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Overcoming oral insulin delivery barriers: application of cell penetrating peptide and silica-based nanoporous

Huining HE, Junxiao YE, Jianyong SHENG, Jianxin WANG, Yongzhuo HUANG, Guanyi CHEN, Jingkang WANG, Victor C YANG

《化学科学与工程前沿（英文）》 2013年 第7卷 第1期   页码 9-19 doi: 10.1007/s11705-013-1306-9

摘要： Oral insulin delivery has received the most attention in insulin formulations due to its high patient compliance and, more importantly, to its potential to mimic the physiologic insulin secretion seen in non-diabetic individuals. However, oral insulin delivery has two major limitations: the enzymatic barrier that leads to rapid insulin degradation, and the mucosal barrier that limits insulin’s bioavailability. Several approaches have been actively pursued to circumvent the enzyme barrier, with some of them receiving promising results. Yet, thus far there has been no major success in overcoming the mucosal barrier, which is the main cause in undercutting insulin’s oral bioavailability. In this review of our group’s research, an innovative silica-based, mucoadhesive oral insulin formulation with encapsulated-insulin/cell penetrating peptide (CPP) to overcome both enzyme and mucosal barriers is discussed, and the preliminary and convincing results to confirm the plausibility of this oral insulin delivery system are reviewed. In vitro studies demonstrated that the CPP-insulin conjugates could facilitate cellular uptake of insulin while keeping insulin’s biologic functions intact. It was also confirmed that low molecular weight protamine (LMWP) behaves like a CPP peptide, with a cell translocation potency equivalent to that of the widely studied TAT. The mucoadhesive properties of the produced silica-chitosan composites could be controlled by varying both the pH and composition; the composite consisting of chitosan (25 wt-%) and silica (75 wt-%) exhibited the greatest mucoadhesion at gastric pH. Furthermore, drug release from the composite network could also be regulated by altering the chitosan content. Overall, the universal applicability of those technologies could lead to development of a generic platform for oral delivery of many other bioactive compounds, especially for peptide or protein drugs which inevitably encounter the poor bioavailability issues.

关键词： insulin     cell penetrating peptide     mucoadhesive composites     oral delivery    

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Cationic and amphipathic cell-penetrating peptides (CPPs): Their structures and

Jennica L. Zaro,Wei-Chiang Shen

《化学科学与工程前沿（英文）》 2015年 第9卷 第4期   页码 407-427 doi: 10.1007/s11705-015-1538-y

摘要： Over the past few decades, cell penetrating peptides (CPPs) have become an important class of drug carriers for small molecules, proteins, genes and nanoparticle systems. CPPs represent a very diverse set of short peptide sequences (10?30 amino acids), generally classified as cationic or amphipathic, with various mechanisms in cellular internalization. In this review, a more comprehensive assessment of the chemical structural characteristics, including net cationic charge, hydrophobicity and helicity was assembled for a large set of commonly used CPPs, and compared to results from numerous drug delivery studies. This detailed information can aid in the design and selection of effective CPPs for use as transport carriers in the delivery of different types of drug for therapeutic applications.

关键词： cell penetrating peptides     amphipathic peptides     drug delivery    

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Multifunctional peptide conjugated amphiphilic cationic copolymer for enhancing ECs targeting, penetrating

Xinghong Duo, Lingchuang Bai, Jun Wang, Jintang Guo, Xiangkui Ren, Shihai Xia, Wencheng Zhang, Abraham Domb, Yakai Feng

《化学科学与工程前沿（英文）》 2020年 第14卷 第5期   页码 889-901 doi: 10.1007/s11705-020-1919-8

摘要： Gene therapy has drawn great attention in the treatments of many diseases, especially for cardiovascular diseases. However, the development of gene carriers with low cytotoxicity and multitargeting function is still a challenge. Herein, the multitargeting REDV-G-TAT-G-NLS peptide was conjugated to amphiphilic cationic copolymer poly( -caprolactone-co-3(S)-methyl-morpholine-2,5-dione)- -polyethyleneimine (PCLMD- -PEI) via a heterobifunctional orthopyridyl disulfide-poly(ethylene glycol)- -hydroxysuccinimide (OPSS-PEG-NHS) linker to prepare PCLMD- -PEI-PEG-REDV-G-TAT-G-NLS copolymers with the aim to develop the gene carriers with low cytotoxicity and high transfection efficiency. The multitargeting micelles were prepared from PCLMD- -PEI-PEG-REDV-G-TAT-G-NLS copolymers by self-assembly method and used to load pEGFP-ZNF580 plasmids (pDNA) to form gene complexes for enhancing the proliferation and migration of endothelial cells (ECs). The loading pDNA capacity was proved by agarose gel electrophoresis assay. These multitargeting gene complexes exhibited low cytotoxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The high internalization efficiency of these gene complexes was confirmed by flow cytometry. The results of transfection demonstrated that these multitargeting gene complexes possessed relatively high transfection efficiency. The rapid migration of ECs transfected by these gene complexes was verified by wound healing assay. Owing to ECs-targeting ability, cell-penetrating ability and nuclear targeting capacity of REDV-G-TAT-G-NLS peptide, the multitargeting polycationic gene carrier with low cytotoxicity and high transfection efficiency has great potential in gene therapy.

关键词： gene carriers     multitargeting function     ECs     transfection efficiency    

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Erratum to: Multifunctional peptide conjugated amphiphilic cationic copolymer for enhancing ECs targeting, penetrating and nuclear accumulation

Xinghong Duo, Lingchuang Bai, Jun Wang, Jintang Guo, Xiangkui Ren, Shihai Xia, Wencheng Zhang, Abraham Domb, Yakai Feng

《化学科学与工程前沿（英文）》 2021年 第15卷 第1期   页码 220-220 doi: 10.1007/s11705-020-1995-9

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Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-

Fufeng LIU,Wenjie DU,Yan SUN,Jie ZHENG,Xiaoyan DONG

《化学科学与工程前沿（英文）》 2014年 第8卷 第4期   页码 433-444 doi: 10.1007/s11705-014-1454-6

摘要： The aggregation of amyloid -protein (A ) is tightly linked to the pathogenesis of Alzheimer’s disease. Previous studies have found that three peptide inhibitors (i.e., KLVFF, VVIA, and LPFFD) can inhibit A aggregation and alleviate A -induced neurotoxicity. However, atomic details of binding modes and binding affinities between these peptide inhibitors and A have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area (MM/PBSA) analysis, we examined the effect of three peptide inhibitors (KLVFF, VVIA, and LPFFD) on their sequence-specific interactions with A and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to A , in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with A , consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and A were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modification and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against A aggregation.

关键词： Alzheimer’s disease     amyloid β-protein     peptide inhibitors     protein-protein interaction     molecular dynamics simulation    

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Cystine oligomers successfully attached to peptide cysteine-rich fibrils

Christian Bortolini,Mingdong Dong

《化学科学与工程前沿（英文）》 2016年 第10卷 第1期   页码 99-102 doi: 10.1007/s11705-016-1554-6

摘要： Amyloid peptides are renowned to be related to neurodegenerative diseases, however, a fruitful avenue is to employ them as high-performance nanomaterials. These materials benefit from the intrinsic outstanding mechanical robustness of the amyloid backbone made of -strands. In this work, we exploited amyloid-like fibrils as functional material to attach pristine L-cysteine aggregates (cystine oligomers) and gold nanoparticles, without the need of templating compounds. This work will open new avenues on functional materials design and their realisation.

关键词： cysteine     peptide fibrils     gold nanoparticles     amyloids     oligomers     nanomaterials    

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Glucagon-like peptide-2 exhibits protective effect on hepatic ischemia-reperfusion injury in rats

null

《医学前沿（英文）》 2015年 第9卷 第3期   页码 368-373 doi: 10.1007/s11684-015-0403-1

摘要：

Glucagon-like peptide-2 (GLP-2) has potent anti-inflammatory effects and protects against experimental ischemia/reperfusion (I/R) injury in pulmonary, intestinal, and myocardial tissue. However, its protective abilities against I/R injury in the liver are unknown. We investigated the potential role of GLP-2 pretreatment on hepatic I/R injury in rats. A total of 24 rats were randomly divided into three groups (n = 8). The first group was the control group; the second group was the vehicle-treated hepatic ischemia/reperfusion (HIR, vehicle saline-treated) group; and the third group was the GLP-2 pretreated I/R (GLP2-IR) group. Each rat in the third group was intraperitoneally administered 5 μg GLP-2 for 5 d before the procedure. A portal triad was created to induce ischemia with a vascular atraumatic clamp. After 40 min, the clamp was released to initiate hepatic reperfusion for 6 h. Blood samples and tissue specimens from the liver were obtained. Alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels significantly increased in the saline-treated HIR group (P<0.001), whereas GLP-2 pretreatment significantly decreased their levels (P<0.01). Our data suggested that GLP-2 pretreatment may have a protective effect on liver I/R injury. However, dose-response studies are necessary to determine the most effective dose.

关键词： ischemia/reperfusion     liver     glucagon-like peptide-2     alanine aminotransferase    

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侵地武器及其气炮实验

林俊德

《中国工程科学》 2003年 第5卷 第11期   页码 25-33

摘要：

简述了侵地武器的发展历史和现状，侵彻战斗部技术在精确制导武器中已被广泛应用，小爆炸威力侵地核武器的开发已经主要不是工程技术方面的问题；介绍了气炮实验技术及其在侵地武器研究中的应用，气炮模拟实验结果表明，岩土侵彻存在良好的力学相似关系，混凝土侵彻同花岗岩侵彻存在许多质的差异；介绍了一种通过侵深实验数据分析计算侵彻弹体加速度、速度和位移变化过程的方法。

关键词： 武器试验     岩土侵彻     气炮     撞击     实验技术    

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The role of natriuretic peptide precursor A gene polymorphism in the development of coronary heart disease

Ripen NSENGA MD, Longxian CHENG PhD, Mei’an HE PhD, Tangchun WU PhD,

《医学前沿（英文）》 2009年 第3卷 第4期   页码 437-442 doi: 10.1007/s11684-009-0074-x

摘要： Natriuretic peptide precursor A (NPPA) is synthesized, stored, and released by atrial myocytes. Previous studies have shown that NPPA plays a significant role in the regulation of coronary circulation and in atherosclerosis. Rs5065 NPPA gene polymorphism leads to the translation of NPPA with two additional arginines and has been suggested to be associated with salt-sensitive hypertension. The purpose of the present study was to investigate the relationship between the rs5065 NPPA gene polymorphism and the risk of coronary heart disease (CHD) in Chinese Han population. We genotyped the single nucleotide polymorphism (SNP) rs5065 NPPA in the human NPPA gene in 1861 sex- and age-matched subjects, comprising of 904 CHD cases and 957 controls of Chinese Han population. Genotyping of SNP was performed with Taqman SNP allelic discrimination assays by means of an ABI 7900HT. Our study showed that the frequencies of rs5065 NPPA C allele in the case and the control groups were 0.012 and 0.005, respectively. There was significant difference in C allele frequency distribution between the two groups (OR=2.607, 95% CI: 1.197−5.678, =0.012). In the case group, there was significant difference between smokers and nonsmokers with subjects carrying C allele (=0.037), and no significant difference in gender, age, fasting total cholesterol (TC), triglycerides (TG), fasting plasma glucose (FPG), body mass index (BMI), and blood pressure (BP) between the cases and the controls (>0.05). Our results suggest that the C allele of rs5065 NPPA gene polymorphism may be associated with the risk of CHD.

关键词： natriuretic peptide precursor A     coronary heart disease     gene polymorphism     allelic discrimination     polymorphism     single nucleotide    

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Significance and strategies in developing delivery systems for bio-macromolecular drugs

Huining HE, Qiuling LIANG, Meong Cheol SHIN, Kyuri LEE, Junbo GONG, Junxiao YE, Quan LIU, Jingkang WANG, Victor YANG

《化学科学与工程前沿（英文）》 2013年 第7卷 第4期   页码 496-507 doi: 10.1007/s11705-013-1362-1

摘要： Successful development of a new drug is prohibitively expensive, and is estimated to cost approximately $100–500 million US dollars for a single clinical drug. Yet, a newly developed drug can only enjoy its patent protection for 18 years, meaning that after this protected time period, any company can manufacture this product and thus the profit generated by this drug entity would reduce dramatically. Most critically, once a drug is being synthesized, its physical, chemical, and biological attributes such as bioavailability and in vivo pharmacokinetics are all completely fixed and cannot be changed. In principal and practice, only the application of an appropriately designed drug delivery system (DDS) is able to overcome such limitations, and yet the cost of developing a novel drug delivery system is less than 10% of that of developing a new drug. Because of these reasons, the new trend in pharmaceutical development has already begun to shift from the single direction of developing new drugs in the past to a combined mode of developing both new drugs and innovative drug delivery systems in this century. Hence, for developing countries with relatively limited financial resources, a smart strategic move would be to focus on the development of new DDS, which has a significantly higher benefit/risk ratio when comparing to the development of a new drug. Because of the unmatched reaction efficiency and a repetitive action mode, the therapeutic activity of a single bio-macromolecular drug (e.g., protein toxins, gene products, etc.) is equivalent to about 10 –10 of that from a conventional small molecule anti-cancer agent (e.g., doxorubicin). Hence, bio-macromolecular drugs have been recognized around the world as the future “drug-of-choice”. Yet, among the>10000 drugs that are currently available, only ~150 of them belong to these bio-macromolecular drugs (an exceedingly low 1.2%), reflecting the difficulties of utilizing these agents in clinical practice. In general, the bottleneck limitations of these bio-macromolecular drugs are two-fold: (1) the absence of a preferential action of the drug on tumor cells as opposed to normal tissues, and (2) the lack of ability to cross the tumor cell membrane. In this review, we provide strategies of how to solve these problems simultaneously and collectively via the development of innovative drug delivery systems. Since worldwide progress on bio-macromolecular therapeutics still remains in the infant stage and thus open for an equal-ground competition, we wish that this review would echo the desire to industrialized countries such as China to set up its strategic plan on developing delivery systems for these bio-macromolecular drugs, thereby realizing their clinical potential.

关键词： delivery systems     bio-macromolecular drugs     cell penetrating peptides    

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Rational Design of and Mechanism Insight into an Efficient Antifreeze Peptide for Cryopreservation

Haishan Qi,Yihang Gao,Lin Zhang,Zhongxin Cui,Xiaojie Sui,Jianfan Ma,Jing Yang,Zhiquan Shu,Lei Zhang,

《工程（英文）》 doi: 10.1016/j.eng.2023.01.015

摘要： The development of effective antifreeze peptides to control ice growth has attracted a significant amount of attention yet still remains a great challenge. Here, we propose a novel design method based on an in-depth investigation of repetitive motifs in various ice-binding proteins (IBPs) with an evolution analysis. In this way, several peptides with notable antifreeze activity were developed. In particular, a designed antifreeze peptide named AVD exhibits ideal ice recrystallization inhibition (IRI), solubility, and biocompatibility, making it suitable for use as a cryoprotective agent (CPA). A mutation analysis and molecular dynamics (MD) simulations indicated that the Thr6 and Asn8 residues of the AVD peptide are fundamental to its ice-binding capacity, while the Ser18 residue can synergistically enhance their interaction with ice, revealing the antifreeze mechanism of AVD. Furthermore, to demonstrate the cryoprotection potential of AVD, the peptide was successfully employed for the cryopreservation of various cells, which demonstrated significant post-freezing cell recovery. This work opens up a new avenue for designing antifreeze materials and provides peptide-based functional modules for synthetic biology.

关键词： Antifreeze peptides     Evolution analysis     Ice recrystallization inhibition     Molecular dynamics simulation     Cryopreservation     Synthetic biology    

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电中性固体表面上多条肽链的吸附过程——粗粒化模拟研究 Research

裘若桑, 肖杰, 陈晓东

《工程（英文）》 2020年 第6卷 第2期   页码 185-194 doi: 10.1016/j.eng.2018.12.012

摘要：

蛋白质在固体表面的吸附过程涉及诸多复杂的分子间相互作用，因此到目前为止仍然无法做到精准调控。通过模拟计算，可以获取固-液界面分子尺度的蛋白质移动机理，从而为预测蛋白质吸附和结垢现象提供可靠的理论依据。本研究通过多尺度粗粒化模型对多条疏水的丙氨酸十二肽在金表面的聚集和吸附过程进行了分析。大约有一半（46.6%）的丙氨酸十二肽可以组成聚集体。30.0%的独立肽链会被快速地吸附到固体表面。这些在表面吸附的肽链经过一段时间的爬行，其中的一些（51.0%）能与吸附在表面的或是游离在溶液中的肽链融合，从而形成吸附在表面的聚集体。这些在固-液界面吸附的肽链使得固体表面性质发生变化。这一变化可能会进一步影响之后溶液中肽链和聚集体在金表面的吸附。本研究揭示的多条肽链吸附机理有希望为进一步研究多个蛋白质分子在固体表面的吸附机理提供理论基础。

关键词： 肽链     聚集体     吸附     粗粒化计算    

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钻地武器的毁伤效应及深地下防护工程关键科学问题

范鹏贤,钱七虎,王明洋

《中国工程科学》 2013年 第15卷 第5期   页码 47-58

摘要：

防护工程是国防威慑力量的重要组成部分，具有重要的战略地位。美俄等军事大国大力发展的深钻地（核）武器已经对我国重要防护工程的生存造成了严重的威胁。本文总结了外军现役钻地（核）武器的性能指标与发展前景，对钻地武器的毁伤效应进行了评估和分析，综述了侵彻效应、爆炸成坑效应、爆炸地冲击效应等方面的研究成果。针对新时期的主要威胁，简述了提高防护工程防护能力的主要措施和技术途径，提出了主被动结合的综合防护体系、深部非线性岩体力学、摆型波与超低摩擦现象、多弹聚集打击效应等目前亟需开展研究的关键科学问题。

关键词： 钻地武器     毁伤效应     深地下     防护工程    

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复杂环境下起伏地形探地雷达逆时偏移成像 Article

John H. Bradford,Janna Privette,David Wilkins,Richard Ford

《工程（英文）》 2018年 第4卷 第5期   页码 661-666 doi: 10.1016/j.eng.2018.09.004

摘要：

探地雷达偏移成像中，基于高程静校正的基准面偏移方法对起伏地表下的复杂地层成像效果较差。为了优化成像效果，本文提出了一种基于麦克斯韦方程组二阶解耦形式的逆时偏移成像（reversetime migration，RTM）算法，该算法特点在于只需计算电场，且可直接从采集面而非基准面进行波场延拓，进而实现地形逆时偏移。数值模拟比较了高程静校正偏移方法和RTM 方法在地表起伏及速度横向变化情况下的成像效果，结果证明RTM 方法成像效果更好。为了进一步验证算法效果，利用美国犹他州珊瑚粉沙丘崎岖地形下的实测数据对两种方法进行了对比分析。研究表明，逆时偏移成像方法能够极大地提高复杂环境下探地雷达深度成像精度。

关键词： 探地雷达     逆时偏移     沙丘     振幅分析    

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大装填比弹侵彻钢筋混凝土实验研究

赵生伟,古仁红,初哲,李明

《中国工程科学》 2009年 第11卷 第8期   页码 44-47

摘要：

设计了一种薄壁弹体，采用YOUNG方程预估该弹体侵彻混凝土靶板的侵彻深度，采用SAMPLL程序预估轴向过载。运用LS-DYNA软件分析弹体的侵彻过程，对材料力学性能进行实验研究。通过在Ø130 mm气炮上的一系列弹体侵彻钢筋混凝土靶实验，考核了弹体的结构强度和侵彻深度。结果表明：弹体在低速侵彻钢筋混凝土靶板时结构不会发生破坏，300 m/s速度下具备侵彻贯穿600 mm钢筋混凝土层的能力。

关键词： 薄壁弹体     钢筋混凝土     侵彻深度    

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标题 作者 时间 类型 操作

Overcoming oral insulin delivery barriers: application of cell penetrating peptide and silica-based nanoporous

Huining HE, Junxiao YE, Jianyong SHENG, Jianxin WANG, Yongzhuo HUANG, Guanyi CHEN, Jingkang WANG, Victor C YANG

期刊论文

Cationic and amphipathic cell-penetrating peptides (CPPs): Their structures and

Jennica L. Zaro,Wei-Chiang Shen

期刊论文

Multifunctional peptide conjugated amphiphilic cationic copolymer for enhancing ECs targeting, penetrating

Xinghong Duo, Lingchuang Bai, Jun Wang, Jintang Guo, Xiangkui Ren, Shihai Xia, Wencheng Zhang, Abraham Domb, Yakai Feng

期刊论文

Erratum to: Multifunctional peptide conjugated amphiphilic cationic copolymer for enhancing ECs targeting, penetrating and nuclear accumulation

Xinghong Duo, Lingchuang Bai, Jun Wang, Jintang Guo, Xiangkui Ren, Shihai Xia, Wencheng Zhang, Abraham Domb, Yakai Feng

期刊论文

Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-

Fufeng LIU,Wenjie DU,Yan SUN,Jie ZHENG,Xiaoyan DONG

期刊论文

Cystine oligomers successfully attached to peptide cysteine-rich fibrils

Christian Bortolini,Mingdong Dong

期刊论文

Glucagon-like peptide-2 exhibits protective effect on hepatic ischemia-reperfusion injury in rats

null

期刊论文

侵地武器及其气炮实验

林俊德

期刊论文

The role of natriuretic peptide precursor A gene polymorphism in the development of coronary heart disease

Ripen NSENGA MD, Longxian CHENG PhD, Mei’an HE PhD, Tangchun WU PhD,

期刊论文

Significance and strategies in developing delivery systems for bio-macromolecular drugs

Huining HE, Qiuling LIANG, Meong Cheol SHIN, Kyuri LEE, Junbo GONG, Junxiao YE, Quan LIU, Jingkang WANG, Victor YANG

期刊论文

Rational Design of and Mechanism Insight into an Efficient Antifreeze Peptide for Cryopreservation

Haishan Qi,Yihang Gao,Lin Zhang,Zhongxin Cui,Xiaojie Sui,Jianfan Ma,Jing Yang,Zhiquan Shu,Lei Zhang,

期刊论文

电中性固体表面上多条肽链的吸附过程——粗粒化模拟研究

裘若桑, 肖杰, 陈晓东

期刊论文

钻地武器的毁伤效应及深地下防护工程关键科学问题

范鹏贤,钱七虎,王明洋

期刊论文

复杂环境下起伏地形探地雷达逆时偏移成像

John H. Bradford,Janna Privette,David Wilkins,Richard Ford

期刊论文

大装填比弹侵彻钢筋混凝土实验研究

赵生伟,古仁红,初哲,李明

期刊论文