位观察者测量结果的一致性,采用独立样本t检验或Mann-Whitney U检验比较各参数值的差异,采用受试者工作特征(receiver operating characteristic, ROC)曲线评估参数预测EC MSI状态的效能。采用Delong检验比较各曲线下面积(area under the curve, AUC)间的差异性。结果两位观察者测量值的一致性均很好(ICC>0.75);MSI组的R2^(*)值及T2值均高于微卫星稳定(microsatellite stabilization, MSS)组,MSI组的T2^(*)值低于MSS组,差异均具有统计学意义(P0.05);联合参数评估EC MSI状态的AUC与单一参数评估EC MSI状态的AUC间差异有统计学意义(P<0.05)。结论 mDixon-Quant及T2 mapping多参数成像均能定量地评估EC MSI状态,两者联合可明显提升预测的效能,具有很好的临床应用前景。

关键词：子宫内膜癌微卫星不稳定 T2定量成像魔镜成像磁共振成像

c-Maf基因在小鼠耳蜗内外毛细胞中的表达及意义

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中华耳科学杂志 2018年第2期16卷 216-220页

作者：宋青玲曲腾飞张伟于树夔何志洲龚树生首都医科大学附属友谊医院耳鼻咽喉头颈外科北京100050 Creighton大学医学院生物医学研究所美国奥马哈ne68178

目的研究c-Maf基因在小鼠耳蜗内、外毛细胞中的表达、分布特点及意义。方法 1)根据形态上的差异分离收集成年小鼠内、外毛细胞,利用Microarray基因芯片技术分别检测内、外毛细胞c-Maf基因RNA水平的表达;2)全耳蜗基底膜铺片,免疫组织化... 详细信息

目的研究c-Maf基因在小鼠耳蜗内、外毛细胞中的表达、分布特点及意义。方法 1)根据形态上的差异分离收集成年小鼠内、外毛细胞,利用Microarray基因芯片技术分别检测内、外毛细胞c-Maf基因RNA水平的表达;2)全耳蜗基底膜铺片,免疫组织化学染色后激光共聚焦显微镜观察c-Maf蛋白在不同发育阶段小鼠耳蜗内、外毛细胞中的分布特点及表达,并使用软件Image Pro Plus进行c-Maf蛋白定量分析。结果 1)耳蜗内、外毛细胞c-Maf基因RNA水平相近;2)c-Maf蛋白主要表达于成年小鼠的耳蜗内外毛细胞胞质,在内毛细胞的核下区表达强于核上区,且在内、外毛细胞的表达强度相近;3)c-Maf蛋白在小鼠出生后0天、7天、12天及成年小鼠耳蜗内、外毛细胞稳定表达。结论 c-Maf蛋白从出生开始在小鼠耳蜗内、外毛细胞上稳定表达,且在成年小鼠内毛细胞的核下区表达较强,表明其可能在毛细胞生长发育以及功能维持中发挥重要的作用。

关键词： c-Maf 耳蜗毛细胞表达发育