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Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides

Acta Pharmaceutica Sinica B 2016年第4期6卷 352-358页

作者： Tingting Lin Ergang liu Huining He Meong Cheol Shin Cheol Moon Victor C.Yang yongzhuo Huang Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis School of Pharmacy Tianjin Medical University Shanghai Institute of Materia Medica Chinese Academy of Sciences College of Pharmacy The University of Michigan College of Pharmacy and Research Institute of Pharmaceutical Sciences Gyeongsang National University College of Pharmacy Sunchon National University

Brain delivery of macromolecular therapeutics (e.g., proteins) remains an unsolved problem because of the formidable blood brain bather (BBB). Although a direct pathway of nose-to-brain transfer provides an answer to circumventing the BBB and has already been intensively investigated for brain delivery of small drugs, new challenges arise for intranasal delivery of proteins because of their larger size and hydrophilicity. h order to overcome the bathers and take advantage of available pathways (e.g., epithelial tight junctions, uptake by olfactory neurons, transport into brain tissues, and intra-brain diffusion), a low molecular weight protamine (LMWP) cell-penetrating peptide was utilized to facilitate nose-to-brain transport. Cell-penetrating peptides (CPP) have been widely used to mediate macromolecular delivery through many kinds of biobarriers. Our results show that conjugates of LMWP proteinsare able to effectively penetrate into the brain after intranasal administration. The CPP-based intranasal method highlights a promising solution for protein therapy of brain diseases. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

关键词： Intranasal protein delivery Brain targeting Cell-penetrating peptide Low molecular weigh protamine Blood brain barrier

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Coverage of 13-Valent Pneumococcal Conjugate Vaccine Among Children 0–15 Months of Age—9 Provinces,China,2019–2021

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China CDC weekly 2023年第17期5卷 379-384页

作者： Lijun liu Zhaonan Zhang Xixi Zhang Changsha Xu Yifan Song Li Li Jiakai Ye Zhiguo Wang Hui Liang Weiyan Zhang Ling Lin Ning Li Shujun Zhang Qianli Ma Wen Du yongzhuo Jiao Lingsheng Cao Qi Qi Lei Cao Wenzhou Yu Sichuan Center for Disease Control and Prevention Chengdu CitySichuan ProvinceChina National Immunization Program Chinese Center for Disease Control and PreventionBeijingChina Suqian Center for Disease Control and Prevention Suqian CityJiangsu ProvinceChina Jiangsu Center for Disease Control and Prevention Nanjing CityJiangsu ProvinceChina Zhejiang Center for Disease Control and Prevention Hangzhou CityZhejiang ProvinceChina Shandong Center for Disease Control and Prevention Jinan CityShandong ProvinceChina Anhui Center for Disease Control and Prevention Hefei CityAnhui ProvinceChina Hubei Center for Disease Control and Prevention Wuhan CityHubei ProvinceChina Hunan Center for Disease Control and Prevention Changsha CityHunan ProvinceChina Guizhou Center for Disease Control and Prevention Guiyang CityGuizhou ProvinceChina Gansu Center for Disease Control and Prevention Lanzhou CityGansu ProvinceChina

Summary What is already known on this topic?Limited data exist regarding the coverage of the 13-valent pneumococcal conjugate vaccine(PCV13)in China.A lack of official statistics,coupled with an insufficient body of published literature,hinders the accurate depiction of the current *** is added by this report?This study investigated the utilization of PCV13 and estimated its coverage in nine provinces across eastern,central,and western China between 2019 and *** an annual increase in PCV13 usage during this period,the overall coverage remained suboptimal.

关键词： spite coverage hinder

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我国畜禽粪便综合利用途径研究

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河南科技学院学报（自然科学版） 2017年第1期45卷 20-24页

作者：王森焦瑞峰马艳华刘永卓郭彦玲任秀娟吴大付河南科技学院资源与环境学院河南新乡453003

畜禽养殖产业为我国农村经济的重要支柱产业.但随着畜禽养殖的规模化、产业化发展,带来的排泄粪便及污水的污染问题备受世人关注,现在更是成为农业面源污染和农村环境污染的主要污染源.分析了粪便排泄对水源、空气质量、土壤环境等各个... 详细信息

畜禽养殖产业为我国农村经济的重要支柱产业.但随着畜禽养殖的规模化、产业化发展,带来的排泄粪便及污水的污染问题备受世人关注,现在更是成为农业面源污染和农村环境污染的主要污染源.分析了粪便排泄对水源、空气质量、土壤环境等各个方面的影响,针对畜禽粪便污染问题提出了将畜禽粪便资源化的治理建议,并指出了畜禽粪便利用中存在的问题以供参考和借鉴.

关键词：畜禽粪便污染资源化治理对策

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河南省中低产田的成因分析及肥力提升对策

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河南科技学院学报（自然科学版） 2016年第5期44卷 12-16页

作者：马艳华焦瑞峰任秀娟刘永卓郭彦玲王森吴大付河南科技学院河南新乡453003

根据中低产田的定义,总结了河南省中低产田的分布和面积.河南省中低产田主要集中在豫西和豫南,两者占河南省中低产田面积的59.61%.豫西中低产田占耕地面积的比例最大,占比达到75.85%,其次是豫南,为72.49%.分析了河南省中低产田的形成原... 详细信息

根据中低产田的定义,总结了河南省中低产田的分布和面积.河南省中低产田主要集中在豫西和豫南,两者占河南省中低产田面积的59.61%.豫西中低产田占耕地面积的比例最大,占比达到75.85%,其次是豫南,为72.49%.分析了河南省中低产田的形成原因,主要包括耕地位置的不同造成的农作制度差异化、土地使用及流转政策等.提出了利用土地整理、种植—养殖—沼气三位一体、秸秆还田、农耕技术推广等措施全面提高河南中低产田生产力.

关键词：河南省中低产田成因肥力提升

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Improved method for synthesis of low molecular weight protamine–siRNA conjugate

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Acta Pharmaceutica Sinica B 2018年第1期8卷 116-126页

作者： Zhili Yu Junxiao Ye Xing Pei Lu Sun Ergang liu Jianxin Wang yongzhuo Huang Seung Jin Lee Huining He Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of PharmacyTianjin Medical University College of Pharmacy Tsinghua University Collaborative Innovation Center of Chemical Science and Chemical Engineering and Technology Tianjin University Key Laboratory of Smart Drug Delivery Ministry of Education & PLA Department of Pharmaceutics School of Pharmacy Fudan University Ministry of Education & PLA Shanghai Institute of Materia Medica Chinese Academy of Sciences Department of Pharmacy Ewha Womans University Seodaemun-gu

RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides(CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine(LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation.

关键词： Cell penetrating peptide siRNA Conjugate Conjugation yield Biomimetic delivery Crosslinker

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Tat-functionalized Ag-Fe_3O_4 nano-composites as tissue-penetrating vehicles for tumor magnetic targeting and drug delivery

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Acta Pharmaceutica Sinica B 2018年第6期8卷 956-968页

作者： Ergang liu Meng Zhang Hui Cui Junbo Gong yongzhuo Huang Jianxin Wang Yanna Cui Weibing Dong Lu Sun Huining He Victor C.Yang State Key Laboratory of Chemical Engineering School of Chemical Engineering and Technology Tianjin University Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis School of Pharmacy Tianjin Medical University Shanghai Institute of Materia Medica Chinese Academy of Sciences Department of Pharmaceutics School of Pharmacy Fudan University & Key Laboratory of Smart Drug Delivery Ministry of Education Department of Pharmaceutical Sciences College of Pharmacy University of Michigan

In this paper, we prepared a dual functional system based on dextrin-coated silver nanoparticles which were further attached with iron oxide nanoparticles and cell penetrating peptide(Tat), producing Tat-modified Ag-Fe_3O_4 nanocomposites(Tat-FeAgNPs). To load drugs, an –SH containing linker, 3-mercaptopropanohydrazide, was designed and synthesized. It enabled the silver carriers to load and release doxorubicin(Dox) in a pH-sensitive pattern. The delivery efficiency of this system was assessed in vitro using MCF-7 cells, and in vivo using null BalB/c mice bearing MCF-7 xenograft tumors. Our results demonstrated that both Tat and externally applied magnetic field could promote cellular uptake and consequently the cytotoxicity of doxorubicin-loaded nanoparticles,with the IC_(50) of Tat-FeAgNP-Dox to be 0.63 mmol/L. The in vivo delivery efficiency of Tat-FeAgNP carrying Cy5 to the mouse tumor was analyzed using the in vivo optical imaging tests, in which TatFeAgNP-Cy5 yielded the most efficient accumulation in the tumor(6.772.4% ID of Tat-FeAgNPs).Anti-tumor assessment also demonstrated that Tat-FeAgNP-Dox displayed the most significant tumor-inhibiting effects and reduced the specific growth rate of tumor by 29.6%(P ? 0.009), which could be attributed to its superior performance in tumor drug delivery in comparison with the control nanovehicles.

关键词： Cell penetrating peptide Tat Silver nanoparticles Magnetic targeting Fe3O4 Hydrazone bond

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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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SrMAlO_(4)(M=La、Y)掺杂BNT基无铅压电陶瓷的结构与电致应变性能研究

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功能材料 2022年第3期53卷 3146-3152页

作者：赵桂媛王娣刘润政郑永卓吕蓉娜郝继功李伟聊城大学材料科学与工程学院山东聊城252059

近年来,钛酸铋钠(BNT)基压电陶瓷材料因其独特的场致相变效应表现出巨大电致应变响应,并在驱动器方面展现出巨大应用潜力。采用传统固相合成工艺制备了具有优异电致应变性能和温度稳定性的(Bi_(0.5)Na_(0.5))_(0.935)Ba_(0.065)TiO_(3)-... 详细信息

近年来,钛酸铋钠(BNT)基压电陶瓷材料因其独特的场致相变效应表现出巨大电致应变响应,并在驱动器方面展现出巨大应用潜力。采用传统固相合成工艺制备了具有优异电致应变性能和温度稳定性的(Bi_(0.5)Na_(0.5))_(0.935)Ba_(0.065)TiO_(3)-xSrMAlO_(4)(xSrMAlO_(4),M=La、Y)系无铅压电陶瓷材料,并研究了SrMAlO_(4)(M=La、Y)组元对陶瓷相结构及电性能的影响。SrMAlO_(4)组元的引入促使陶瓷的相结构由三方-四方共存相向单一伪立方相转变,并破坏了基体材料的铁电有序性,诱导出弱极性相,进而大幅度提高了材料的电致应变性能。当SrMAlO_(4)掺杂含量为0.9%(摩尔分数)时,材料获得了最佳的电致应变性能:70 kV/cm电场下,其单向应变值分别为0.39%(M=La)和0.44%(M=Y),对应大信号d_(33)^(*)常数分别为557 pm/V(M=La)和629 pm/V(M=Y),高应变响应来源于电场驱动下弱极性态到铁电态的转变。此外发现,经0.9%(摩尔分数)SrMAlO_(4)(M=Y)改性的陶瓷材料在室温至100℃之间表现出优异的温度稳定性,在驱动器等器件方面展现出良好的应用潜力。

关键词：无铅压电陶瓷钛酸铋钠相结构电致应变

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基坑局部堆载回压对下卧隧道隆起影响

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湖南科技大学学报（自然科学版） 2020年第1期35卷 49-55页

作者：肖勇卓刘刚中国矿业大学力学与土木工程学院江苏徐州221116 中国矿业大学深部岩土力学与地下工程国家重点实验室江苏徐州221116

为在有下卧隧道的基坑开挖过程中实现及时有效的控制隧道隆起,本文提出局部临时堆载措施,并根据Mindlin公式采用MATLAB软件分析局部堆载的3项参数即堆载力、堆载面积和堆载位置对附加应力的影响,基于某基坑案例采用FLAC3D软件进行正交... 详细信息

为在有下卧隧道的基坑开挖过程中实现及时有效的控制隧道隆起,本文提出局部临时堆载措施,并根据Mindlin公式采用MATLAB软件分析局部堆载的3项参数即堆载力、堆载面积和堆载位置对附加应力的影响,基于某基坑案例采用FLAC3D软件进行正交模拟验证.结果表明,堆载力对隧道隆起影响最大,堆载面积次之,堆载位置最小.隧道隆起值随堆载力增大呈比例减小,并随堆载面积增加而逐渐减小,减小幅度逐渐减缓,且随堆载中心与隧道轴线距离缩短,其影响程度逐渐增大.在实际工程中,优先考虑预留合适尺寸的土体并施加堆载作为局部堆载措施.当隧道位于基坑下部时,局部堆载力不得少于原有土体自重的50%,堆载面积应大于基坑总面积的5%;当隧道位于基坑侧面时,局部堆载力不得少于原有土体自重的1倍,堆载面积应大于基坑总面积的7.5%,才能有效控制隧道沉降.

关键词：下卧隧道隧道隆起局部堆载堆载力堆载面积堆载位置

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围岩松动圈理论计算方法的评述与展望

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煤炭学报 2021年第1期46卷 46-56页

作者：刘刚肖勇卓朱俊福靖洪文中国矿业大学力学与土木工程学院江苏徐州221116 中国矿业大学深部岩土力学与地下工程国家重点实验室江苏徐州221008

研究围岩松动圈的目的是指导地下工程的设计与施工,相比于现场实测和数值模拟分析,理论计算围岩松动圈更为方便快捷。综述了2种主要的松动圈理论计算方法——强度准则法和数学模型法。强度准则法以Mohr-Coulomb准则、Hoek-Brown准则和Dr... 详细信息

研究围岩松动圈的目的是指导地下工程的设计与施工,相比于现场实测和数值模拟分析,理论计算围岩松动圈更为方便快捷。综述了2种主要的松动圈理论计算方法——强度准则法和数学模型法。强度准则法以Mohr-Coulomb准则、Hoek-Brown准则和Druker-Prager准则为主,普遍经塑性区半径推导、松动区与塑性区界分和岩石强度参数修正可得到较准确的松动圈半径,其关键在于松动区的边界条件和岩石软化方法,并建议以应力梯度作为边界条件和以参数反演修正岩石参数进行计算,同时也简要评述了以动静力学思路和统一强度准则为基础的松动圈计算。数学模型法主要是基于对松动圈影响因素的研究,常采用神经网络模型和支持向量机模型,以及未确知聚类模型和多元回归函数拟合等,其关键在于松动圈影响因素的选择和建模选型。松动圈影响因素选择的重点在于次要因素,而建模选型在于引入其他模型对原有模型的核心元素进行寻优。建议应因地制宜地选择影响因素或引入灰色预测模型,同时必须经本地数据库训练修正后使模型达到最佳。实际工程中,由于强度准则法基于均质岩体中静水应力作用下的圆形巷道模型,巷道半径和侧应力系数取值及岩性不均一将会严重影响计算精度;数学模型法受制于影响因素考虑不足及现有数据库噪声等条件而难以提高预测精度。结合围岩松动圈实测技术,由于受众多因素影响,巷道同一横断面内、同一巷道相邻地段的松动圈均在一定范围内波动,故任何非实测方法均不能精确预测松动圈厚度。在工程应用中,不主张在难以符合强度准则法的假设条件或者数学模型中未知的次要因素影响较大的条件下采用计算的方法确定松动圈厚度。后续研究可从新强度准则推导或多个单预测模型相结合与数据等维等方面进行,同时应关注在深部多种地质条件下松动圈的理论计算以及矩形和其它非规则形状巷道松动圈的理论计算,并提高预测精度。

关键词：围岩松动圈强度准则法数学模型法预测精度实测方法

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